Research activity information

• Impact of prenatal manganese and selenium exposure on childhood thyroid hormone parameters up to 4 years of age: Japan environment and children’s study
  Takeshi Yamaguchi; Hiroyoshi Iwata; Sachiko Itoh; Yu Ait Bamai; Atsuko Ikeda; Keitaro Makino; Mariko Itoh; Rahel Mesfin Ketema; Naomi Tamura; Rieko Yamamoto; Maki Tojo; Kensuke Oba; Shuntaro Morikawa; Yasuaki Saijo; Yoshiya Ito; Reiko Kishi
  Environment International, 110353, 110353, Elsevier BV, Jun. 2026
  Scientific journal
• The impact of folic acid supplementation in early to mid-pregnancy on the risk of hypertensive disorders of pregnancy: the Japan environment and children’s study
  Akira Oku; Yoshihiro Saito; Hiroyoshi Iwata; Sachiko Itoh; Ami Hosokawa; Takeshi Yamaguchi; Mariko Itoh; Keitaro Makino; Maki Tojo; Hidemichi Watari; Yoshiya Ito; Yasuaki Saijo; Reiko Kishi; Michihiro Kamijima; Shin Yamazaki; Maki Fukami; Reiko Kishi; Chiharu Ota; Koichi Hashimoto; Kenichi Sakurai; Shuichi Ito; Ryoji Shinohara; Hidekuni Inadera; Takeo Nakayama; Ryo Kawasaki; Yasuhiro Takeshima; Hideki Nagashima; Narufumi Suganuma; Mayumi Tsuji; Kimitoshi Nakamura
  BMC Pregnancy and Childbirth, Springer Science and Business Media LLC, 06 Mar. 2026
  Scientific journal
• The impact of folic acid supplementation in early to mid-pregnancy on the risk of hypertensive disorders of pregnancy: the Japan environment and children’s study
  Akira Oku; Yoshihiro Saito; Hiroyoshi Iwata; Sachiko Itoh; Ami Hosokawa; Takeshi Yamaguchi; Mariko Itoh; Keitaro Makino; Maki Tojo; Hidemichi Watari; Yoshiya Ito; Yasuaki Saijo; Reiko Kishi; Michihiro Kamijima; Shin Yamazaki; Maki Fukami; Reiko Kishi; Chiharu Ota; Koichi Hashimoto; Kenichi Sakurai; Shuichi Ito; Ryoji Shinohara; Hidekuni Inadera; Takeo Nakayama; Ryo Kawasaki; Yasuhiro Takeshima; Hideki Nagashima; Narufumi Suganuma; Mayumi Tsuji; Kimitoshi Nakamura
  BMC Pregnancy and Childbirth, Springer Science and Business Media LLC, 06 Mar. 2026
  Scientific journal
• Associations of prenatal exposure to organophosphate pesticides with eczema and allergic rhinoconjunctivitis in 4-year-old children: The Japan Environment and Children's Study
  Megasari Marsela; Hiroyoshi Iwata; Yu Ait Bamai; Mariko Itoh; Rahel Mesfin Ketema; Takeshi Yamaguchi; Yasuaki Saijo; Yoshiya Ito; Sachiko Itoh; Keiko Yamazaki; Naomi Tamura; Keitaro Makino; Maki Tojo; Reiko Kishi; Atsuko Ikeda
  Environmental Research, 123839, 123839, Elsevier BV, Feb. 2026
  Scientific journal
• Childhood obesity and DNA methylation in an epigenome-wide association study: findings from the Hokkaido Birth Cohort
  Hiroyoshi Iwata; Chihiro Miyashita; Takeshi Yamaguchi; Atsuko Ikeda; Ryu Miura; Machiko Minatoya; Naomi Tamura; Yu Ait Bamai; Sachiko Itoh; Keiko Yamazaki; Rahel Mesfin Ketema; Mariko Itoh; Maki Tojo; Rieko Yamamoto; Keitaro Makino; Reiko Kishi
  Clinical Epigenetics, Springer Science and Business Media LLC, 01 Dec. 2025
  Scientific journal
• Toxic metals and trace elements in maternal blood and urinary tract infection during the first 2 years of life: The Japan Environment and Children's Study
  Keitaro Makino; Hiroyoshi Iwata; Takeshi Yamaguchi; Atsuko Ikeda; Yu Ait Bamai; Sachiko Itoh; Mariko Itoh; Maki Tojo; Naomi Tamura; Rieko Yamamoto; Rahel Mesfin Ketema; Yasuaki Saijo; Yoshiya Ito; Reiko Kishi
  Science of The Total Environment, 1006, 180895, 180895, Elsevier BV, Dec. 2025
  Scientific journal
• Stability and variability of Edinburgh Postnatal Depression Scale networks among postpartum women: Insights from the Japan Environment and Children's Study
  Yasuhiko Ebina; Sachiko Ito; Takeshi Yamaguchi; Hiroyoshi Iwata; Reiko Kishi
  Journal of Affective Disorders, 391, 119992, 119992, Elsevier BV, Dec. 2025
  Scientific journal
• The impact of pediatric constipation on appendicitis: a prospective birth cohort in the Japan Environment and Children's Study.
  Hiroyoshi Iwata; Takeshi Yamaguchi; Sachiko Itoh; Yu Ait Bamai; Atsuko Ikeda; Keitaro Makino; Mariko Itoh; Maki Tojo; Rieko Yamamoto; Naomi Tamura; Rahel Mesfin Ketema; Yasuaki Saijo; Yoshiya Ito; Reiko Kishi
  BMC pediatrics, 25, 1, 962, 962, 26 Nov. 2025, [International Magazine]
  English, Scientific journal, BACKGROUND: This study aimed to examine the association between constipation and appendicitis in children using data from a nationwide birth cohort, the Japan Environment and Children's Study (JECS). METHODS: Data were obtained from 64,772 children and their mothers participating in JECS, which included over 100,000 pregnancies across 15 regional centres in Japan. Pediatric constipation was assessed at age three using the Rome III criteria, while appendicitis cases were identified between ages three to four. Logistic regression analyses, including univariable and multivariable models, were conducted to evaluate associations. Additional analyses were stratified by sex. RESULTS: Among the 64,772 children analyzed, 156 cases of appendicitis were identified between the ages of 3 and 4 years. Logistic regression suggested a possible association between constipation and an increased risk of appendicitis (univariable odds ratio [OR]: 1.38, 95% confidence interval [CI]: 0.87–2.10; multivariable OR: 1.36, 95% CI: 0.86–2.06). Although the associations did not reach statistical significance, the point estimates consistently indicated a trend toward increased risk. CONCLUSION: Although our analyses of children aged 3–4 years did not yield statistically significant associations, the observed trends may suggest a potential link between constipation and appendicitis. These findings should be interpreted only as exploratory, and further studies in different age groups, including older children and adults, are warranted to confirm or refute this possible association. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12887-025-06263-7.
• Prediction of Kawasaki disease coronary artery lesions in the Japan Environment and Children’s Study
  Hiroyoshi Iwata; Takeshi Yamaguchi; Naomi Tamura; Yu Ait Bamai; Atsuko Ikeda; Mariko Itoh; Rieko Yamamoto; Maki Tojo; Rahel Mesfin Ketema; Keiko Yamazaki; Sachiko Itoh; Keitaro Makino; Satoru Shida; Yasuaki Saijo; Yoshiya Ito; Reiko Kishi
  Annals of Pediatric Cardiology, 18, 5, 437, 446, Ovid Technologies (Wolters Kluwer Health), Sep. 2025
  Scientific journal, Objective:
  
  This study aimed to validate a composite of previously identified risk factors for predicting coronary artery lesions in Japanese children with Kawasaki Disease (KD).
  
  Materials and Methods:
  
  Children diagnosed with KD from the Japan Environment and Children’s Study (JECS) cohort were included. We assessed the discriminative ability of the model using the area under the curve (AUC) and evaluated its calibration using calibration plots. Based on clinical insights, we derived our original model, which consisted of variables established in previous score models or studies. Using the bootstrap method, internal validation was assessed with the AUC and calibration slope.
  
  Results:
  
  Our analysis included 959 children with KD, derived from 104,062 pediatric records contained in the JECS. Our model comprised the following variables: sex, hematocrit, platelet count, C-reactive protein, and serum sodium levels. The mean and 95% confidence intervals of the AUCs for the Harada, Egami, and Kobayashi models were 0.66 (0.59–0.72), 0.59 (0.52–0.66), and 0.64 (0.56–0.72), respectively. Our score model with bootstrap analyses produced an AUC of 0.80 (0.68–0.91) and a calibration slope of 1.01.
  
  Conclusions:
  
  We built and evaluated our score model using indicators that were easily accessible with a moderate-to-high AUC and stable calibration results, indicating the high reliability of the model for clinical application. Further studies are required to validate our model in other cohorts.
• Impact of prenatal exposure to per- and polyfluoroalkyl substances on developmental delays in 4-year-old children: The Japan Environment and Children’s study
  Mariko Itoh; Sumitaka Kobayashi; Hiroyoshi Iwata; Yu Ait Bamai; Rahel Mesfin Ketema; Takeshi Yamaguchi; Keiko Yamazaki; Naomi Tamura; Maki Tojo; Satoshi Suyama; Sachiko Itoh; Chihiro Miyashita; Yasuaki Saijo; Yoshiya Ito; Shoji F. Nakayama; Michihiro Kamijima; Reiko Kishi
  Environment International, 198, 109434, 109434, Elsevier BV, Apr. 2025
  Scientific journal
• Mediation of prenatal cotinine and 8-hydroxy-2’-deoxyguanosine levels on infant birth size in the Japan Environment and Children’s Study (JECS)
  Sumitaka Kobayashi; Hiroyoshi Iwata; Takeshi Yamaguchi; Naomi Tamura; Mariko Itoh; Maki Tojo; Keiko Yamazaki; Sachiko Itoh; Chihiro Miyashita; Yu Ait Bamai; Yukihiro Sato; Yasuaki Saijo; Yoshiya Ito; Reiko Kishi
  Reproductive Toxicology, 108905, 108905, Elsevier BV, Apr. 2025
  Scientific journal
• Phosphate Flame Retardants and Plasticizers and Their Association with Reproductive and Steroid Hormone Levels among Peripubertal-Aged Children: The Hokkaido Birth Cohort Study.
  Atsuko Ikeda; Takeshi Yamaguchi; Yu Ait Bamai; Maarten Roggeman; Yoshinori Ikenaka; Yi Zeng; Ayaka Yasuda; Rahel Mesfin Ketema; Megasari Marsela; Celine Gys; Fatima den Ouden; Sachiko Itoh; Akie Nakamura; Takeya Kitta; Masafumi Kon; Atsushi Manabe; Adrian Covaci; Reiko Kishi
  Environmental science & technology, 59, 10, 4820, 4831, 18 Mar. 2025, [International Magazine]
  English, Scientific journal, This cross-sectional study investigated associations between exposure to organophosphate flame retardants and plasticizers (PFRs) and reproductive and steroid hormones in peripubertal children from the Hokkaido Birth Cohort (429 children aged 9-12 years; between September 2017 and March 2020). Thirteen urinary PFR metabolites and 14 plasma steroid hormones were investigated using LC-MS/MS and four reproductive hormones were investigated using immunoassays. Linear regression for single PFR, quantile g-computation, and Bayesian machine kernel regression (BKMR) models for the PFR mixtures were used to examine the association between hormones and PFRs. Among boys, significant positive associations were observed between estradiol and ΣTCIPP and ΣTBOEP, and inverse associations were identified between insulin-like factor-3 (INSL3) and ΣTCIPP, and between luteinizing hormone (LH) and ΣEHDPHP. The PFR mixture was associated with the trends of increasing estradiol and androstenedione, and decreasing cortisol, cortisone, LH, inhibin B, and INSL3. Among girls, androstenedione and ΣTCIPP, testosterone and ΣEHDPHP, (androstenedione + testosterone)/DHEA-S and ΣTCIPP, and ΣEHDPHP and ΣTPHP were significantly correlated. The PFR mixture showed trends of increasing testosterone, androstenedione, and inhibin B, and decreasing cortisol, cortisone, and INSL3. Individual PFRs and PFR mixtures altered steroids and reproductive hormones in peripubertal children.
• Japanese growth charts stratified by birth weight in 500-gram increments: findings from the Japan environment and children’s study
  Takeshi Yamaguchi; Naomi Tamura; Hiroyoshi Iwata; Sachiko Itoh; Mariko Itoh; Maki Tojo; Keitaro Makino; Yasuaki Saijo; Akie Nakamura; Yoshiya Ito; Kazutoshi Cho; Akinori Moriichi; Yumi Kono; Taro Yamauchi; Reiko Kishi
  Clinical Pediatric Endocrinology, Japanese Society for Pediatric Endocrinology, 2025
  Scientific journal
• Association between prenatal tobacco exposure and attention-deficit/hyperactivity disorder related characteristics at 6 and 8 years: a birth cohort in Japan
  Mariko Itoh; Sumitaka Kobayashi; Shinkichi Nishihara; Chihiro Miyashita; Keiko Yamazaki; Naomi Tamura; Satoshi Suyama; Atsuko Ikeda; Sachiko Itoh; Yu Ait Bamai; Takeshi Yamaguchi; Hideyuki Masuda; Sharon Hanley; Reiko Kishi
  BMJ Open, 14, 12, e087406, e087406, BMJ, 26 Dec. 2024
  Scientific journal, Objectives
  
  To examine the association between maternal plasma cotinine concentrations during pregnancy and attention-deficit/hyperactivity disorder (ADHD) related characteristics in children.
  
  Design
  
  Prospective birth cohort study from the Hokkaido Study on Environment and Children’s Health.
  
  Setting
  
  Hokkaido, Japan.
  
  Participants
  
  A total of 7217 children were included in the analysis. Their mothers were recruited to this study between 2003 and 2012 during early pregnancy. Blood samples of mothers in their third trimester of pregnancy were obtained.
  
  Main outcome measures
  
  ADHD-related characteristics screened by the ADHD-Rating Scale (ADHD-RS) in children at 6 and 8 years of age.
  
  Results
  
  The mothers were classified into three groups according to plasma cotinine levels (median=0.22 ng/mL)—non-smokers (≤0.21 ng/mL), passive smokers (0.22–11.48 ng/mL) and active smokers (≥11.49 ng/mL). ADHD was suspected in 302 (8.6%), 334 (10.9%) and 90 (14.5%) children in the non-smoker, passive smoker and active smoker groups, respectively. Children born to mothers in the smoking group had a statistically significant increased risk of ADHD-related characteristics (adjusted RR=1.49, 95% CI=1.19–1.86 and adjusted RR=1.20, 95% CI=1.03–1.40 for the active and passive smoking groups, respectively).
  
  Conclusion
  
  This large Japanese cohort study suggests an association between smoking during pregnancy and the risk of ADHD in children 6 and 8 years of age.
• Organophosphate flame retardants associated with increased oxidative stress biomarkers and elevated FeNO levels in general population of children: The Hokkaido study.
  Yi Zeng; Yu Ait Bamai; Houman Goudarzi; Rahel Mesfin Ketema; Maarten Roggeman; Fatima den Ouden; Celine Gys; Sachiko Ito; Satoshi Konno; Adrian Covaci; Reiko Kishi; Atsuko Ikeda
  The Science of the total environment, 957, 177756, 177756, 20 Dec. 2024, [International Magazine]
  English, Scientific journal, Our previous study found that exposure to higher organophosphate flame retardants (PFRs) was associated with increased prevalence of wheeze and type 2 inflammation among school-aged children. It remains unclear whether PFR exposure elevates oxidative stress in these general pediatric population, thereby potentially contributing to the development of allergic diseases. This study examined the associations between individual and mixture exposure to PFRs and oxidative stress in children aged 9-12 years (n = 423). The oxidative stress biomarkers included 4-hydroxynonenal (4-HNE) and hexanoyl-lysine (HEL) for lipid peroxidation, and 8-hydroxy-2'-deoxyguanosine (8-OHdG) for DNA damage. We also examined the mediation effects of oxidative stress on the relationships between PFR exposure and health outcomes: wheeze and type 2 inflammation biomarkers, including fraction of exhaled nitric oxide (FeNO) and blood eosinophils. Higher concentrations of tris(1,3-dichloro-2-propyl) phosphate (TDCIPP), Σ triphenyl phosphate (ΣTPHP), Σ tris(2-butoxyethyl) phosphate (ΣTBOEP), and Σ 2-Ethylhexyldiphenyl phosphate (ΣEHDPHP) metabolites were significantly associated with higher levels of 4-HNE. Elevated concentrations of TDCIPP, ΣTPHP, and ΣTBOEP were positively associated with HEL. Higher ΣTPHP and ΣTBOEP were positively associated with 8-OHdG. The PFR mixture was positively associated with all three oxidative stress biomarkers according to the Quantile g-computation and Bayesian kernel machine regression models. Oxidative stress biomarkers mediated 11.4 % to 15.3 % of the association between PFRs and FeNO ≥35 ppb. PFR exposure was positively associated with oxidative stress markers of DNA damage and lipid peroxidation, which may contribute to elevated type 2 inflammation among school-aged children. These findings, identified in the general pediatric population at low exposure levels, highlight the need for ongoing attention to the allergic symptoms posed by PFR exposure.
• Association between maternal multimorbidity and neurodevelopment of offspring: a prospective birth cohort study from the Japan Environment and Children’s Study
  Takanobu Akagi; Yasuaki Saijo; Eiji Yoshioka; Yukihiro Sato; Kentaro Nakanishi; Yasuhito Kato; Ken Nagaya; Satoru Takahashi; Yoshiya Ito; Hiroyoshi Iwata; Takeshi Yamaguchi; Chihiro Miyashita; Sachiko Ito; Reiko Kishi
  BMJ Open, 14, 8, e082585, e082585, BMJ, 03 Aug. 2024
  Scientific journal, Objectives
  
  To investigate the association between multimorbidity during pregnancy and neurodevelopmental delay in offspring using data from a Japanese nationwide birth cohort study.
  
  Design
  
  This study was a prospective birth cohort study.
  
  Setting
  
  This study population included 104 059 fetal records who participated in The Japan Environment and Children’s Study from 2011 to 2014.
  
  Participants
  
  Pregnant women whose children had undergone developmental testing were included in this analysis.
  
  Primary and secondary outcome measures
  
  Neurodevelopment of offspring was assessed using the Japanese version of the Ages and Stages Questionnaire, third edition, comprising five developmental domains. The number of comorbidities among the pregnant women was categorised as zero, single disease or multimorbidity (two or more diseases). Maternal chronic conditions included in multimorbidity were defined as conditions with high prevalence among women of reproductive age. A multivariate logistic regression analysis was conducted to examine the association between multimorbidity in pregnant women and offspring development.
  
  Results
  
  Pregnant women with multimorbidity, single disease and no disease accounted for 3.6%, 30.6% and 65.8%, respectively. The ORs for neurodevelopmental impairment during the follow-up period were similar for infants of mothers with no disease comorbidity and those with a single disease comorbidity. However, the ORs for neurodevelopmental impairment were significantly higher for children born to mothers with multimorbidity compared with those born to healthy mothers.
  
  Conclusion
  
  An association was observed between the number of comorbidities in pregnant women and developmental delay in offspring. Multimorbidity in pregnant women may be associated with neurodevelopmental delay in their offspring. Further research is required in this regard in many other regions of the world.
• Correction to: Prenatal metal concentrations and physical abnormalities in the Japan Environment and Children’s Study (Pediatric Research, (2023), 10.1038/s41390-023-02851-4)
  Yuichi Nakamura; Sumitaka Kobayashi; Kazutoshi Cho; Sachiko Itoh; Chihiro Miyashita; Takeshi Yamaguchi; Hiroyoshi Iwata; Naomi Tamura; Yasuaki Saijo; Yoshiya Ito; Yoshitaka Seto; Ryota Honjo; Akiko Ando; Yuta Furuse; Atsushi Manabe; Reiko Kishi; Michihiro Kamijima; Shin Yamazaki; Yukihiro Ohya; Reiko Kishi; Nobuo Yaegashi; Koichi Hashimoto; Chisato Mori; Shuichi Ito; Zentaro Yamagata; Hidekuni Inadera; Takeo Nakayama; Tomotaka Sobue; Masayuki Shima; Hiroshige Nakamura; Narufumi Suganuma; Koichi Kusuhara; Takahiko Katoh
  Pediatric Research, 95, 6, 1659, 1661, May 2024
  Scientific journal
• Prenatal risk factors of indoor environment and incidence of childhood eczema in the Japan environment and children's study.
  Yu Ait Bamai; Chihiro Miyashita; Atsuko Ikeda-Araki; Keiko Yamazaki; Sumitaka Kobayashi; Sachiko Itoh; Yasuaki Saijo; Yoshiya Ito; Eiji Yoshioka; Yukihiro Sato; Reiko Kishi; Michihiro Kamijima; Shin Yamazaki; Yukihiro Ohya; Nobuo Yaegashi; Koichi Hashimoto; Chisato Mori; Shuichi Ito; Zentaro Yamagata; Hidekuni Inadera; Takeo Nakayama; Tomotaka Sobue; Masayuki Shima; Hiroshige Nakamura; Narufumi Suganuma; Koichi Kusuhara; Takahiko Katoh
  Environmental research, 118871, 118871, 03 Apr. 2024, [International Magazine]
  English, Scientific journal, The quality of indoor environment is a risk factor for early childhood eczema and atopic dermatitis; however, its influence during pregnancy on childhood eczema in Japan has not been investigated. In this study, we aimed to determine the indoor environmental factors that are associated with eczema in children up to 3 years of age, using national birth cohort data from the Japan Environment and Children's Study (JECS). Information on indoor environments and eczema symptoms until 3 years of age was collected using self-administered questionnaires to the mothers. A total of 71,883 and 58,639 mother-child pairs at 1.5- and 3-years-old, respectively, were included in the former analyses. To account for prenatal indoor risk factors, 17,568 (1.5-years-old) and 7063 (3-years-old) children without indoor mold and/or ETS exposure were included in the final analysis. A higher mold index, gas heater use, parquet flooring use, and frequent insecticide use showed significantly increased risks for childhood eczema up to 3 years of age. These associations were consistent after stratification analysis among children whose parents did not have a history of allergies. The updated WHO guidelines on indoor air quality should be implemented based on recent findings regarding the effects of prenatal exposure to indoor dampness on health effects of children further in life, including asthma, respiratory effects, eczema, and other immunological effects.
• Vitamin D concentration in maternal serum during pregnancy: Assessment in Hokkaido in adjunct study of the Japan Environment and Children's Study (JECS).
  Ko Nakanishi; Mami Mutoh; Sachiko Itoh; Sumitaka Kobayashi; Takeshi Yamaguchi; Hiroyoshi Iwata; Naomi Tamura; Momoko Koishi; Machiko Kasai; Emi Kikuchi; Nanae Yasuura; Reiko Kishi; Yoshiaki Sato
  PloS one, 19, 11, e0312516, 2024, [International Magazine]
  English, Scientific journal, BACKGROUND: Vitamin D is an essential nutrient for maintaining blood calcium and phosphorus levels and controlling bone density. Deficiency in it leads to rickets, osteomalacia, osteoporosis, and various other diseases. Recently, it has gained attention for reportedly reducing the risk of COVID-19 severity. However, there are no reports evaluating pregnant women in the Hokkaido region of Japan. This study aims to elucidate the current status of vitamin D levels in pregnant women in the Hokkaido region. METHODS: This study measured the serum concentrations of Vitamin D2 and D3 in 206 pregnant women participating in the Japan Environment and Children's Study-Hokkaido sub-cohort at the Hokkaido Regional Center. It analyzed the relationship between these concentrations and the months, seasons, and sunshine hours. RESULTS: The mean maternal age was 31.7 ± 4.7 years, and the mean prepregnancy BMI was 21.0 ± 2.5 kg/m2. Only two women have given birth at least once. Regarding sunscreen use, 65 participants (31.6%) responded "often" or "sometimes." Five women used the supplement containing Vitamin D. The value of 25(OH)D2 was above 1 ng/ml in four of them. The average 25(OH)D3 level was 12.1 ng/ml, with a median of 11.0 ng/ml. Four participants (1.9%) had levels below 5 ng/ml. The highest median of 25(OH)D3 was in July, and the lowest was in April. The concentration of 25(OH)D3 was significantly higher in summer than in winter. A correlation was found between 25(OH)D3 and sunshine hours, with 25(OH)D3 concentrations gradually increasing as sunshine hours increase. CONCLUSION: It was found that almost all pregnant women in Hokkaido were deficient in vitamin D. It is necessary to implement measures to enhance vitamin D levels in pregnant women to safeguard the health of women and fetuses in Hokkaido.
• Heavy metals and trace elements in maternal blood and prevalence of congenital limb abnormalities among newborns: the Japan Environment and Children's Study.
  Atsuko Ikeda; Megasari Marsela; Chihiro Miyashita; Takeshi Yamaguchi; Yasuaki Saijo; Yoshiya Ito; Hiroyoshi Iwata; Sachiko Itoh; Mariko Itoh; Keiko Yamazaki; Naomi Tamura; Sumitaka Kobayashi; Reiko Kishi
  Environmental health and preventive medicine, 29, 36, 36, 2024, [Domestic magazines]
  English, Scientific journal, BACKGROUND: Heavy metals such as lead (Pb) and cadmium (Cd) have been associated with adverse pregnancy and developmental outcomes, including congenital abnormalities. This study investigated the association between exposure to heavy metals and trace elements during fetal life and congenital limb abnormalities in infants. METHODS: This study is based on a prospective ongoing nationwide birth cohort from the Japan Environment and Children's Study (JECS). The concentrations of Cd, Pb, mercury (Hg), selenium (Se), and manganese (Mn) were measured in maternal blood collected during the mid-late trimesters. Inclusion criteria were available from questionnaires filled in during pregnancy, including information about congenital limb abnormalities at birth or at one month. To examine the associations with limb anomalies and individual chemicals, logistic regression models were applied following log-transformation or division into quartiles of Cd, Pb, Hg, Se, and Mn concentrations. To assess the associations with the heavy metals and trace elements mixture, quantile g-computation was employed. All models were adjusted for age, maternal smoking history, maternal alcohol intake, history of smoking, and infant sex. RESULTS: Data from 90,163 participants were included in the analysis, of whom 369 had congenital limb abnormalities in any of the collected information, and 89,794 had none. Among the 369 cases of congenital limb abnormalities, there were 185 and 142 cases of polydactyly and syndactyly, respectively. The median concentrations of Pb, Cd, Hg, Se, and Mn were 5.85, 0.66, 3.64, 168, and 15.3 ng/g, respectively. There were no associations between maternal blood concentrations of Pb [adjusted odd ratio = 0.83; 95% confidence interval = 0.61, 1.11], Cd [0.87; 0.68, 1.10], Hg [0.88; 0.73, 1.07], Se [1.07; 0.44, 2.59], and Mn [0.91; 0.64, 1.30] with congenital limb abnormalities. No significant association was observed between the mixture of heavy metals and trace elements [0.85; 0.72, 1.02] and any congenital limb abnormalities. Moreover, there was no association with all polydactylies and all syndactylies, or any type of abnormality as a subdivision. CONCLUSION: At the maternal exposure levels of Cd, Pb, Hg, Se, and Mn assessed in the present study, no association was identified with the risk of developing congenital limb abnormalities in children.
• The association between flooring materials and childhood asthma: A prospective birth cohort in the Japan Environment and Children's Study.
  Hiroyoshi Iwata; Atsuko Ikeda; Mariko Itoh; Sachiko Itoh; Rahel Mesfin Ketema; Naomi Tamura; Chihiro Miyashita; Takeshi Yamaguchi; Keiko Yamazaki; Rieko Yamamoto; Maki Tojo; Yasuaki Saijo; Yoshiya Ito; Reiko Kishi
  PloS one, 19, 7, e0305957, 2024, [International Magazine]
  English, Scientific journal, BACKGROUND: Childhood asthma is known to be affected by a range of factors, including conditions in the indoor environment. While flooring material influences indoor air conditions, the potential association between flooring materials and childhood asthma remains poorly understood in Japan. OBJECTIVE: The present study aims to assess the association between childhood asthma incidence and the primary flooring material with the ongoing prospective nationwide birth cohort data of the Japan Environment and Children's Study (JECS). METHODS: The JECS gathered data on mothers and children through 15 Regional Centres across Japan. The present study assessed flooring materials used in the home and asthma incidence at age four among children born between 2011 and 2014. We implemented logistic regressions, setting asthma incidence among the children as the outcome and home floor type as the exposure. Additional analyses were conducted, stratifying the home's age as a proxy for tatami age, to assess whether the potential effect of tatami flooring on asthma risk is influenced by its age. RESULTS: The present study included total of 75,629 infants. For tatami flooring, the main multivariable regression and additional sub-group regression for homes over ten years old produced odds ratios of 1.09; 95% Confidence Interval (CI) [1.01-1.17] and 1.10; 95% CI [1.00-1.21] compared with flooring, respectively. CONCLUSION: These results imply that exposure to tatami flooring, particularly in older homes, may be associated with childhood asthma incidence. Moreover, our study highlights the importance of evaluating the relationship between regional and cultural differences between asthma and flooring materials.
• Oral survey of second-grade elementary school students in Hokkaido, Japan: Adjunct study in Sapporo Study Area of the Japan Environment and Children’s Study （JECS）
  菊池媛美; 武藤麻未; 中西康; 保浦(山崎)七愛; 笠井満知子; 伊藤佐智子; 小林澄貴; 山口健史; 山口健史; 遠藤諒俊; 春藤彩花; 柴田真友子; 鈴木悠人; 齊藤紫; 岸玲子; 佐藤嘉晃
  The Journal of Hokkaido Orthodontic Society, 51, 1, 1, 6, Hokkaido Orthodontic Society, Dec. 2023, [Peer-reviewed], [Domestic magazines]
  Japanese, Scientific journal
• The association between prenatal per-and polyfluoroalkyl substance levels and Kawasaki disease among children of up to 4 years of age: A prospective birth cohort of the Japan Environment and Children's study.
  Hiroyoshi Iwata; Sumitaka Kobayashi; Mariko Itoh; Sachiko Itoh; Rahel Mesfin Ketema; Naomi Tamura; Chihiro Miyashita; Takeshi Yamaguchi; Keiko Yamazaki; Hideyuki Masuda; Yu Ait Bamai; Yasuaki Saijo; Yoshiya Ito; Shoji F Nakayama; Michihiro Kamijima; Reiko Kishi
  Environment international, 183, 108321, 108321, 11 Nov. 2023, [International Magazine]
  English, Scientific journal, Kawasaki disease (KD) is common among pediatric patients and is associated with an increased risk of later cardiovascular complications, though the precise pathophysiology of KD remains unknown. Per- and polyfluoroalkyl substances (PFAS) have gathered notoriety as the causal pathogens of numerous diseases as well as for their immunosuppressive effects. The present epidemiological study aims to assess whether PFAS may affect KD risk. We evaluated research participants included in the ongoing prospective nationwide birth cohort of the Japan Environment and Children's Study (JECS). Among the over 100,000 pregnant women enrolled in the JECS study, 28 types of PFAS were measured in pregnancy in a subset of participants (N = 25,040). The JECS followed their children born between 2011 and 2014 (n total infants = 25,256; n Kawasaki disease infants = 271), up to age four. Among the 28 types of PFAS, those which were detected in >60 % of participants at levels above the method reporting limit (MRL) were eligible for analyses. Multivariable logistic regressions were implemented on the seven eligible PFAS, adjusting for multiple comparison effects. Finally, we conducted Weighted Quantile Sum (WQS) and Bayesian kernel machine regression (BKMR) to assess the effects of the PFAS mixture on KD. Therefore, we ran the BKMR model using kernel mechanical regression equations to examine PFAS exposure and the outcomes of KD. Upon analysis, the adjusted multivariable regression results did not reach statistical significance for the seven eligible substances on KD, while odds ratios were all under 1.0. WQS regression was used to estimate the mixture effect of the seven eligible PFAS, revealing a negative correlation with KD incidence; similarly, BKMR implied an inverse association between the PFAS mixture effect and KD incidence. In conclusion, PFAS exposure was not associated with increased KD incidence.
• Exposure to organophosphate flame retardants and plasticizers is positively associated with wheeze and FeNO and eosinophil levels among school-aged children: The Hokkaido study.
  Yi Zeng; Houman Goudarzi; Yu Ait Bamai; Rahel Mesfin Ketema; Maarten Roggeman; Fatima den Ouden; Celine Gys; Chihiro Miyashita; Sachiko Ito; Satoshi Konno; Adrian Covaci; Reiko Kishi; Atsuko Ikeda-Araki
  Environment international, 181, 108278, 108278, Nov. 2023, [International Magazine]
  English, Scientific journal, Exposure to organophosphate flame retardants and plasticizers (PFRs) increases the risk of asthma and allergies. However, little is known about its association with type 2 inflammation (T2) biomarkers used in the management of allergies. The study investigated associations among urinary PFR metabolite concentrations, allergic symptoms, and T2 biomarkers. The data and samples were collected between 2017 and 2020, including school children (n = 427) aged 9-12 years living in Sapporo City, Japan, among the participants of "The Hokkaido Study on Environment and Children's Health." Thirteen urinary PFR metabolites were measured by LC-MS/MS. Allergic symptoms were assessed using the International Study of Asthma and Allergies in Childhood questionnaire. For T2 biomarkers, the peripheral blood eosinophil counts, fraction of exhaled nitric oxide level (FeNO), and serum total immunoglobulin E level were measured. Multiple logistic regression analysis, quantile-based g-computation (qg-computation), and Bayesian kernel machine regression (BKMR) were used to examine the associations between the health outcomes of the individual PFRs and the PFR mixtures. The highest concentration of PFR was Σtris(1-chloro-isopropyl) phosphates (ΣTCIPP) (Median:1.20 nmol/L). Tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) was significantly associated with a high odds ratio (OR, 95%CI:1.36, 1.07-1.72) for wheeze. TDCIPP (OR, 95%CI:1.19, 1.02-1.38), Σtriphenyl phosphate (ΣTPHP) (OR, 95%CI:1.81, 1.40-2.37), and Σtris(2-butoxyethyl) phosphate (ΣTBOEP) (OR, 95%:1.40, 1.13-1.74) were significantly associated with increased odds of FeNO (≥35 ppb). ΣTPHP (OR, 95%CI:1.44, 1.15-1.83) was significantly associated with high eosinophil counts (≥300/μL). For the PFR mixtures, a one-quartile increase in all PFRs (OR, 95%CI:1.48, 1.18-1.86) was significantly associated with high FeNO (≥35 ppb) in the qg-computation model. The PFR mixture was positively associated with high FeNO (≥35 ppb) and eosinophil counts (≥300/μL) in the BKMR models. These results may suggest that exposure to PFRs increases the probability of asthma, allergies, and T2 inflammation.
• Prenatal metal concentrations and physical abnormalities in the Japan Environment and Children's Study.
  Yuichi Nakamura; Sumitaka Kobayashi; Kazutoshi Cho; Sachiko Itoh; Chihiro Miyashita; Takeshi Yamaguchi; Hiroyoshi Iwata; Naomi Tamura; Yasuaki Saijo; Yoshiya Ito; Yoshitaka Seto; Ryota Honjo; Akiko Ando; Yuta Furuse; Atsushi Manabe; Reiko Kishi
  Pediatric research, 19 Oct. 2023, [International Magazine]
  English, Scientific journal, BACKGROUND: The association between prenatal metal exposure and congenital anomalies is unclear. We aimed to examine the association between exposure to cadmium, lead, mercury, selenium, and manganese and physical abnormalities. METHODS: Data from 89,887 pregnant women with singleton pregnancies who participated in the Japan Environment and Children's Study (JECS) were used. The correlation between maternal blood metal concentrations and physical abnormalities during the second or third trimester was investigated using logistic regression models. Physical anomalies included those observed at birth or at 1 month, primarily from ICD-10 Chapter 17, particularly congenital anomalies associated with environmental factors (e.g., hypospadias, cryptorchidism, cleft lip and palate, digestive tract atresia, congenital heart disease, and chromosomal abnormalities) and minor abnormalities. RESULTS: After adjusting for covariates, the OR (95% CIs) of physical abnormalities for a one-unit rise in Mn concentrations in all individuals were 1.26 (1.08, 1.48). The OR (95% CIs) of physical abnormalities in the 4th quartile (≥18.7 ng/g) were 1.06 (1.01, 1.13) (p-value for the trend = 0.034) compared with those in the 1st quartile (≤12.5 ng/g). CONCLUSION: In Japan, maternal blood Mn concentrations above threshold during pregnancy may slightly increase the incidence of physical abnormalities. IMPACT: Physical abnormalities (including minor anomalies and congenital anomalies) are associated with prenatal manganese concentrations. They are not associated with cadmium, lead, mercury, and selenium concentrations.
• Report of 20 years using the DOHaD life-course approach: The Hokkaido birth cohort study on environment and children’s health
  Sumitaka Kobayashi; Chihiro Miyashita; Sachiko Itoh; Reiko Kishi
  DOHaD研究, 11, 2, 63, 95, The Japan Society for Developmental Origins of Health and Disease (DOHaD-Japan), Mar. 2023, [Peer-reviewed], [Domestic magazines]
  Japanese, Scientific journal
• Neurodevelopmental delay up to the age of 4 years in infants born to women with gestational diabetes mellitus: The Japan Environment and Children's Study.
  Yoshihiro Saito; Sumitaka Kobayashi; Sachiko Ito; Chihiro Miyashita; Takeshi Umazume; Kazutoshi Cho; Hidemichi Watari; Yoshiya Ito; Yasuaki Saijo; Reiko Kishi
  Journal of diabetes investigation, 13, 12, 2054, 2062, Dec. 2022, [Domestic magazines]
  English, Scientific journal, AIMS/INTRODUCTION: This study aimed to investigate the neurodevelopment of infants born to women with gestational diabetes mellitus (GDM). MATERIALS AND METHODS: Data from the National Birth Cohort in the Japan Environment and Children's Study from 2011 to 2014 (n = 81,705) were used. Japan uses the GDM guidelines of the International Association of Diabetes and Pregnancy Study Groups. The Japanese translation of the Ages and Stages Questionnaires, third Edition, was used to assess neurodevelopment in the following domains: communication skills, gross motor skills, fine motor skills, problem-solving ability, and personal and social skills. The survey was carried out every 6 months from the age of 6 months to 4 years (total of eight times). Generalized estimating equations were used to evaluate the association between maternal GDM and neurodevelopmental delay based on odds ratios (ORs) and 95% confidence intervals (95% CIs). RESULTS: Neurodevelopmental delays, particularly in problem-solving ability, fine motor skills, and personal and social skills, were significantly higher in infants born to women with GDM than in those born to women without GDM (adjusted OR 1.24, 95% CI 1.12-1.36; adjusted OR 1.15, 95% CI 1.03-1.27; and adjusted OR 1.18, 95% CI 1.04-1.33). Furthermore, stratification showed no significant increase in the adjusted ORs (95% CIs) of girls. CONCLUSIONS: Neurodevelopment was significantly delayed up to 4 years-of-age among boys born to women with GDM.
• Null Association Between Isolated Orofacial Clefts and Sleep Duration: A Cohort Study From the Japan Environment and Children's Study
  Yukihiro Sato; Eiji Yoshioka; Yasuaki Saijo; Yasuhito Kato; Ken Nagaya; Satoru Takahashi; Yoshiya Ito; Sumitaka Kobayashi; Yu Ait Bamai; Keiko Yamazaki; Sachiko Itoh; Chihiro Miyashita; Atsuko Ikeda-Araki; Reiko Kishi
  The Cleft Palate-Craniofacial Journal, 105566562211284, 105566562211284, SAGE Publications, 26 Sep. 2022
  Scientific journal, Although children with orofacial clefts have an increased risk for sleep-disordered breathing, no studies have examined the association of sleep duration. Thus, this study aimed to examine associations between orofacial clefts and sleep duration at 1 month, 6 months, 1 year, and 3 years of age in Japan.
  
  A cohort study from the Japan Environment and Children's Study.
  
  This study consisted of 91 497 children, including ones with isolated cleft lip and palate (n = 69), isolated cleft lip only (n = 48), and isolated cleft palate only (n = 37), for which recruitment was undertaken during 2011 to 2014.
  
  Seep durations (hours per day) at 1 month, 6 months, 1 year, and 3 years of age, as reported by their mothers.
  
  In the control group, mean sleep durations and standard deviations at 1 month, 6 months, 1 year, and 3 years of age were 15.2 (2.5), 13.6 (1.9), 12.9 (1.6), and 11.6 (1.2) h, respectively. Compared to the control group, linear regression models reported effect sizes and 95% confidence intervals shorter than 1 h for sleep duration of each type of isolated orofacial cleft at each time point.
  
  This study suggested null associations between isolated orofacial clefts and sleep duration at 1 month, 6 months, 1 year, and 3 years of age. Children with isolated orofacial clefts had sufficient mean sleep duration.
• Associated congenital anomalies and syndromes of 248 infants with orofacial clefts born between 2011 and 2014 in the Japan Environment and Children's Study
  Yukihiro Sato; Eiji Yoshioka; Yasuaki Saijo; Yasuhito Kato; Ken Nagaya; Satoru Takahashi; Yoshiya Ito; Sumitaka Kobayashi; Yu Ait Bamai; Keiko Yamazaki; Sachiko Itoh; Chihiro Miyashita; Atsuko Ikeda‐Araki; Reiko Kishi; Michihiro Kamijima; Shin Yamazaki; Yukihiro Ohya; Reiko Kishi; Nobuo Yaegashi; Koichi Hashimoto; Chisato Mori; Shuichi Ito; Zentaro Yamagata; Hidekuni Inadera; Takeo Nakayama; Hiroyasu Iso; Masayuki Shima; Hiroshige Nakamura; Narufumi Suganuma; Koichi Kusuhara; Takahiko Katoh
  Congenital Anomalies, Wiley, 23 Sep. 2022
  Scientific journal
• Evaluating association of smoking status during pregnancy with adverse birth outcomes using urinary cotinine concentration: The Japan environment and Children's study (JECS)
  Yuki Kunori; Yasuaki Saijo; Eiji Yoshioka; Yukihiro Sato; Tomoko Kanaya; Kentaro Nakanishi; Yasuhito Kato; Ken Nagaya; Satoru Takahashi; Yoshiya Ito; Sachiko Itoh; Sumitaka Kobayashi; Chihiro Miyashita; Atsuko Ikeda-Araki; Reiko Kishi; Michihiro Kamijima; Shin Yamazaki; Yukihiro Ohya; Reiko Kishi; Nobuo Yaegashi; Koichi Hashimoto; Chisato Mori; Shuichi Ito; Zentaro Yamagata; Hidekuni Inadera; Takeo Nakayama; Tomotaka Sobue; Masayuki Shima; Hiroshige Nakamura; Narufumi Suganuma; Koichi Kusuhara; Takahiko Katoh
  Environmental Research, 114302, 114302, Elsevier BV, Sep. 2022
  Scientific journal
• Maternal dietary folate intake with folic acid supplements and wheeze and eczema in children aged 2 years in the Japan Environment and Children’s Study
  Hideyuki Masuda; Sumitaka Kobayashi; Chihiro Miyashita; Sachiko Itoh; Yu Ait Bamai; Yasuaki Saijo; Yoshiya Ito; Reiko Kishi; Atsuko Ikeda-Araki
  PLOS ONE, 17, 8, e0272968, e0272968, Public Library of Science (PLoS), 22 Aug. 2022
  Scientific journal, Maternal intake of folic acid supplements is reportedly associated with the risk of early-onset allergies in offspring. However, only a few studies have considered the intake of both folic acid supplements and dietary folate. Here, the relationship between maternal intake of folic acid supplements and allergic symptoms such as wheeze and eczema in offspring was analyzed while considering dietary folate intake. We examined 84,361 mothers and 85,114 children in the Japan Environment and Children’s Study. The participants were divided into three groups depending on maternal folic acid supplementation (“no use,” “occasional use,” and “daily use”). Each group was then subdivided into three groups based on total folic acid and dietary folate intake. Outcomes were determined considering the wheeze and eczema status of each child at the age of 2 years. The status was based on the International Study of Asthma and Allergies in Childhood. It was found that 22.1% of the mothers took folic acid supplements daily. In contrast, 56.3% of the mothers did not take these supplements. Maternal intake of folic acid supplements was not associated with wheeze and eczema in the offspring. In contrast, only dietary folate intake was positively associated with wheeze at the age of 2 (adjusted odds ratio, 1.103; 95% confidence interval, 1.003–1.212). However, there is no scientific evidence of a biological mechanism that clarifies this result. Potential confounders such as other nutrition, outdoor/indoor air pollution, and genetic factors may have affected the results. Therefore, further studies on the association between maternal intake of folic acid and allergic symptoms at the age of 3 or above are needed to confirm the results of this study.
  
  Trial registration
  
  UMIN Clinical Trials Registry (number: UMIN000030786)
• Potential determinants of T helper 2 markers and their distribution in school-aged children
  Houman Goudarzi; Atsuko Ikeda-Araki; Yu Ait Bamai; Sachiko Ito; Tasuku Inao; Isao Yokota; Chihiro Miyashita; Reiko Kishi; Satoshi Konno
  Allergology International, Elsevier BV, Aug. 2022
  Scientific journal
• Impact of prenatal exposure to mercury and selenium on neurodevelopmental delay in children in the Japan Environment and Children’s Study using the ASQ-3 questionnaire: a prospective birth cohort
  Sumitaka Kobayashi; Sachiko Itoh; Chihiro Miyashita; Yu Ait Bamai; Takeshi Yamaguchi; Hideyuki Masuda; Mariko Itoh; Keiko Yamazaki; Naomi Tamura; Sharon J.B. Hanley; Atsuko Ikeda-Araki; Yasuaki Saijo; Yoshiya Ito; Miyuki Iwai-Shimada; Shin Yamazaki; Michihiro Kamijima; Reiko Kishi
  Environment International, 107448, 107448, Elsevier BV, Aug. 2022
  Scientific journal
• TSH and FT4 reference intervals in pregnancy: a systematic review and individual participant data meta-analysis.
  Joris A J Osinga; Arash Derakhshan; Glenn E Palomaki; Ghalia Ashoor; Tuija Männistö; Spyridoula Maraka; Liangmiao Chen; Sofie Bliddal; Xuemian Lu; Peter N Taylor; Tanja G M Vrijkotte; Fang-Biao Tao; Suzanne J Brown; Farkhanda Ghafoor; Kris Poppe; Flora Veltri; Lida Chatzi; Bijay Vaidya; Maarten A C Broeren; Beverley M Shields; Sachiko Itoh; Lorena Mosso; Polina V Popova; Anna D Anopova; Reiko Kishi; Ashraf Aminorroaya; Maryam Kianpour; Abel López-Bermejo; Emily Oken; Amna Pirzada; Marina Vafeiadi; Wichor M Bramer; Eila Suvanto; Jun Yoshinaga; Kun Huang; Judit Bassols; Laura Boucai; Ulla Feldt-Rasmussen; Elena N Grineva; Elizabeth N Pearce; Erik K Alexander; Victor J M Pop; Scott M Nelson; John P Walsh; Robin P Peeters; Layal Chaker; Kypros H Nicolaides; Mary E D'Alton; Tim I M Korevaar
  The Journal of clinical endocrinology and metabolism, 21 Jul. 2022, [International Magazine]
  English, Scientific journal, CONTEXT: Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology. OBJECTIVE: 1) To provide an overview of published reference intervals for TSH and FT4 in pregnancy, 2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts. METHODS: 1) Ovid MEDLINE, EMBASE and Web of Science were searched until the 12th of December 2021. Studies were assessed in duplicate. 2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy. RESULTS: 1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines. 2) 22 cohorts involving 63,198 participants, were included in the meta-analysis. Not excluding TPOAb-positive participants led to a rise of the upper limits of TSH in all cohorts, especially in the first (mean: +17.4%[range +1.6 to +30.3%]) and second trimester (mean: +9.8% [range +0.6 to +32.3%]). The use of the 95th percentile led to considerable changes in upper limits, varying from -10.8% to -21.8% for TSH and -1.2% to -13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting. CONCLUSIONS: We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.
• Association between maternal caffeine intake during pregnancy and child development at 6 and 12 months: The Japan Environment and Children's Study
  Shinkichi Nishihara; Sumitaka Kobayashi; Atsuko Ikeda-Araki; Chihiro Miyashita; Sachiko Itoh; Keiko Yamazaki; Yu Ait Bamai; Naomi Tamura; Hideyuki Masuda; Mariko Itoh; Yasuaki Saijo; Yoshiya Ito; Reiko Kishi
  Early Human Development, 105607, 105607, Elsevier BV, Jun. 2022
  Scientific journal
• Association of prenatal exposure to dioxin-like compounds, polychlorinated biphenyl, and methylmercury with event-related brain potentials in school-aged children: The Hokkaido study.
  Keiko Yamazaki; Sachiko Itoh; Atsuko Ikeda-Araki; Chihiro Miyashita; Tsuguhide Hori; Noriyuki Hachiya; Reiko Kishi
  Neurotoxicology, 91, 11, 21, 28 Apr. 2022, [International Magazine]
  English, Scientific journal, Previous studies have indicated that prenatal exposure to dioxin-like compounds (DLC) or polychlorinated biphenyl (PCB) has a negative association with neurodevelopment in school-aged children. Event-related brain potentials (ERP) can reveal subtle and specific differences in the modulation of cognitive processes that are assumed when they are associated with lower levels of prenatal exposure to DLC or PCBs. This prospective birth cohort study was conducted to examine the association between prenatal exposure to relatively low levels of DLC, PCB or methylmercury (MeHg), and ERP. A total of 55 children who were 13 years old participated in a 3-stimulus oddball task to detect P3a and P3b waves. The task required participants to respond to a target among random stimuli at two difficulty levels. The P3a amplitude reflects an automated attention capture process, and P3b reflects a voluntary attention allocation process. We analyzed DLC congeners in blood samples from four groups, including 7 polychlorinated dibenzo-p-dioxins (PCDD), 10 polychlorinated dibenzofuranes (PCDF), 4 non-ortho PCBs, and 8 mono-ortho PCBs. PCB-153 was chosen as an indicator because of its high correlation with the sum of 58 NDL (non-dioxin-like)-PCBs. MeHg exposure level was assessed by the mercury concentration in hair samples (HHg) taken during the perinatal period. The reaction time to the target stimulus during the oddball task shortened with the increasing MeHg exposure level. Furthermore, P3b latency, which reflect response decision and correlates with reaction time, was also shortened with increasing MeHg level in the difficult condition. These results are counterintuitive because shorter reaction times or rapid decision making reflected by P3 latency are generally favorable. This might be due to nutritional factors such as fatty acids, which have beneficial effects on brain development. The P3a amplitude decreased with non- and mono-ortho PCB and HHg levels, regardless of the difficulty level, and with PCDD, PCDF, and total DLC levels, especially in the difficult condition. P3b latency shortened with HHg, and P3b amplitude decreased with mono-ortho PCBs and PCB-153 in both conditions and with PCDD, PCDF, non-ortho PCBs, and total DLC in the difficult condition. In conclusion, we found an association between prenatal exposure to DLC and a decrease in both P3a and P3b amplitude, even when DLC levels were lower than in most previous studies. Additionally, our results suggest that the automated attention capture process reflected by P3a is associated with maternal MeHg exposure and that the voluntary attention allocation process reflected by P3b is associated with PCB-153. However, these results should be interpreted with caution because of the limitations on sample size, population bias, and statistical analyses.
• Association between maternal thyroid function and risk of gestational hypertension and pre-eclampsia: a systematic review and individual-participant data meta-analysis.
  Freddy J K Toloza; Arash Derakhshan; Tuija Männistö; Sofie Bliddal; Polina V Popova; David M Carty; Liangmiao Chen; Peter Taylor; Lorena Mosso; Emily Oken; Eila Suvanto; Sachiko Itoh; Reiko Kishi; Judit Bassols; Juha Auvinen; Abel López-Bermejo; Suzanne J Brown; Laura Boucai; Aya Hisada; Jun Yoshinaga; Ekaterina Shilova; Elena N Grineva; Tanja G M Vrijkotte; Jordi Sunyer; Ana Jiménez-Zabala; Isolina Riaño-Galan; Maria-Jose Lopez-Espinosa; Larry J Prokop; Naykky Singh Ospina; Juan P Brito; Rene Rodriguez-Gutierrez; Erik K Alexander; Layal Chaker; Elizabeth N Pearce; Robin P Peeters; Ulla Feldt-Rasmussen; Mònica Guxens; Leda Chatzi; Christian Delles; Jeanine E Roeters van Lennep; Victor J M Pop; Xuemian Lu; John P Walsh; Scott M Nelson; Tim I M Korevaar; Spyridoula Maraka
  The lancet. Diabetes & endocrinology, 10, 4, 243, 252, Apr. 2022, [International Magazine]
  English, Scientific journal, BACKGROUND: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT4 concentrations were not associated with the outcomes measured. INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies. FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.
• Association of exposure to prenatal perfluoroalkyl substances and estrogen receptor 1 polymorphisms with the second to fourth digit ratio in school-aged children: The Hokkaido study
  Yoko Nishimura; Kimihiko Moriya; Sumitaka Kobayashi; Atsuko Ikeda- Araki; Fumihiro Sata; Takahiko Mitsui; Sachiko Itoh; Chihiro Miyashita; Kazutoshi Cho; Masafumi Kon; Michiko Nakamura; Takeya Kitta; Sachiyo Murai; Reiko Kishi; Nobuo Shinohara
  Reproductive Toxicology, 109, 10, 18, Elsevier BV, Apr. 2022
  Scientific journal
• Relations of mold, stove, and fragrance products on childhood wheezing and asthma: A prospective cohort study from the Japan Environment and Children's Study.
  Yasuaki Saijo; Eiji Yoshioka; Yukihiro Sato; Hiroshi Azuma; Yusuke Tanahashi; Yoshiya Ito; Sumitaka Kobayashi; Machiko Minatoya; Yu Ait Bamai; Keiko Yamazaki; Sachiko Itoh; Chihiro Miyashita; Atsuko Ikeda-Araki; Reiko Kishi; Michihiro Kamijima; Shin Yamazaki; Yukihiro Ohya; Nobuo Yaegashi; Koichi Hashimoto; Chisato Mori; Shuichi Ito; Zentaro Yamagata; Hidekuni Inadera; Takeo Nakayama; Hiroyasu Iso; Masayuki Shima; Youichi Kurozawa; Narufumi Suganuma; Koichi Kusuhara; Takahiko Katoh
  Indoor air, 32, 1, e12931, Jan. 2022, [International Magazine]
  English, Scientific journal, This prospective cohort study aimed to examine the associations between mold growth, type of stoves, and fragrance materials and early childhood wheezing and asthma, using data from the Japan Environment and Children's Study. Mold growth at home, usage of kerosene/gas stove, wood stove/fireplace, and air freshener/deodorizer were surveyed using a questionnaire at 1.5-year-old, and childhood wheezing and doctor-diagnosed asthma during the previous year were obtained using a 3-year-old questionnaire. Multilevel logistic regression analysis was performed to evaluate the association between exposure to childhood wheezing and asthma. A total of 60 529 children were included in the analysis. In multivariate analyses, mold growth and wood stove/fireplace had significantly higher odds ratios (ORs) for wheezing (mold growth: 1.13; 95% CI, 1.06-1.22; wood stove/fireplace: 1.23; 95% CI, 1.03-1.46). All four exposures had no significant ORs for childhood doctor-diagnosed asthma; however, in the supplemental analysis of northern regions, wood stove/fireplace had a significantly higher OR for asthma. Mold growth and wood stove/fireplace had significant associations with childhood wheezing in the northern regions. Mold elimination in the dwellings and use of clean heating (no air pollution emissions) should be taken into consideration to prevent and improve childhood wheezing and asthma.
• The association between prenatal perfluoroalkyl substance exposure and symptoms of attention-deficit/hyperactivity disorder in 8-year-old children and the mediating role of thyroid hormones in the Hokkaido study
  Sachiko Itoh; Keiko Yamazaki; Satoshi Suyama; Atsuko Ikeda-Araki; Chihiro Miyashita; Yu Ait Bamai; Sumitaka Kobayashi; Hideyuki Masuda; Takeshi Yamaguchi; Houman Goudarzi; Emiko Okada; Ikuko Kashino; Takuya Saito; Reiko Kishi
  Environment International, 159, 107026, 107026, Elsevier BV, Jan. 2022
  Scientific journal
• Association between pre-pregnancy body mass index and gestational weight gain and perinatal outcomes in pregnant women diagnosed with gestational diabetes mellitus: The Japan Environment and Children's Study.
  Yoshihiro Saito; Sumitaka Kobayashi; Atsuko Ikeda-Araki; Sachiko Ito; Chihiro Miyashita; Takashi Kimura; Takumi Hirata; Akiko Tamakoshi; Michinori Mayama; Kiwamu Noshiro; Kinuko Nakagawa; Takeshi Umazume; Kentaro Chiba; Satoshi Kawaguchi; Mamoru Morikawa; Kazutoshi Cho; Hidemichi Watari; Yoshiya Ito; Yasuaki Saijo; Reiko Kishi
  Journal of diabetes investigation, 13, 5, 889, 899, 30 Nov. 2021, [Domestic magazines]
  English, Scientific journal, AIMS/INTRODUCTION: We investigated the association between gestational diabetes mellitus (GDM) and perinatal outcomes stratified by pre-pregnancy body mass index (BMI) and/or gestational weight gain (GWG). MATERIALS AND METHODS: Data from the national birth cohort in the Japan Environment and Children's Study from 2011 to 2014 (n = 85,228) were used. Japan uses GDM guidelines of the International Association of Diabetes and Pregnancy Study Groups. The odds ratios (ORs) of perinatal outcomes were compared between women with and those without GDM. RESULTS: The OR (95% confidence interval [CI]) of having an SGA infant in the GDM group with a pre-pregnancy BMI of ≥25.0 kg/m2 and insufficient GWG (<2.75 kg) was 1.78 (1.02-3.12). The OR of having a large-for-gestational-age (LGA) infant of same BMI group with excessive GWG (>7.25 kg) was 2.04 (1.56-2.67). The OR of hypertensive disorders of pregnancy (HDP) was higher in women with a BMI ≥18.5 kg/m2 in the GDM group than in the non-GDM group. CONCLUSIONS: LGA and HDP were associated with pre-pregnancy BMI and GWG in either normal weight or overweight/obese women, and the relationship was strengthened when GDM was present. Women with GDM and a BMI of ≥25.0 kg/m2 are at risk of having SGA and LGA infants depending on GWG.
• Hypertensive Disorders during Pregnancy and Anthropometric Measurement of Children up to 7 Years of Age: The Hokkaido Birth Cohort Study in Japan.
  Kritika Poudel; Sumitaka Kobayashi; Chihiro Miyashita; Takeshi Yamaguchi; Naomi Tamura; Atsuko Ikeda-Araki; Yu Ait Bamai; Sachiko Itoh; Keiko Yamazaki; Hideyuki Masuda; Mariko Itoh; Reiko Kishi
  International journal of environmental research and public health, 18, 20, 18 Oct. 2021, [International Magazine]
  English, Scientific journal, Hypertensive disorders during pregnancy (HDP) increase the risk of offspring with a low birth weight, preterm birth and small-for-gestational age; however, evidence of the anthropometric measurements during early childhood remains limited. We aimed to understand the associations between maternal HDP and anthropometric measurements of children aged up to seven years in a Japanese cohort. In total, 20,926 mother-infant pairs participated in the Hokkaido Study on Environment and Children's Health, Japan, from 2002 to 2013. Medical reports were used to confirm HDP exposure, while weight, height, height z score, and weight z score were the outcomes. The prevalence of HDP in the study population was 1.7%. The birth height of male children born to HDP mothers was smaller as compared to those born to non-HDP mothers. When adjusted with covariates, the linear regressions showed significant changes in birth weight (β: -79.3; 95% confidence interval [CI]: -154.8, -3.8), birth height (-0.67; 95% CI: -1.07, -0.26), weight at seven years (1.21; 95% CI: 0.13, 2.29), and weight gain between four and seven years (1.12; 95% CI: 0.28, 1.96) of male children exposed to HDP. Differences were more significant in male children than female. Our study showed that despite low birth weight, male children exposed to HDP caught up with their growth and gained more weight by seven years of age compared with male children not exposed to HDP, whereas no such differences were observed in female children; however, this finding requires replication.
• Associations among maternal perfluoroalkyl substance levels, fetal sex-hormone enzymatic gene polymorphisms, and fetal sex hormone levels in the Hokkaido study.
  Sumitaka Kobayashi; Fumihiro Sata; Atsuko Ikeda-Araki; Chihiro Miyashita; Sachiko Itoh; Houman Goudarzi; Yusuke Iwasaki; Takahiko Mitsui; Kimihiko Moriya; Nobuo Shinohara; Kazutoshi Cho; Reiko Kishi
  Reproductive toxicology (Elmsford, N.Y.), 105, 221, 231, Oct. 2021, [International Magazine]
  English, Scientific journal, Prenatal sex hormones affect fetal growth; for example, prenatal exposure to low levels of androgen accelerates female puberty onset. We assessed the association of perfluoroalkyl substances (PFASs) in maternal sera and infant genotypes of genes encoding enzymes involved in sex steroid hormone biosynthesis on cord sera sex hormone levels in a prospective birth cohort study of healthy pregnant Japanese women (n = 224) recruited in Sapporo between July 2002 and October 2005. We analyzed PFAS and five sex hormone levels using liquid chromatography-tandem mass spectrometry. Cytochrome P450 (CYP) 17A1 (CYP17A1 rs743572), 19A1 (CYP19A1 rs10046, rs700519, and rs727479), 3β-hydroxysteroid dehydrogenase type 1 (HSD3B1 rs6203), type 2 (HSD3B2 rs1819698, rs2854964, and rs4659175), 17β-hydroxysteroid dehydrogenase type 1 (HSD17B1 rs605059, rs676387, and rs2676531), and type 3 (HSD17B3 rs4743709) were analyzed using real-time PCR. Multiple linear regression models were used to establish the influence of log10-transformed PFAS levels and infant genotypes on log10-transformed sex steroid hormone levels. When the interaction between perfluorooctanesulfonate (PFOS) levels and female infant genotype CYP17A1 (rs743572) on the androstenedione (A-dione) levels was considered, the estimated changes (95 % confidence intervals) in A-dione levels against PFOS levels, female infant genotype CYP17A1 (rs743572)-AG/GG, and interaction between them showed a mean increase of 0.445 (0.102, 0.787), mean increase of 0.392 (0.084, 0.707), and mean reduction of 0.579 (0.161, 0.997) (Pint = 0.007), respectively. Moreover, a female-specific interaction with testosterone levels was observed. A-dione and T levels showed positive main effects and negative interaction with PFOS levels and the female infant CYP17A1 genotype.
• Association between the Concentrations of Metallic Elements in Maternal Blood during Pregnancy and Prevalence of Abdominal Congenital Malformations: The Japan Environment and Children's Study.
  Chihiro Miyashita; Yasuaki Saijo; Yoshiya Ito; Atsuko Ikeda-Araki; Sachiko Itoh; Keiko Yamazaki; Sumitaka Kobayashi; Yu Ait Bamai; Hideyuki Masuda; Naomi Tamura; Mariko Itoh; Takeshi Yamaguchi; Shin Yamazaki; Reiko Kishi; The Japan Environment And Children's Study Group
  International journal of environmental research and public health, 18, 19, 26 Sep. 2021, [International Magazine]
  English, Scientific journal, Abdominal congenital malformations are responsible for early mortality, inadequate nutrient intake, and infant biological dysfunction. Exposure to metallic elements in utero is reported to be toxic and negatively impacts ontogeny. However, no prior study has sufficiently evaluated the effects of exposure to metallic elements in utero on abdominal congenital malformations. The aim of the present study was to evaluate associations between metallic elements detected in maternal blood during pregnancy and congenital abdominal malformations. Data from participants in the Japan Environment and Children's Study was used in the present study, and contained information on singleton and live birth infants without congenital abnormalities (control: n = 89,134) and abdominal malformations (case: n = 139). Heavy metals such as mercury (Hg), lead (Pb), cadmium (Cd), and trace elements of manganese (Mn) and selenium (Se) were detected in maternal serum samples during mid- and late-gestation. Infant congenital abnormalities were identified from delivery records at birth or one month after birth by medical doctors. In a multivariate analysis adjusted to account for potential confounders, quartiles of heavy metals and trace elements present in maternal blood were not statistically correlated to the prevalence of abdominal congenital malformations at birth. This study is the first to reveal the absence of significant associations between exposure levels to maternal heavy metals and trace elements in utero and the prevalence of abdominal congenital malformations in a large cohort of the Japanese population. Further studies are necessary to investigate the impact of exposure to heavy metals and trace elements via maternal blood in offspring after birth.
• Maternal psychological distress, education, household income, and congenital heart defects: a prospective cohort study from the Japan environment and children's study.
  Yasuaki Saijo; Eiji Yoshioka; Yukihiro Sato; Hiroshi Azuma; Yusuke Tanahashi; Yoshiya Ito; Sumitaka Kobayashi; Machiko Minatoya; Yu Ait Bamai; Keiko Yamazaki; Sachiko Itoh; Chihiro Miyashita; Atsuko Ikeda-Araki; Reiko Kishi
  BMC pregnancy and childbirth, 21, 1, 544, 544, 07 Aug. 2021, [International Magazine]
  English, Scientific journal, BACKGROUND: The influence of maternal psychological distress on infant congenital heart defects (CHDs) has not been thoroughly investigated. Furthermore, there have been no reports on the combined effect of maternal psychological distress and socioeconomic status on infant CHDs. This study aimed to examine whether maternal psychological distress, socioeconomic status, and their combinations were associated with CHD. METHODS: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant women between 2011 and 2014. Maternal psychological distress was evaluated using the Kessler Psychological Distress Scale in the first trimester, while maternal education and household income were evaluated in the second and third trimesters. The outcome of infant CHD was determined using the medical records at 1 month of age and/or at birth. Crude- and confounder-adjusted logistic regression analyses were performed to evaluate the association between maternal psychological distress and education and household income on infant CHD. RESULTS: A total of 93,643 pairs of mothers and infants were analyzed, with 1.1% of infants having CHDs. Maternal psychological distress had a significantly higher odds ratio in the crude analysis but not in the adjusted analysis, while maternal education and household income were statistically insignificant. In the analysis of the combination variable of lowest education and psychological distress, the P for trend was statistically significant in the crude and multivariate model excluding anti-depressant medication, but the significance disappeared in the full model (P = 0.050). CONCLUSIONS: The combination of maternal psychological distress and lower education may be a possible indicator of infant CHD.
• Association between Early Life Child Development and Family Dog Ownership: A Prospective Birth Cohort Study of the Japan Environment and Children's Study.
  Machiko Minatoya; Atsuko Ikeda-Araki; Chihiro Miyashita; Sachiko Itoh; Sumitaka Kobayashi; Keiko Yamazaki; Yu Ait Bamai; Yasuaki Saijo; Yukihiro Sato; Yoshiya Ito; Reiko Kishi; The Japan Environment And Children's Study Group
  International journal of environmental research and public health, 18, 13, 02 Jul. 2021, [International Magazine]
  English, Scientific journal, Pets may play a role in the social-emotional development of children. In particular, some studies have suggested that family dog ownership is associated with better health outcomes. To date, no study has assessed child development in association with dog ownership of different time points. The purpose of the current study was primary to investigate whether "ever" family dog ownership was associated with early child development, and secondary to further examine whether associations between family dog ownership and early child development differ among family dog ownership of status, including "past only", "current only", and "always" groups, using the data of family dog ownership obtained at multiple time points. Associations between family dog ownership and infant development at 3 years of age were examined using data from a nationwide prospective birth cohort study, the Japan Environment and Children's Study (n = 78,941). "Ever" family dog ownership was categorized to "past only", "current only", and "always". We observed that children with "ever" family dog ownership showed a significantly decreased risk of developmental delay in the communication (odds ratio [OR] = 0.87; 95% confidence interval [CI]: 0.78, 0.96), gross motor (OR = 0.83; 95% CI: 0.76, 0.92), problem-solving (OR = 0.89; 95% CI: 0.83, 0.96) and personal-social (OR = 0.86; 95% CI: 0.72, 0.92) domains compared to children with "never" family dog ownership. Furthermore, a significantly decreased risk of developmental delay in gross motor function was observed in association with living with dogs in the "past only" (OR = 0.83; 95% CI: 0.73, 0.95) and "always" (OR = 0.86; 95% CI: 0.75, 0.98). In addition, a decreased risk of developmental delay in the problem-solving domain was associated with "past" family dog ownership (OR = 0.87; 95% CI: 0.79, 0.97) and in the personal-social domain was associated with "always" family dog ownership (OR = 0.81; 95% CI = 0.68, 0.95). Given the possible positive association between early life child development and family dog ownership, living with dogs may be an important factor to be considered when assessing child development.
• Prenatal alcohol exposure and adverse fetal growth restriction: findings from the Japan Environment and Children's Study.
  Kazutoshi Cho; Sumitaka Kobayashi; Atsuko Araki; Chihiro Miyashita; Sachiko Itoh; Yasuaki Saijo; Yoshiya Ito; Kazuo Sengoku; Tsuyoshi Baba; Hisanori Minakami; Yuichi Nakamura; Reiko Kishi
  Pediatric research, 92, 1, 291, 298, 04 Jun. 2021, [International Magazine]
  English, Scientific journal, BACKGROUNDS: Japanese studies on the association between maternal alcohol consumption and fetal growth are few. This study assessed the effect of maternal alcohol consumption on fetal growth. METHODS: This prospective birth cohort included 95,761 participants enrolled between January 2011 and March 2014 in the Japan Environment and Children's Study. Adjusted multiple linear and logistic regression models were used to assess the association between prenatal alcohol consumption and infant birth size. RESULTS: Consumption of a weekly dose of alcohol in the second/third trimester showed a significant negative correlation with standard deviation (SD; Z) scores for body weight, body length, and head circumference at birth, respectively. Consumption of a weekly dose of alcohol during the second/third trimester had a significant positive correlation with incidences of Z-score ≤ -1.5 for birth head circumference. Associations between alcohol consumption in the second/third trimester and Z-score ≤ -1.5 for birth weight or birth length were not significant. Maternal alcohol consumption in the second/third trimester above 5, 20, and 100 g/week affected body weight, body length, and head circumference at birth, respectively. CONCLUSION: Low-to-moderate alcohol consumption during pregnancy might affect fetal growth. Public health policies for pregnant women are needed to stop alcohol consumption during pregnancy. IMPACT: This study examined the association between maternal alcohol consumption and fetal growth restriction in 95,761 pregnant Japanese women using the prospective birth cohort. Maternal alcohol consumption in the second/third trimester more than 5, 20, and 100 g/week might affect fetal growth in body weight, body length, and head circumference, respectively. The findings are relevant and important for educating pregnant women on the adverse health effects that prenatal alcohol consumptions have on infants.
• Hokkaido birth cohort study on environment and children's health: cohort profile 2021.
  Reiko Kishi; Atsuko Ikeda-Araki; Chihiro Miyashita; Sachiko Itoh; Sumitaka Kobayashi; Yu Ait Bamai; Keiko Yamazaki; Naomi Tamura; Machiko Minatoya; Rahel Mesfin Ketema; Kritika Poudel; Ryu Miura; Hideyuki Masuda; Mariko Itoh; Takeshi Yamaguchi; Hisanori Fukunaga; Kumiko Ito; Houman Goudarzi
  Environmental health and preventive medicine, 26, 1, 59, 59, 22 May 2021, [International Magazine]
  English, Scientific journal, BACKGROUND: The Hokkaido Study on Environment and Children's Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary objectives are to (1) examine the effects that low-level environmental chemical exposures have on birth outcomes, including birth defects and growth retardation; (2) follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders, as well as perform a longitudinal observation of child development; (3) identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) identify the additive effects of various chemicals, including tobacco. METHODS: The purpose of this report is to provide an update on the progress of the Hokkaido Study, summarize recent results, and suggest future directions. In particular, this report provides the latest details from questionnaire surveys, face-to-face examinations, and a collection of biological specimens from children and measurements of their chemical exposures. RESULTS: The latest findings indicate different risk factors of parental characteristics on birth outcomes and the mediating effect between socioeconomic status and children that are small for the gestational age. Maternal serum folate was not associated with birth defects. Prenatal chemical exposure and smoking were associated with birth size and growth, as well as cord blood biomarkers, such as adiponectin, leptin, thyroid, and reproductive hormones. We also found significant associations between the chemical levels and neuro development, asthma, and allergies. CONCLUSIONS: Chemical exposure to children can occur both before and after birth. Longer follow-up for children is crucial in birth cohort studies to reinforce the Developmental Origins of Health and Disease hypothesis. In contrast, considering shifts in the exposure levels due to regulation is also essential, which may also change the association to health outcomes. This study found that individual susceptibility to adverse health effects depends on the genotype. Epigenome modification of DNA methylation was also discovered, indicating the necessity of examining molecular biology perspectives. International collaborations can add a new dimension to the current knowledge and provide novel discoveries in the future.
• DNA methylation of GFI1 as a mediator of the association between prenatal smoking exposure and ADHD symptoms at 6 years: the Hokkaido Study on Environment and Children's Health.
  Kunio Miyake; Chihiro Miyashita; Atsuko Ikeda-Araki; Ryu Miura; Sachiko Itoh; Keiko Yamazaki; Sumitaka Kobayashi; Hideyuki Masuda; Tadao Ooka; Zentaro Yamagata; Reiko Kishi
  Clinical epigenetics, 13, 1, 74, 74, 07 Apr. 2021, [International Magazine]
  English, Scientific journal, BACKGROUND: Prenatal smoking exposure has been associated with childhood attention-deficit/hyperactivity disorder (ADHD). However, the mechanism underlying this relationship remains unclear. We assessed whether DNA methylation differences may mediate the association between prenatal smoking exposure and ADHD symptoms at the age of 6 years. RESULTS: We selected 1150 mother-infant pairs from the Hokkaido Study on the Environment and Children's Health. Mothers were categorized into three groups according to plasma cotinine levels at the third trimester: non-smokers (≤ 0.21 ng/mL), passive smokers (0.21-11.48 ng/mL), and active smokers (≥ 11.49 ng/mL). The children's ADHD symptoms were determined by the ADHD-Rating Scale at the age of 6 years. Maternal active smoking during pregnancy was significantly associated with an increased risk of ADHD symptoms (odds ratio, 1.89; 95% confidence interval, 1.14-3.15) compared to non-smoking after adjusting for covariates. DNA methylation of the growth factor-independent 1 transcriptional repressor (GFI1) region, as determined by bisulfite next-generation sequencing of cord blood samples, mediated 48.4% of the total effect of the association between maternal active smoking during pregnancy and ADHD symptoms. DNA methylation patterns of other genes (aryl-hydrocarbon receptor repressor [AHRR], cytochrome P450 family 1 subfamily A member 1 [CYP1A1], estrogen receptor 1 [ESR1], and myosin IG [MYO1G]) regions did not exert a statistically significant mediation effect. CONCLUSIONS: Our findings demonstrated that DNA methylation of GFI1 mediated the association between maternal active smoking during pregnancy and ADHD symptoms at the age of 6 years.
• Mediating Factors Between Parental Socioeconomic Status and Small for Gestational Age in Infants: Results from the Hokkaido Study on Environment and Children’s Health
  Naomi Tamura; Tomoyuki Hanaoka; Kumiko Ito; Atsuko Araki; Chihiro Miyashita; Sachiko Ito; Sumitaka Kobayashi; Yoichi Ito; Hisanori Minakami; Kazutoshi Cho; Toshiaki Endo; Tsuyoshi Baba; Kazuo Sengoku; Toshinobu Miyamoto; Katsuhiko Ogasawara; Reiko Kishi
  Maternal and Child Health Journal, 25, 4, 645, 655, Springer Science and Business Media LLC, Apr. 2021
  Scientific journal
• Prevalence of childhood wheeze and modified DNA methylation at 7 years of age according to maternal folate levels during pregnancy in the Hokkaido Study.
  Chihiro Miyashita; Atsuko Araki; Ryu Miura; Yu Ait Bamai; Sumitaka Kobayashi; Sachiko Itoh; Kumiko Ito; Meng-Shan Tsai; Reiko Kishi
  Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, 32, 3, 514, 523, Apr. 2021, [International Magazine]
  English, Scientific journal, BACKGROUND: A high dose of folic acid during pregnancy may increase the risk of asthma, wheezing, and respiratory disease in childhood. Folate acid can modify inflammation and immune susceptibility of offspring with some epigenetic differentiation, including DNA methylation. This study evaluated associations between maternal folate levels during pregnancy and childhood wheezing; furthermore, the study assessed whether maternal folate-modified DNA methylation is related to asthma. Methods Participants in the current study were 6651 mother-child pairs who had complete data on characteristics and who had completed at least one of the International Study of Asthma and Allergies in Childhood questionnaires when the child was 1, 2, 4, and 7 years of age. Moreover, a case-control study to assess DNA methylation at 7 years of age was conducted among 136 children who experienced wheezing and a control group of 139 children with no history of allergies. Results The median of maternal serum was 16.76 nmol/L, assayed by chemiluminescent immunoassay. We found significantly increased adjusted odds ratios of childhood wheezing at 2 years age according to maternal folate levels, compared with the lowest folate quartile (odds ratio [95% confidence interval] = highest; 1.27 [1.03, 1.56], and second, 1.27 [1.05, 1.55]); however, no changes were observed at 1, 4, and 7 years of age. In a case-control study, no association of maternal folate levels with DNA methylation was observed. Conclusion Our results suggest that maternal folate did not affect persistent wheezing in school-aged children, or DNA methylation of gasdermin B, orosomucoid-like 3, and Ikaros family zinc finger 3 at 7 years of age.
• Hypertensive Disorders during Pregnancy (HDP), Maternal Characteristics, and Birth Outcomes among Japanese Women: A Hokkaido Study.
  Kritika Poudel; Sumitaka Kobayashi; Chihiro Miyashita; Atsuko Ikeda-Araki; Naomi Tamura; Yu Ait Bamai; Sachiko Itoh; Keiko Yamazaki; Hideyuki Masuda; Mariko Itoh; Kumiko Ito; Reiko Kishi
  International journal of environmental research and public health, 18, 7, 24 Mar. 2021, [International Magazine]
  English, Scientific journal, Hypertension during pregnancy causes a greater risk of adverse birth outcomes worldwide; however, formal evidence of hypertensive disorders during pregnancy (HDP) in Japan is limited. We aimed to understand the association between maternal characteristics, HDP, and birth outcomes. In total, 18,833 mother-infant pairs were enrolled in the Hokkaido study on environment and children's health, Japan, from 2002 to 2013. Medical records were used to identify hypertensive disorders and birth outcomes, namely, small for gestational age (SGA), SGA at full term (term-SGA), preterm birth (PTB), and low birth weight (LBW). The prevalence of HDP was 1.9%. Similarly, the prevalence of SGA, term-SGA, PTB, and LBW were 7.1%, 6.3%, 7.4%, and 10.3%, respectively. The mothers with HDP had increased odds of giving birth to babies with SGA (2.13; 95% Confidence Interval (CI): 1.57, 2.88), PTB (3.48; 95%CI: 2.68, 4.50), LBW (3.57; 95%CI: 2.83, 4.51) than normotensive pregnancy. Elderly pregnancy, low and high body mass index, active and passive smoking exposure, and alcohol consumption were risk factors for different birth outcomes. Therefore, it is crucial for women of reproductive age and their families to be made aware of these risk factors through physician visits, health education, and various community-based health interventions.
• Lower respiratory tract infections and orofacial clefts: a prospective cohort study from the Japan Environment and Children's Study.
  Yukihiro Sato; Eiji Yoshioka; Yasuaki Saijo; Toshinobu Miyamoto; Hiroshi Azuma; Yusuke Tanahashi; Yoshiya Ito; Sumitaka Kobayashi; Machiko Minatoya; Yu Ait Bamai; Keiko Yamazaki; Sachiko Ito; Chihiro Miyashita; Atsuko Araki; Reiko Kishi
  Journal of epidemiology, 13 Jan. 2021, [Domestic magazines]
  English, Scientific journal, BACKGROUND: Lower respiratory tract infections (LRTIs) are a cause of inpatient and outpatient care among children. Although orofacial clefts seem to be associated with LRTIs, epidemiological studies are scarce on this topic. This study aimed to examine whether infants with orofacial clefts were associated with LRTIs. METHODS: This prospective cohort study used data from the Japan Environment and Children's Study, whose baseline recruitment was conducted during 2011-2014. This study included 81,535 participants. The number of infants with cleft lip and palate (CLP), cleft lip (CL), and cleft palate only (CP) was 67, 49, and 36, respectively. We defined history of LRTIs until 12 months' age reported by their mothers as the dependent variable. Accumulated breastfeeding duration was used as potential mediators. RESULTS: The incidence proportion of LRTIs among the control group was 6.0%. The incidence proportion among infants with CLP, CL, and CP were 11.9%, 14.3%, and 5.6%, respectively. After adjusting for covariates, compared with the control group, infants with CLP and CL were associated with risk of LRTIs (incidence risk ratio [IRR] of CLP = 2.38 [95% confidence interval = 1.30, 4.36] and of CL = 2.73 [1.40, 5.33]) , but not ones with CP (1.08 [0.28, 4.15]). Accumulated breastfeeding duration decreased the IRR of CLP only (IRR of CLP = 2.16 [1.19, 3.93]). CONCLUSIONS: Infants with orofacial clefts aged 1 year have a potentially high incidence proportion of LRTIs. Accumulated breastfeeding duration might mediate the associations of CLP.
• Parental educational level and childhood wheezing and asthma: A prospective cohort study from the Japan Environment and Children's Study.
  Yasuaki Saijo; Eiji Yoshioka; Yukihiro Sato; Toshinobu Miyamoto; Hiroshi Azuma; Yusuke Tanahashi; Yoshiya Ito; Sumitaka Kobayashi; Machiko Minatoya; Yu Ait Bamai; Keiko Yamazaki; Sachiko Itoh; Chihiro Miyashita; Atsuko Araki; Reiko Kishi
  PloS one, 16, 4, e0250255, 2021, [International Magazine]
  English, Scientific journal, BACKGROUND: The influence of mothers' and fathers' educational levels in separate evaluations of asthma has not been fully investigated. This study aims to examine the associations of the mother's and fathers' educational levels with childhood wheeze and asthma adjusting for crude and pre-and post-natal modifiable risk factors. METHODS: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant women from 2011 to 2014. The mother's and father's educational levels were surveyed by a questionnaire during the pregnancy, and childhood wheezing and doctor-diagnosed asthma were estimated using a 3-year questionnaire. Multilevel logistic regression analysis was performed to evaluate the association between the mother's and father's educational levels and childhood wheezing and asthma, adjusted for pre-and post-natal factors. RESULTS: A total of 69,607 pairs of parents and their single infants were analyzed. We found 17.3% of children had wheezing and 7.7% had asthma. In crude analyses, lower educational level of parents was associated with an increased risk of childhood wheezing and asthma. After full adjustment, a lower educational level of mothers was associated with an increased risk of childhood asthma (junior high school (reference: high school); odds ratio (OR): 1.17, 95% CI, 1.01-1.36), and higher educational level, especially the mother's, was associated with an increased risk of childhood wheezing (technical junior college, technical/vocational college, or associate degree (ECD3); OR: 1.12, 95% CI, 1.06-1.18, bachelor's degree, or postgraduate degree; OR: 1.10, 95% CI, 1.03-1.18), and asthma (ECD3; OR: 1.13, 95% CI, 1.04-1.21). CONCLUSIONS: Parents' lower educational level was a crude risk factor for childhood wheezing and asthma. However, an increased risk of wheezing due to mothers' higher educational level was found after adjusting for pre-and post-natal factors.
• Risk factors for motor coordination problems in preschool-age children.
  Satoshi Suyama; Kazuyori Yagyu; Atsuko Araki; Chihiro Miyashita; Sachiko Itoh; Machiko Minatoya; Keiko Yamazaki; Naomi Tamura; Akio Nakai; Takuya Saito; Reiko Kishi
  Pediatrics international : official journal of the Japan Pediatric Society, 62, 10, 1177, 1183, Oct. 2020, [International Magazine]
  English, Scientific journal, BACKGROUND: Motor coordination problems (MCP) in children can sometimes be diagnosed as developmental coordination disorder. Early intervention for developmental coordination disorder is necessary because it often continues into adolescence, causing mental and physical complications. Few studies have investigated the prevalence of childhood MCP in the Japanese population, examining the risk factors for MCP. We therefore investigated the prenatal factors associated with MCP in preschool-age children. METHODS: This study was based on a prospective cohort study, the Hokkaido Study on Environment and Children's Health. Mothers of 4,851 children who reached the age of 5 years within the study-period received questionnaires, including the Japanese version of the Developmental Coordination Disorder Questionnaire (DCDQ-J). We examined the risk factors associated with MCP using logistic regression analysis. RESULTS: Of 3,402 returned DCDQ-J questionnaires, 3,369 were answered completely. From the 3,369 children, we categorized having MCP by using two cut-off scores: that of the DCDQ'07 and the cut-off at the 5th percentile of a total DCDQ-J score. Comparing children with and without MCP, we found significant differences in the education level of the mothers, annual household income during pregnancy, maternal alcohol consumption and smoking during pregnancy, and sex and age of the children at the time of completing the DCDQ-J by both categorizations. Adjusted logistic regression analysis revealed that maternal smoking during the first trimester of pregnancy and male sex were significantly associated with MCP. CONCLUSIONS: Our results suggest that maternal smoking during pregnancy is the main factor associated with MCP in preschool-age children.
• Associations between prenatal exposure to organochlorine pesticides and thyroid hormone levels in mothers and infants: The Hokkaido study on environment and children's health.
  Keiko Yamazaki; Sachiko Itoh; Atsuko Araki; Chihiro Miyashita; Machiko Minatoya; Tamiko Ikeno; Shizue Kato; Kaori Fujikura; Futoshi Mizutani; Yoichi Chisaki; Reiko Kishi
  Environmental research, 189, 109840, 109840, Oct. 2020, [International Magazine]
  English, Scientific journal, Organochlorine pesticides (OCPs) are environmental contaminants with potentially adverse effects on neurodevelopment. Previous findings on the association between prenatal exposure to OCPs and the maternal or infant thyroid hormone system are inconsistent. Moreover, the influence of exposure to multiple OCPs and other chemical compounds is not clearly understood. Our study therefore aimed to examine the association between OCP exposure and both maternal and infant thyroid hormone systems. We also explored multiple exposure effects of OCPs and the influence of each compound using weighted quantile sum (WQS) methods. The study population included 514 participants in the Hokkaido study, recruited from 2002 to 2005 at one hospital in Sapporo, Japan. To quantify 29 OCPs, maternal blood samples were analyzed using gas chromatography/mass spectrometry. Blood samples for measuring thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from mothers during the early gestational stage (mean 11.4 weeks), and from infants between 7 and 43 days of age. The data of 333 mother child pairs with OCP and thyroid hormone measurements were included in the final analyses. Multivariate regression models showed a negative association between maternal FT4 and levels of o,p'-dichlorodiphenyldichloroethylene (DDE), o,p'-dichlorodiphenyltrichloroethane (DDT), and dieldrin. The WQS analysis showed that o,p'-DDT (48.6%), cis-heptachlorepoxide (22.8%), dieldrin (15.4%) were the primary contributors to the significant multiple exposure effect of OCPs on maternal FT4. For infants, we found a positive association between FT4 and cis-nonachlor and mirex. The most contributory compounds in the multiple exposure effect were trans-nonachlor (27.1%) and cis-nonachlor (13.8%), while several compounds contributed to the WQS via small weights (0.4-9.1%). These results indicate that OCPs, even at very low levels, may influence maternal and child thyroid hormone levels, which could modulate child development.
• Trajectories of the Psychological Status of Mothers of Infants With Nonsyndromic Orofacial Clefts: A Prospective Cohort Study From the Japan Environment and Children's Study.
  Yukihiro Sato; Eiji Yoshioka; Yasuaki Saijo; Toshinobu Miyamoto; Kazuo Sengoku; Hiroshi Azuma; Yusuke Tanahashi; Yoshiya Ito; Sumitaka Kobayashi; Machiko Minatoya; Yu Ait Bamai; Keiko Yamazaki; Sachiko Ito; Chihiro Miyashita; Atsuko Araki; Reiko Kishi
  The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association, 58, 3, 1055665620951399, 1055665620951399, 26 Aug. 2020, [International Magazine]
  English, Scientific journal, OBJECTIVE: This study examined psychological status trajectories of mothers of infants with nonsyndromic orofacial clefts in Japan. DESIGN: Prospective cohort study. SETTING: Data from the Japan Environment and Children's Study. PARTICIPANTS: Infants with a nonsyndromic cleft (N = 148) including cleft lip and palate (CLP; n = 72), cleft lip (CL; n = 46), and cleft palate (CP; n = 30). The control group included unaffected infants (N = 84 454). MAIN OUTCOME MEASURES: At 15 weeks and 27 weeks of pregnancy and 12 months after birth, the Kessler Psychological Distress Scale (clinical cutoff ≥5) was used. At 1 month and 6 months after birth, the Edinburgh Postnatal Depression Scale (clinical cutoff ≥9) was used. RESULTS: Prenatal diagnosis rates were unavailable. Mothers of infants with CLP had higher psychological distress than controls at 27 weeks of pregnancy (prevalence ratio [PR] = 1.36, 95% CI: 1.06-1.74) and postnatal depression at 1 month after birth (PR = 2.21, 95% CI: 1.53-3.19). Mothers of infants with CP showed heightened psychological distress at 27 weeks of pregnancy (PR = 1.62, 95% CI: 1.21-2.17) and postnatal depression 6 months after birth (PR = 1.86, 95% CI: 1.01-3.43). There was no significant association between CL and maternal psychological status. At 12 months after birth, no differences in distress were found between mothers of infants with a cleft and controls. CONCLUSIONS: Mothers of infants with orofacial clefts may need psychosocial support, particularly during pregnancy and the first year after birth.
• Temporal trends and determinants of PFR exposure in the Hokkaido Study.
  Michiel Bastiaensen; Yu Ait Bamai; Atsuko Araki; Houman Goudarzi; Satoshi Konno; Sachiko Ito; Chihiro Miyashita; Yiming Yao; Reiko Kishi; Adrian Covaci
  International journal of hygiene and environmental health, 228, 113523, 113523, Jul. 2020, [International Magazine]
  English, Scientific journal, The phase-out of polybrominated diphenyl ethers (PBDE) flame retardants has led to the rapid increase of alternatives such as phosphate flame retardants and plasticizers (PFRs) in many consumer products. Exposure to these additive chemicals is widespread and potentially harmful to humans and the environment. In the present study, we assessed the exposure to PFRs through the analysis of metabolites in urine collected from 7-year old children from Hokkaido, Japan between 2012 and 2017. This allowed us to investigate temporal and seasonal trends for PFR metabolite concentrations and to study determinants of exposure. Thirteen metabolites of seven PFRs were measured in morning spot urine samples (n = 400). Multiple regression models were used to quantify the yearly increase in metabolite concentrations per sampling year. Information on the demographics, indoor environment and dietary habits of the participants were derived from self-administered questionnaires. PFR metabolite concentrations were comparable to our previous study of school children (7-12 years old). Eight PFR metabolites were detected in >50% of the samples. During the study time period, concentrations of three metabolites increased significantly: bis(1,3-dichloro-2-propyl) phosphate (BDCIPP; 13.3% per year), 1-hydroxy-2-propyl bis(1-chloro-2-propyl) phosphate (BCIPHIPP; 12.9% per year), and 2-ethylhexyl phenyl phosphate (EHPHP; 6.7% per year). We also found seasonality as a determinant for several PFR metabolites, with 2-fold higher levels in summer for BCIPHIPP and BDCIPP. Concentrations were also significantly impacted by ventilation habits. More frequent window opening or use of mechanical ventilation was consistently associated with higher levels of PFR metabolites in children's urine. This is the first study to show that human exposure to PFRs has increased in recent years in Japan, which indicates that further research into this class of chemicals is warranted.
• Association of exposure to prenatal phthalate esters and bisphenol A and polymorphisms in the ESR1 gene with the second to fourth digit ratio in school-aged children: Data from the Hokkaido study.
  Yoko Nishimura; Kimihiko Moriya; Sumitaka Kobayashi; Atsuko Araki; Fumihiro Sata; Takahiko Mitsui; Sachiko Itoh; Chihiro Miyashita; Kazutoshi Cho; Masafumi Kon; Michiko Nakamura; Takeya Kitta; Sachiyo Murai; Reiko Kishi; Nobuo Shinohara
  Steroids, 159, 108637, 108637, Jul. 2020, [International Magazine]
  English, Scientific journal, Phthalates and bisphenol A (BPA) are estrogenic endocrine disruptors. Polymorphisms in the gene encoding estrogen receptor 1 (ESR1) may contribute to the ratio of the lengths of the second and fourth digits (2D:4D), which is considered an index of prenatal exposure to sex hormones. Thus, we investigated whether ESR1 polymorphisms modify the effects of prenatal exposure to phthalates and BPA on 2D:4D in a birth cohort. Maternal serum in the first trimester was used to determine prenatal exposure to these compounds. Six hundred twenty-three children (7 years of age) provided mean 2D:4D from photocopies and were genotyped for single nucleotide polymorphisms in ESR1, particularly PvuII (T > C, dbSNP: rs2234693), XbaI (A > G, dbSNP: rs9340799), and rs2077647 (A > G). The associations among compound exposure, mean 2D:4D, and ESR1 polymorphisms were assessed by multiple linear regression adjusted for potential cofounding factors. Boys with the AG/GG genotype at rs2077647 in the group exposed to high levels of mono(2-ethylhexyl) phthalate (MEHP) or Σ Di(2-ethylhexyl) phthalate (DEHP) showed feminized 2D:4D compared with boys with the AA genotype at rs2077647 who had low exposure to MEHP or ΣDEHP (MEHP: increase in mean 2D:4D of 1.51%, 95% confidence interval [CI]: 0.40-2.63; ΣDEHP: increase in mean 2D:4D of 1.37%, 95% CI: 0.25-2.49). No significant differences were found among girls. There were no associations between mean 2D:4D and metabolites other than MEHP or BPA. These data suggest that ESR1 polymorphisms modify the effects of prenatal exposure to DEHP on mean 2D:4D among boys.
• Factors correlating with serum birch pollen IgE status in pregnant women in Hokkaido, Japan: The Japan Environment and Children's Study (JECS).
  Yasuaki Saijo; Eiji Yoshioka; Yukihiro Sato; Toshinobu Miyamoto; Kazuo Sengoku; Yoshiya Ito; Sachiko Itoh; Chihiro Miyashita; Atsuko Araki; Reiko Kishi
  The World Allergy Organization journal, 13, 6, 100128, 100128, Jun. 2020, [International Magazine]
  English, Scientific journal, Background: Birch pollen allergy affects pregnant women, and such allergy may affect the development of allergic diseases in their children. Using nationwide birth cohort data, this study aimed to investigate the prevalence of birch pollen IgE positivity and to identify correlating factors in pregnant women in Hokkaido, Japan, a high-latitude island. Methods: Participants included 6856 pregnant women. Participants responded to questionnaires regarding lifestyle factors and history of allergies. Data regarding parity, height, and pre-pregnancy weight were collected from medical records. Blood samples were obtained from participants during the first trimester of pregnancy, and serum allergen-specific IgE titers were determined. Results: The serum of 30.2% participants was positive for birch pollen IgE (≥0.35 UA/mL). Such positivity significantly correlated with a history of other allergic diseases, particularly food allergy and allergic rhinitis/hay fever. In multivariate logistic regression analysis, pre-pregnancy high body mass index (BMI ≥ 25) significantly correlated with birch pollen IgE positivity [odds ratio (OR), 1.24; 95% CI, 1.05-1.47; reference BMI, 18.5-24.9] and higher income (≥10 million yen per year; OR,0.55; 95% CI, 0.37-0.81; reference, household income < 2 million yen per year), and second quintile level physical activity (OR,0.75; 95% CI, 0.63-0.88; reference, the first quintile of physical activity) had significant protective effects. Conclusions: Birch pollen IgE positivity in pregnant women was positively associated with food allergy, allergic rhinitis, pre-pregnant high BMI, and was negatively associated with light exercise and high household income in Hokkaido. Trial registration: UMIN000030786.
• Effect of the occupational environment of parents on cryptorchidism.
  Takahiko Mitsui; Atsuko Araki; Chihiro Miyashita; Sachiko Ito; Takeya Kitta; Kimihiko Moriya; Nobuo Shinohara; Masayuki Takeda; Reiko Kishi
  Pediatrics international : official journal of the Japan Pediatric Society, 62, 11, 1256, 1263, 24 May 2020, [International Magazine]
  English, Scientific journal, BACKGROUND: The early detection and treatment of cryptorchidism are necessary to preserve male fertility. This study aimed to assess the effect of parents' occupational environment on the incidence of cryptorchidism in their sons. METHODS: The study enrolled 51 316 newborn males, whose mothers were recruited in the Japan Environment and Children's Study. We analyzed cryptorchidism incidence in male newborns according to 14 categories of occupation of their parents. We also analyzed the effect of the mother's occupational environment during gestation, including working and night-shift work, on cryptorchidism incidence. Information on occupations was obtained from self-administered questionnaires. Cryptorchidism was identified through a survey at birth or 1 month after birth using medical records. RESULTS: Cryptorchidism was identified in 305 male infants (0.59%) at birth or 1 month after birth. Weight, height, head circumference, and chest circumference at birth were significantly lower in male infants with cryptorchidism than in those without the condition. Gestational age was also shorter in mothers whose infants developed cryptorchidism. Moreover, maternal age at delivery and smoking during gestation also had an effect on cryptorchidism incidence. However, multivariate analysis of the 14 categories of occupation of parents during gestation showed no significant effect on cryptorchidism incidence in their male infants. CONCLUSIONS: This study revealed that the work environment of parents did not significantly affect the incidence of cryptorchidism in their sons. However, this study might have underestimated mild and transient cases of cryptorchidism. Further studies are necessary to investigate the risk factors of cryptorchidism in relation to parents' occupation.
• Population attributable fractions of modifiable risk factors for nonsyndromic orofacial clefts: a prospective cohort study from the Japan Environment and Children's Study.
  Yukihiro Sato; Eiji Yoshioka; Yasuaki Saijo; Toshinobu Miyamoto; Kazuo Sengoku; Hiroshi Azuma; Yusuke Tanahashi; Yoshiya Ito; Sumitaka Kobayashi; Machiko Minatoya; Yu Ait Bamai; Keiko Yamazaki; Sachiko Itoh; Chihiro Miyashita; Atsuko Araki; Reiko Kishi
  Journal of epidemiology, 31, 4, 272, 279, 25 Apr. 2020, [Domestic magazines]
  English, Scientific journal, BACKGROUND: Population impact of modifiable risk factors on orofacial clefts is still unknown. This study aimed to estimate population attributable fractions (PAFs) of modifiable risk factors for nonsyndromic cleft lip with or without cleft palate (CL±P) and cleft palate only (CP) in Japan. METHODS: We conducted a prospective cohort study using data from the Japan Environment and Children's Study, which recruited pregnant women from 2011 to 2014. We estimated the PAFs of maternal alcohol consumption, psychological distress, maternal active and passive smoking, abnormal body mass index (BMI) (<18.5 and ≥25 kg/m2), and non-use of a folic acid supplement during pregnancy for nonsyndromic CL±P and CP in infants. RESULTS: A total of 94,174 pairs of pregnant women and their single babies were included. Among them, there were 146 nonsyndromic CL±P cases and 41 nonsyndromic CP cases. The combined adjusted PAF for CL±P of the modifiable risk factors excluding maternal alcohol consumption was 34.3%. Only maternal alcohol consumption was not associated with CL±P risk. The adjusted PAFs for CL±P of psychological distress, maternal active and passive smoking, abnormal BMI, and non-use of a folic acid supplement were 1.4% (95% confidence interval = -10.7, 15.1), 9.9% (-7.0, 26.9), 10.8% (-9.9, 30.3), 2.4% (-7.5, 14.0), and 15.1% (-17.8, 41.0), respectively. We could not obtain PAFs for CP due to the small sample size. CONCLUSIONS: We reported the population impact of the modifiable risk factors on CL±P, but not CP. This study might be useful in planning the primary prevention of CL±P.
• Combined exposure to phthalate esters and phosphate flame retardants and plasticizers and their associations with wheeze and allergy symptoms among school children.
  Atsuko Araki; Yu Ait Bamai; Michiel Bastiaensen; Nele Van den Eede; Toshio Kawai; Tazuru Tsuboi; Chihiro Miyashita; Sachiko Itoh; Houman Goudarzi; Satoshi Konno; Adrian Covaci; Reiko Kishi
  Environmental research, 183, 109212, 109212, Apr. 2020, [International Magazine]
  English, Scientific journal, BACKGROUND: Phthalate esters and phosphate flame retardants and plasticizers (PFRs) are both used as plasticizers and are commonly detected in indoor environments. Although both phthalates and PFRs are known to be associated with children's wheeze and allergic symptoms, there have been no previous studies examining the effects of mixtures of these exposures. OBJECTIVES: To investigate the association between exposure to mixtures of phthalate esters and PFRs, and wheeze and allergic symptoms among school-aged children. METHODS: A total of 128 elementary school-aged children were enrolled. Metabolites of 3 phthalate esters and 7 PFRs were measured in urine samples. Parent-reported symptoms of wheeze, rhinoconjunctivitis, and eczema were evaluated using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire. In the primary model, we created a phthalate ester and PFR mixture exposure index, and estimated odds ratios (ORs) using weighted quantile sum (WQS) regression and quantile g (qg)-computation. The two highest chemicals according to qg-computation weight %s were combined to create a combination high × high exposure estimate, with ORs calculated using the "low × low" exposure group as the reference category. Concentrations of each metabolite were corrected by multiplying this value by the sex- and body size-Standardised creatinine concentration and dividing by the observed creatinine value. All models were adjusted for sex, grade, dampness index and annual house income. RESULTS: The odds ratio of rhinoconjunctivitis for the association between exposure to chemical mixtures according to the WQS index positive models was; OR = 2.60 (95% confidence interval [CI]: 1.38-5.14). However, wheeze and eczema of the WQS index positive model, none of the WQS index negative models or qg-computation result yielded statistically significant results. Combined exposure to the two highest WQS weight %s of "high-high" ΣTCIPP and ΣTPHP was associated with an increased prevalence of rhino-conjunctivitis, OR = 5.78 (1.81-18.43) to the "low × low" group. CONCLUSIONS: Significant associations of mixed exposures to phthalates and PFRs and increased prevalence of rhinoconjunctivitis was found among elementary school-aged children in the WQS positive model. Mixed exposures were not associated with any of allergic symptoms in the WQS negative model or qg-computation approach. However, the combined effects of exposure to two PFRs suggested an additive and/or multiplicative interaction, potentially increasing the prevalence of rhinoconjunctivitis. A further study with a larger sample size is needed to confirm these results.
• Cat and Dog Ownership in Early Life and Infant Development: A Prospective Birth Cohort Study of Japan Environment and Children's Study.
  Machiko Minatoya; Atsuko Araki; Chihiro Miyashita; Sachiko Itoh; Sumitaka Kobayashi; Keiko Yamazaki; Yu Ait Bamai; Yasuaki Saijyo; Yoshiya Ito; Reiko Kishi; The Japan Environment And Children's Study Group
  International journal of environmental research and public health, 17, 1, 27 Dec. 2019, [Peer-reviewed], [International Magazine]
  English, Scientific journal, Contact with companion animals has been suggested to have important roles in enhancing child development. However, studies focused on child development and pet ownership at a very early age are limited. The purpose of the current study was to investigate child development in relation to pet ownership at an early age in a nationwide prospective birth cohort study: the Japan Environment and Children's Study. Associations between cat and dog ownership at six months and infant development at 12 months of age were examined in this study. Infant development was assessed using the Ages & Stages QuestionnairesTM (ASQ-3) at 12 months. Among participants of (Japan Environment and Children's Study) JECS, those with available data of cat and dog ownership at six months and data for the ASQ-3 at 12 months were included (n = 78,868). Having dogs showed higher percentages of pass in all five domains measured by ASQ-3 (communication, gross motor, fine motor, problem-solving, and personal-social) compared to those who did not have dogs. Significantly decreased odds ratios (ORs) of developmental delays were observed in association with having dogs in all fix domains (communication: OR = 0.73, gross motor: OR = 0.86, fine motor: OR = 0.84, problem-solving: OR = 0.90, personal-social: OR = 0.83). This study suggested that early life dog ownership may reduce the risks of child developmental delays.
• Prenatal tobacco exposure and ADHD symptoms at pre-school age: the Hokkaido Study on Environment and Children's Health.
  Machiko Minatoya; Atsuko Araki; Sachiko Itoh; Keiko Yamazaki; Sumitaka Kobayashi; Chihiro Miyashita; Seiko Sasaki; Reiko Kishi
  Environmental health and preventive medicine, 24, 1, 74, 74, 07 Dec. 2019, [International Magazine]
  English, Scientific journal, BACKGROUND: There have been inconsistent findings reported on maternal passive smoking during pregnancy and child risk of ADHD. In this study, ADHD symptoms at pre-school age children in association with prenatal passive and active tobacco smoke exposure determined by maternal plasma cotinine levels in the third trimester were investigated. METHODS: This was a follow-up study of the birth cohort: the Hokkaido Study on Environment and Children's Health. Children whose parents answered Strengths and Difficulties Questionnaire (SDQ) to identify child ADHD symptoms (hyperactivity/inattention and conduct problems) and total difficulties at age 5 years with available maternal plasma cotinine level at the third trimester were included (n = 3216). Cotinine levels were categorized into 4 groups; ≦ 0.21 ng/ml (non-smoker), 0.22-0.51 ng/ml (low-passive smoker), 0.52-11.48 ng/ml (high-passive smoker), and ≧ 11.49 ng/ml (active smoker). RESULTS: Maternal cotinine levels of active smokers were significantly associated with an increased risk of total difficulties (OR = 1.67) and maternal low- and high-passive smoking also increased the risk (OR = 1.11, 1.25, respectively) without statistical significance. Similarly, maternal cotinine levels of active smokers were associated with an increased risk of hyperactivity/inattention (OR = 1.49). Maternal low- and high-passive smoking and active smoking increased the risk of hyperactivity/inattention (OR = 1.45, 1.43, and OR = 1.59, respectively) only in boys. CONCLUSION: Our findings suggested that maternal active smoking during pregnancy may contribute to the increased risk of child total difficulties and hyperactivity/inattention at pre-school age. Pregnant women should be encouraged to quit smoking and avoid exposure to tobacco smoke.
• Association between perfluoroalkyl substance exposure and thyroid hormone/thyroid antibody levels in maternal and cord blood: The Hokkaido Study.
  Sachiko Itoh; Atsuko Araki; Chihiro Miyashita; Keiko Yamazaki; Houman Goudarzi; Machiko Minatoya; Yu Ait Bamai; Sumitaka Kobayashi; Emiko Okada; Ikuko Kashino; Motoyuki Yuasa; Toshiaki Baba; Reiko Kishi
  Environment international, 133, Pt A, 105139, 105139, Dec. 2019, [International Magazine]
  English, Scientific journal, BACKGROUND: Thyroid antibodies (TAs) are the most common cause of hypothyroidism during gestation. Although previous studies found that prenatal exposure to perfluoroalkyl substances (PFASs) disrupts thyroid hormones (THs) in humans, their effects on TAs during the perinatal period have not been investigated. OBJECTIVE: To explore the associations between prenatal exposure to eleven different PFASs from two different groups (carboxylates and sulfonates) and the expression of THs and TAs in maternal and cord blood while considering maternal TA status. METHODS: In a prospective birth cohort (the Hokkaido Study), we included 701 mother‑neonate pairs recruited in 2002-2005 for whom both prenatal maternal and cord blood samples were available. Eleven PFASs were measured in maternal plasma obtained at 28-32 weeks of gestation using ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. THs and TAs including thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid peroxidase antibody (TPOAb), and thyroglobulin antibody (TgAb) were measured in maternal blood during early pregnancy (median 11 gestational weeks), and in cord blood at birth. RESULTS: The median levels of TgAb and TPOAb in maternal serum were 15.0 and 6.0 IU/mL, respectively. The median TgAb level in neonates was 38.0 IU/mL, and TPOAb were detected in only 12.3% of samples. Maternal FT3 level was positively associated with PFAS levels in both TA-positive and TA-negative mothers. Maternal perfluorooctanoate was inversely associated with maternal TPOAb. Among boys, some maternal PFASs were associated with higher TSH and lower FT3 levels in maternal TA-negative group, while perfluorodecanoic acid was associated with lower TSH in maternal TA-positive group. Among girls, some PFAS of mothers showed associations with lower TSH and higher FT3 in maternal TA-negative group, while perfluorododecanoic acid was associated with lower FT4 in maternal TA-positive. Maternal PFASs showed associations with boy's TgAb inversely in maternal TA-negative group and with girl's TgAb positively in maternal TA-positive group. CONCLUSIONS: Our results suggest thyroid disrupting effects of PFAS exposure and susceptibility vary depending on maternal TA levels.
• Multiple exposures to organophosphate flame retardants alter urinary oxidative stress biomarkers among children: The Hokkaido Study.
  Yu Ait Bamai; Michiel Bastiaensen; Atsuko Araki; Houman Goudarzi; Satoshi Konno; Sachiko Ito; Chihiro Miyashita; Yiming Yao; Adrian Covaci; Reiko Kishi
  Environment international, 131, 105003, 105003, Oct. 2019, [International Magazine]
  English, Scientific journal, Organophosphate flame retardants (PFRs) are used as additives in plastics and other applications such as curtains and carpets as a replacement for brominated flame retardants. As such, exposure to PFR mixtures is widespread, with children being more vulnerable than adults to associated health risks such as allergies and inflammation. Oxidative stress is thought to be able to modulate the development of childhood airway inflammation and atopic dermatitis. To evaluate these associations, the present study investigated the relationship between urinary PFR metabolites, their mixtures and urinary oxidative stress biomarkers in children as part of the Hokkaido Study on Environment and Children's Health. The levels of the oxidative stress biomarkers, such as 8-hydroxy-2'-deoxyguanosine (8-OHdG), hexanoyl-lysine (HEL), and 4-hydroxynonenal (HNE), and of 14 PFR metabolites were measured in morning spot urine samples of 7-year-old children (n = 400). Associations between PFR metabolites or PFR metabolite mixtures and oxidative stress biomarkers were examined by multiple regression analysis and weighted quantile sum regression analysis, respectively. We found that the non-chlorinated PFR metabolites, 2-ethylhexyl phenyl phosphate (EHPHP), bis(2-butoxyethyl) phosphate (BBOEP), and diphenyl phosphate (DPHP) were associated with increased levels of oxidative stress biomarkers. Furthermore, the PFR metabolite mixture was associated with increased levels of HEL and HNE, but not 8-OHdG. The combination of elevated top 2 PFR metabolites was not associated with higher urinary oxidative stress marker levels. This is the first study to report associations between urinary PFR metabolites and oxidative stress biomarkers among children.
• Dose-dependent associations between prenatal caffeine consumption and small for gestational age, preterm birth, and reduced birthweight in the Japan Environment and Children's Study.
  Sumitaka Kobayashi; Fumihiro Sata; Katsuyuki Murata; Yasuaki Saijo; Atsuko Araki; Chihiro Miyashita; Sachiko Itoh; Machiko Minatoya; Keiko Yamazaki; Yu Ait Bamai; Reiko Kishi
  Paediatric and perinatal epidemiology, 33, 3, 185, 194, May 2019, [International Magazine]
  English, Scientific journal, BACKGROUND: Few previous studies have investigated the association between prenatal caffeine intake and birth size (small for gestational age [SGA], preterm birth, and birthweight Z-score) in Japan. OBJECTIVES: We examined the dose-dependency of this association (prenatal caffeine consumption and birth size) as part of the Japan Environment and Children's Study. METHODS: A prospective birth cohort included 94 876 fetuses in Japan. Participants were enrolled between January 2011 and March 2014. Adjusted multiple linear regression and Cox regression models were used to examine the association between prenatal caffeine levels and infant birth size. RESULTS: The median estimated caffeine consumption during pregnancy was 125.5 mg/day, as determined by self-administered questionnaires. There were 7252 SGA infants (7.6%) and 4281 preterm birth infants (4.5%). Compared with infants of mothers whose caffeine consumption during pregnancy was in the lowest quartile (4.2 to <86.4 mg/day), infants of mothers whose caffeine consumption was in the highest quartile 4 (205.5-5080.0 mg/day) were at an increased risk of SGA (relative risk [RR] 1.18, 95% confidence interval [CI] 1.10, 1.27), and at an increased risk of preterm birth at the second trimester of gestation (RR 1.94, 95% CI 1.12, 3.37), with a 0.32-day reduction in gestational age (95% CI -0.52, -0.12) and with a 0.07 reduction in birthweight Z-score observed (95% CI -0.09, -0.05). CONCLUSIONS: Prenatal caffeine consumption was associated with birth size. However, as the association between prenatal caffeine consumption and birth size was likely confounded by unpredicted potential factors, our confidence in the true causality of the association is moderate.
• Association Between Maternal Serum Folate Concentrations in the First Trimester and the Risk of Birth Defects: The Hokkaido Study of Environment and Children's Health.
  Kumiko Ito; Tomoyuki Hanaoka; Naomi Tamura; Seiko Sasaki; Chihiro Miyashita; Atsuko Araki; Sachiko Ito; Hisanori Minakami; Kazutoshi Cho; Toshiaki Endo; Tsuyoshi Baba; Toshinobu Miyamoto; Kazuo Sengoku; Akiko Tamakoshi; Reiko Kishi
  Journal of epidemiology, 29, 4, 164, 171, 05 Apr. 2019, [Domestic magazines]
  English, Scientific journal, BACKGROUND: Low red blood cell folate concentrations during early pregnancy might cause neural tube defects. However, the association between folate concentrations and birth defects of other neural crest cell-derived organs remains unknown. We investigated the associations between birth defects and first-trimester serum folate concentrations in a birth-cohort study in Japan. METHODS: In total, 14,896 women who were prior to 13 weeks of gestation were enrolled from 2003 through 2012. Birth defect information was obtained from medical records and questionnaires. The association between folate levels in the first trimester and birth defects categorized as ICD-10 cord defects and neural crest cell-derived organ defects was examined. The crude and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) per log-transformed folate concentration were calculated using logistic regression. RESULTS: Blood samples were obtained at a mean of 10.8 weeks of gestation. Median serum folate level was 16.5 (interquartile range, 13.4-21.5) nmol/L, and the deficiency level (less than 6.8 nmol/L) was 0.7%. There were 358 infants with birth defects. The adjusted odds ratio for any birth defect, ventricular septal defects, and cleft lip was 0.99 (95% CI, 0.74-1.32), 0.63 (95% CI, 0.30-1.33), and 4.10 (95% CI, 0.96-17.58), respectively. There were no significant associations between first-trimester maternal serum folate and the risk of birth defects. CONCLUSIONS: We were unable to demonstrate a relationship between maternal serum folate in the first trimester and birth defects. Potential confounding factors may have influenced our results.
• Association of blood mercury levels during pregnancy with infant birth size by blood selenium levels in the Japan Environment and Children's Study: A prospective birth cohort.
  Sumitaka Kobayashi; Reiko Kishi; Yasuaki Saijo; Yoshiya Ito; Koji Oba; Atsuko Araki; Chihiro Miyashita; Sachiko Itoh; Machiko Minatoya; Keiko Yamazaki; Yu Ait Bamai; Tosiya Sato; Shin Yamazaki; Shoji F Nakayama; Tomohiko Isobe; Hiroshi Nitta
  Environment international, 125, 418, 429, Apr. 2019, [International Magazine]
  English, Scientific journal, BACKGROUND: It is necessary to determine whether there are adverse health effects of prenatal exposure to long-term, low levels of mercury and selenium. However, there are limited that reports on the association between mercury levels by selenium levels and birth size. Therefore, we examined whether maternal mercury levels during pregnancy had any effect on infant birth size, and size, and whether selenium levels influenced this relationship. OBJECTIVES: To examine the association between mercury and selenium levels during pregnancy with infant birth size. METHODS: The Japan Environment and Children's Study is a prospective birth cohort conducted between 2011 and 2014. Total mercury levels and total selenium levels in maternal blood during the second and third trimesters were measured using Inductively Coupled Plasma-Mass Spectrometry. Birth weight and small-for-gestational-age were confirmed by medical records. Small-for-gestational-age was defined as birth weight below the 10th percentile according to standard percentile for gender, parity, and gestational age. Multiple linear and logistic regression analyses were used to examine the association between maternal mercury exposure and birth weight or small-for-gestational-age adjusted for confounders (including maternal age and body mass index pregnancy). RESULTS: Overall, 15,444 pregnant women were included in this study. Median (inter-quartile range) of blood mercury and selenium levels were 3.66 (2.59-5.18) ng/g and 170.0 (158.0-183.0) ng/g, respectively. Compared to infants of mothers with the highest blood selenium level, those of mothers with the lowest blood selenium level had neither a significant birth weight increase (9 g, 95% confidence interval: -6, 25) nor a significant odds ratio for small-for-gestational-age (0.903, 95% confidence interval: 0.748, 1.089). Compared to infants of mothers with the lowest blood mercury level, those of mothers with the highest blood mercury level had neither a significant birth weight reduction (-12 g, 95% confidence interval: -27, 4) nor a significant odds ratio for small-for-gestational-age (0.951, 95% confidence interval: 0.786, 1.150). Compared to infants of mothers with the lowest quartile of maternal blood mercury level, all infants of mothers with the highest quartile of maternal blood mercury level had a reduced birth head circumference of 0.073 cm (95% confidence interval: -0.134, -0.011). CONCLUSIONS: There was no association between maternal blood mercury levels and small-for-gestational-age and birth weight among 15,444 pregnant women. In a Japanese population, which has a relatively higher blood mercury level than reported in Western population, reduced birth size was not found to be associated with blood mercury levels, with the exception of birth head circumference.
• Association between maternal passive smoking and increased risk of delivering small-for-gestational-age infants at full-term using plasma cotinine levels from The Hokkaido Study: a prospective birth cohort.
  Sumitaka Kobayashi; Fumihiro Sata; Tomoyuki Hanaoka; Titilola Serifat Braimoh; Kumiko Ito; Naomi Tamura; Atsuko Araki; Sachiko Itoh; Chihiro Miyashita; Reiko Kishi
  BMJ open, 9, 2, e023200, 19 Feb. 2019, [International Magazine]
  English, Scientific journal, OBJECTIVES: To investigate the association between plasma cotinine level measured at the 8th gestational month and the delivery of small-for-gestational-age (SGA) infants, using a highly sensitive ELISA method. DESIGN: Prospective birth cohort study from The Hokkaido Study on Environment and Children's Health. SETTING: Hokkaido, Japan. PARTICIPANTS: Our sample included 15 198 mother-infant pairs enrolled in 2003-2012. MAIN OUTCOME MEASURES: SGA, defined as a gestational age-specific weight Z-score below -2. RESULTS: The number of SGA infants was 192 (1.3%). The cotinine cut-off level that differentiated SGA infants from other infants was 3.03 ng/mL for both the total population and the full-term births subgroup (sensitivity 0.307; positive predictive value 2.3%). Compared with infants of mothers with a plasma cotinine level of <3.03 ng/mL, infants of mothers with a plasma cotinine level of ≥3.03 ng/mL showed an increased OR for SGA in the total population and the full-term infant group (2.02(95% CI 1.45 to 2.83) and 2.44(95% CI 1.73 to 3.44), respectively). CONCLUSION: A plasma cotinine level of ≥3.03 ng/mL, which included both passive and active smokers, was associated with an increased risk of SGA. This finding is of important relevance when educating pregnant women about avoiding prenatal passive and active smoking due to the adverse effects on their infants, even those born at full-term.
• Effects of prenatal sex hormones on behavioral sexual dimorphism.
  Takahiko Mitsui; Atsuko Araki; Chihiro Miyashita; Sachiko Ito; Tamiko Ikeno; Seiko Sasaki; Takeya Kitta; Kimihiko Moriya; Kazutoshi Cho; Keita Morioka; Reiko Kishi; Nobuo Shinohara; Masayuki Takeda; Katsuya Nonomura
  Pediatrics international : official journal of the Japan Pediatric Society, 61, 2, 140, 146, Feb. 2019, [International Magazine]
  English, Scientific journal, BACKGROUND: We investigated the association between the hormone environment during the prenatal period using cord blood, and gender-role play behavior in school-aged children. METHODS: A total of 879 school-aged children (433 boys and 446 girls) in a prospective birth cohort study in Hokkaido were enrolled to analyze the relationship between cord blood level of the sex hormones estradiol (E), testosterone (T), progesterone (P), and dehydroepiandrosterone (DHEA), and the Pre-School Activities Inventory (PSAI) score. The PSAI evaluated sex-typical characteristics, the type of preferred toys and play activities. The PSAI consists of 12 masculine and 12 feminine items, and the composite scores were calculated by subtracting the feminine score from the masculine score. Higher scores indicated male-typical behavior. RESULTS: Composite and masculine PSAI scores were significantly higher in boys. Meanwhile, the feminine score was significantly lower in boys. Although T and P were significantly higher in boys, E/T was significantly higher in girls. In a multivariate regression model, including covariates of social factors, there was no correlation between any of the hormones and PSAI score in boys. In girls, only P and E/T were positively correlated with the feminine score. CONCLUSIONS: Prenatal sex hormone exposure may influence the dimorphic brain development and behavior in school-aged girls. Furthermore, the cord blood hormone levels may not fully reflect the hormone environment during the prenatal period.
• The relationship between prenatal psychological stress and placental abruption in Japan, The Japan Environment and Children's Study (JECS).
  Yasuyuki Kawanishi; Eiji Yoshioka; Yasuaki Saijo; Toshihiro Itoh; Toshinobu Miyamoto; Kazuo Sengoku; Yoshiya Ito; Sachiko Ito; Chihiro Miyashita; Atsuko Araki; Toshiaki Endo; Kazutoshi Cho; Hisanori Minakami; Reiko Kishi
  PloS one, 14, 7, e0219379, 2019, [International Magazine]
  English, Scientific journal, BACKGROUND: Prenatal psychological stress may increase the risk of placental abruption (PA). This study aimed to clarify the effects of psychological distress during pregnancy and exposure to stressful life events in the year before or during pregnancy on the occurrence of PA in Japanese women. METHODS: Using a nationwide prospective birth cohort study, we obtained data from 103,099 women between January 2011 and March 2014. Information on exposure to 14 stressful life events and psychological distress (Kessler 6 scale) was collected using a self-administered questionnaire during pregnancy. Clinical diagnoses of PA were obtained from medical records. A total of 80,799 women with singleton births were analyzed using logistic regression models that adjusted for possible confounders. RESULTS: PA was diagnosed in 335 (0.4%) women. There was no significant difference in the Kessler 6 score during pregnancy between the PA group and non-PA group. Exposure to the death of a child in the year before or during pregnancy was significantly associated with PA in multigravid women (adjusted odds ratio [aOR] 3.57; 95% confidence interval [CI] 1.50-8.34). A spouse's loss of employment was significantly associated with PA in parous women (aOR 3.25; 95% CI 1.40-7.56). CONCLUSIONS: This study identified the possible effects of exposure to the death of a child on PA occurrence that adjusted for important confounding factors.
• Association between ESR1 polymorphisms and second to fourth digit ratio in school-aged children in the Hokkaido Study.
  Yoko Nishimura; Kimihiko Moriya; Sumitaka Kobayashi; Atsuko Araki; Fumihiro Sata; Takahiko Mitsui; Sachiko Itoh; Chihiro Miyashita; Kazutoshi Cho; Masafumi Kon; Michiko Nakamura; Takeya Kitta; Sachiyo Murai; Reiko Kishi; Nobuo Shinohara
  Steroids, 141, 55, 62, Jan. 2019, [International Magazine]
  English, Scientific journal, The ratio of the lengths of the 2nd and 4th digits (2D:4D) is considered an index of prenatal exposure to androgen. Indeed, androgen receptors have been linked to digit length, but estrogen receptors are rarely investigated in this context. Thus, we investigated the association between estrogen receptor 1 (ESR1) genetic polymorphisms and 2D:4D in school-aged children. The 2D:4D ratios were determined using Vernier calipers from photocopies of palms provided by 1800 children aged 7 years who were enrolled in an ongoing prospective cohort study in Hokkaido, Japan. The children were genotyped using cord blood collected at birth for single nucleotide polymorphisms in ESR1, specifically PvuII (T > C, dbSNP: rs2234693), XbaI (A > G, dbSNP: rs9340799), and rs2077647 (A > G). The association between ESR1 polymorphisms and 2D:4D was assessed by multiple linear regression adjusted for potential cofounding factors. Boys with the GG genotype at rs9340799 had a significantly lower 2D:4D in the right hand than boys with the AA/AG genotype (-0.96% lower, 95% confidence interval: -1.68 to -0.24). However, this association was detected only in boys born to non-smoking mothers. No significant differences were found between rs9340799 polymorphisms and 2D:4D among girls. There was also no link between 2D:4D and polymorphisms at rs2234693 and rs2077647. These data suggest that rs9340799 polymorphisms in ESR1 may contribute to digit length and 2D:4D.
• Association between prenatal exposure to organochlorine pesticides and the mental and psychomotor development of infants at ages 6 and 18 months: The Hokkaido Study on Environment and Children's Health.
  Keiko Yamazaki; Atsuko Araki; Sonomi Nakajima; Chihiro Miyashita; Tamiko Ikeno; Sachiko Itoh; Machiko Minatoya; Sumitaka Kobayashi; Futoshi Mizutani; Yoichi Chisaki; Reiko Kishi
  Neurotoxicology, 69, 201, 208, Dec. 2018, [International Magazine]
  English, Scientific journal, Organochlorine pesticides (OCPs) are environmental contaminants that persist in the environment and bioaccumulate through the food chain in humans and animals. Although previous studies have shown an association between prenatal OCP exposure and subsequent neurodevelopment, the levels of OCPs included in these studies were inconsistent. A hospital-based prospective birth cohort study was conducted to examine the associations between prenatal exposure to relatively low levels of OCPs and neurodevelopment in infants at 6 (n=164) and 18 (n=115)months of age. Blood samples were analyzed using gas chromatography/mass spectrometry techniques to quantify 29 OCPs. The Bayley Scales of Infant Development 2nd edition (BSID-II) was used to assess the Mental and Psychomotor Developmental Index. After controlling for confounders, we found an inverse association between prenatal exposure to cis-heptachlor epoxide and the Mental Developmental Index at 18 months of age. Furthermore, infants born to mothers with prenatal concentrations of cis-heptachlor epoxide in the highest quartile had Mental Developmental Index scores -9.8 (95% confidence interval: -16.4, -3.1) lower than that recorded for infants born to mothers with concentrations of cis-heptachlor epoxide in the first quartile (p for trend <0.01). These results support the hypothesis that prenatal exposure to OCPs, especially cis-heptachlor epoxide, may have an adverse effect on the neurodevelopment of infants at specific ages, even at low levels.
• Association of maternal serum concentration of hydroxylated polychlorinated biphenyls with maternal and neonatal thyroid hormones: The Hokkaido birth cohort study.
  Sachiko Itoh; Toshiaki Baba; Motoyuki Yuasa; Chihiro Miyashita; Sumitaka Kobayashi; Atsuko Araki; Seiko Sasaki; Jumboku Kajiwara; Tsuguhide Hori; Takashi Todaka; Kaori Fujikura; Sonomi Nakajima; Shizue Kato; Reiko Kishi
  Environmental research, 167, 583, 590, Nov. 2018, [International Magazine]
  English, Scientific journal, BACKGROUND: Evidence on the toxicity of hydroxylated metabolites of polychlorinated biphenyls (OH-PCBs) for thyroid hormones (TH) is limited, and the underlying mechanism remains unknown. OBJECTIVES: We aimed to investigate the effects of environmental prenatal exposure to OH-PCBs and maternal and neonatal TH levels, taking the maternal-fetal TH transfer into account. METHODS: In this prospective birth cohort (the "Hokkaido study") we included 222 mother-neonate pairs. We measured five OH-PCB isomers in maternal serum samples either during pregnancy or within 5 days of delivery. Thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from maternal blood samples at an early gestational stage (median; 11.1 weeks) and from heel prick samples of neonates between 4 and 7 days after birth. Multiple linear regression analysis and structural equation modeling (SEM) were performed to investigate the associations between maternal OH-PCB and maternal and neonatal TH levels. RESULTS: Median concentration of ∑OH-PCBs was 25.37 pg/g wet weight. The predominant isomer was 4-OH-CB187, followed by 4-OH-CB146+3-OH-CB153. In the fully adjusted linear regression analysis, maternal ∑OH-PCBs was positively associated with maternal FT4, and 4-OH-CB187 was positively associated with both maternal and neonatal FT4 levels. Maternal OH-PCBs showed no significant association with TSH among mothers and neonates. Path analysis indicated the indirect pathway from 4-OH-CB187 exposure to increased neonatal FT4, via maternal THs and neonatal TSH. CONCLUSIONS: These findings suggest that maternal exposure to OH-PCBs during pregnancy may increase both maternal and neonatal FT4 levels. Neonatal FT4 is presumed to be increased by prenatal 4-OH-CB187 indirectly, and this process may be mediated by maternal THs and neonatal TSH.
• Contrasting associations of maternal smoking and pre-pregnancy BMI with wheeze and eczema in children.
  Houman Goudarzi; Satoshi Konno; Hirokazu Kimura; Atsuko Araki; Chihiro Miyashita; Sachiko Itoh; Yu Ait Bamai; Hiroki Kimura; Kaoruko Shimizu; Masaru Suzuki; Yoichi M Ito; Masaharu Nishimura; Reiko Kishi
  The Science of the total environment, 639, 1601, 1609, 15 Oct. 2018, [International Magazine]
  English, Scientific journal, BACKGROUND: Childhood allergies are dynamic and associated with environmental factors. The influence of prenatal maternal smoking and obesity on childhood allergies and their comorbidities remains unclear, especially in prospective cohorts with serial longitudinal observations. OBJECTIVE: We examined time trends in the prevalence and comorbidity of childhood allergies, including wheeze, eczema, and rhinoconjunctivitis, using a large-scale, population-based birth cohort in Japan, and assessed the effects of prenatal maternal smoking and BMI on the risk of childhood allergies. METHODS: Parents completed the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaires about symptoms of allergies and their risk factors at age 1, 2, 4, and 7 years. Complete data from all pre- and postnatal questionnaires at age 1, 2, 4, and 7 were available for 3296 mother-child pairs. RESULTS: We observed significant overlap of childhood allergies at 1, 2, 4, and 7 years. Maternal serum cotinine during pregnancy was associated with increased risk of wheezing in the children at age 1, 2, and 4 but disappeared at age 7. In contrast, maternal cotinine levels were inversely associated with the prevalence of eczema in children at age 7. We additionally observed that maternal pre-pregnancy BMI, not children's BMI, had a positive association with wheeze and an inverse association with eczema in 7-year-old children, respectively. We did not find any association of examined maternal factors and rhinoconjunctivitis. CONCLUSIONS: We demonstrated contrasting association of prenatal maternal smoking and high BMI with postnatal wheeze and eczema. For precise assessment of allergy-associated risk factors, we need to contrast risk factors for different allergic diseases since focusing solely on one allergic disease may result in misleading information on the role of different risk factors.
• Prenatal exposure to bisphenol A and phthalates and behavioral problems in children at preschool age: the Hokkaido Study on Environment and Children's Health.
  Machiko Minatoya; Sachiko Itoh; Keiko Yamazaki; Atsuko Araki; Chihiro Miyashita; Naomi Tamura; Jun Yamamoto; Yu Onoda; Kazuki Ogasawara; Toru Matsumura; Reiko Kishi
  Environmental health and preventive medicine, 23, 1, 43, 43, 07 Sep. 2018, [International Magazine]
  English, Scientific journal, BACKGROUND: Studies reported adverse behavioral development including internalizing and externalizing problems in association with prenatal exposure to bisphenol A (BPA) and phthalates; however, findings were not sufficient due to using different assessment tools and child ages among studies. This study aimed to examine associations between maternal serum levels of BPA and phthalate metabolites and behavioral problems at preschool age. METHODS: The Strengths and Difficulties Questionnaire (SDQ) was used to assess behavioral problems at 5 years of age. BPA and phthalate metabolite levels in the first trimester maternal serum was determined by LC-MS/MS for 458 children. Variables used for adjustment were parental ages, maternal cotinine levels, family income during pregnancy, child sex, birth order, and age at SDQ completed. RESULTS: The median concentrations of BPA, MnBP, MiBP, MEHP, and MECPP, primary and secondary metabolites of phthalates, were 0.062, 26.0, 7.0, 1.40, and 0.20 ng/ml, respectively. MECPP level was associated with increase conduct problem risk (OR = 2.78, 95% CI 1.36-5.68) overall and the association remained after child sex stratification, and odds ratios were increased with wider confidence interval (OR = 2.85, 95% CI 1.07-7.57 for boys, OR = 4.04, 95% CI 1.31-12.5 for girls, respectively). BPA, ∑DBPm (MnBP + MiBP), and ∑DEHPm (MEHP+MECPP) levels were not associated with any of the child behavioral problems. CONCLUSIONS: Our analyses found no significant association between BPA or summation of phthalate metabolite levels and any of the behavioral problems at 5 years of age but suggested possible association between MECPP levels and increased risk of conduct problems.
• Sex-related differences in the associations between maternal dioxin-like compounds and reproductive and steroid hormones in cord blood: The Hokkaido study.
  Chihiro Miyashita; Atsuko Araki; Takahiko Mitsui; Sachiko Itoh; Houman Goudarzi; Seiko Sasaki; Jumboku Kajiwara; Tsuguhide Hori; Kazutoshi Cho; Kimihiko Moriya; Nobuo Shinohara; Katsuya Nonomura; Reiko Kishi
  Environment international, 117, 175, 185, Aug. 2018, [International Magazine]
  English, Scientific journal, BACKGROUND: Prenatal exposure to dioxin-like compounds (DLCs) irreversibly affects fetal reproductive and steroid hormone synthesis. OBJECTIVE: This study aimed to assess the relationships between maternal DLCs and cord blood reproductive and steroid hormones. METHODS: Participants in this study were pregnant women who enrolled in the Sapporo Cohort of the Hokkaido Study between 2002 and 2005. We quantified 29 DLCs during the 2nd and 3rd trimesters in maternal blood. Additionally, we measured the concentrations of progesterone, estradiol (E2), testosterone (T), androstenedione, dehydroepiandrosterone (DHEA), cortisol, cortisone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin, inhibin B, and insulin-like factor-3 (INSL3) in cord blood samples. RESULTS: Data from 183 mother-child pairs were analyzed. We observed sex-dependent associations of DLCs on T/E2 ratios, DHEA, cortisol, cortisone, adrenal androgen/glucocorticoid (AA/GC: sum of DHEA and androstenedione)/(sum of cortisol and cortisone) ratios and SHBG. An increase in maternal DLCs related to decreased T/E2 ratios and SHBG and inhibin B levels, and increased AA/GC ratios and FSH and DHEA levels in male cord blood samples. However, an increase in maternal mono-ortho polychlorinated biphenyls related to increased cortisol, cortisone, and SHBG levels, and decreased DHEA levels and AA/GC ratios in female cord blood samples. CONCLUSIONS: Prenatal exposure to DLCs alters steroidogenesis and suppresses the secretion of inhibin B in male cord blood. Relationships between maternal DLCs and cord blood hormones differ between boys and girls. Further studies are required to clarify whether the effects of in utero exposure to DLCs on adrenal hormones extend into infancy and puberty.
• Relationship between adrenal steroid hormones in cord blood and birth weight: The Sapporo Cohort, Hokkaido Study on Environment and Children's Health.
  Takahiko Mitsui; Atsuko Araki; Houman Goudarzi; Chihiro Miyashita; Sachiko Ito; Seiko Sasaki; Takeya Kitta; Kimihiko Moriya; Kazutoshi Cho; Keita Morioka; Reiko Kishi; Nobuo Shinohara; Masayuki Takeda; Katsuya Nonomura
  American journal of human biology : the official journal of the Human Biology Council, 30, 4, e23127, Jul. 2018, [International Magazine]
  English, Scientific journal, OBJECTIVES: We investigated the relationship between steroid hormone levels in cord blood and birth weight. METHODS: Among 514 participants in a prospective birth cohort study in Sapporo, the following hormone levels were measured in 294 stored cord blood samples from 135 males and 159 females: androstenedione, dehydroepiandrosterone (DHEA), cortisol, and cortisone. Birth weight information was obtained from medical records. RESULTS: Androstenedione/DHEA was significantly higher in males than in females, while DHEA was significantly higher in females. Birth weight was significantly higher in males than in females. Regarding cortisone, androstenedione/DHEA, and cortisone/cortisol, a correlation was observed with birth weight in males but not in females. CONCLUSIONS: Prenatal adrenal steroids as well as converting enzymes such as 11ß-hydrosteroid dehydrogenase type 2 and 3ß-hydrosteroid dehydrogenase may have an impact on prenatal physical development.
• Determinants and Temporal Trends of Perfluoroalkyl Substances in Pregnant Women: The Hokkaido Study on Environment and Children's Health.
  Meng-Shan Tsai; Chihiro Miyashita; Atsuko Araki; Sachiko Itoh; Yu Ait Bamai; Houman Goudarzi; Emiko Okada; Ikuko Kashino; Hideyuki Matsuura; Reiko Kishi
  International journal of environmental research and public health, 15, 5, 14 May 2018, [International Magazine]
  English, Scientific journal, Perfluoroalkyl substances (PFAS) are persistent bio-accumulative chemicals that impact the health of pregnant women and their children. PFAS derive from environmental and consumer products, which depend on human lifestyle, socioeconomic characteristics, and time variation. Here, we aimed to explore the temporal trends of PFAS in pregnant women and the characteristics related to maternal PFAS concentration. Our study is part of the Hokkaido Study on Environment and Children's Health, the Hokkaido large-scale cohort that recruited pregnant women between 2003 and 2011. Blood samples were acquired from pregnant women during the third trimester to measure PFAS and cotinine concentrations. Maternal basic information was collected with a baseline structured questionnaire. Eleven PFAS were measured from 2123 samples with ultra-performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry. Eight PFAS were above 80% detection rate and were included in the final analysis. We used multivariable linear regression to analyze the association of pregnant women characteristics with the levels of eight PFAS. The temporal trend of PFAS was observed in two periods (August 2003 to January 2006 and February 2006 to July 2012). The concentration of perfluorooctane sulfonate (PFOS) significantly decreased from August 2003 to January 2006 and from February 2006 to July 2012. The concentrations of perfluorododecanoic acid (PFDoDA), perfluoroundecanoic acid (PFUnDA), and perfluorotridecanoic acid (PFTrDA) increased significantly between August 2003 and January 2006, whereas they decreased significantly between February 2006 and July 2012. Women with pre-pregnancy body mass index (BMI) >25 kg/m² had lower PFUnDA, PFDoDA, and PFTrDA levels than did those with normal BMI (18.5⁻24.9 kg/m²). Pregnant women, who were active smokers (cotinine > 11.49 ng/mL), had higher PFOS than the non-smokers (cotinine < 0.22 ng/mL). Lower levels of PFHxS, PFOS, PFOA, PFNA, and PFDA were observed in women, who had given birth to more than one child. There were also significant positive associations between PFAS levels and annual income or maternal education. PFAS levels varied in women with higher pre-pregnancy BMI, active smoking status, higher education level and annual income. The causes of the individual PFAS differences should be explored in an independent study.
• Prevalence and Risk of Birth Defects Observed in a Prospective Cohort Study: The Hokkaido Study on Environment and Children's Health.
  Tomoyuki Hanaoka; Naomi Tamura; Kumiko Ito; Seiko Sasaki; Atsuko Araki; Tamiko Ikeno; Chihiro Miyashita; Sachiko Ito; Hisanori Minakami; Kazutoshi Cho; Toshiaki Endo; Tsuyoshi Baba; Toshinobu Miyamoto; Kazuo Sengoku; Reiko Kishi
  Journal of epidemiology, 28, 3, 125, 132, 05 Mar. 2018, [Domestic magazines]
  English, Scientific journal, BACKGROUND: Prevalence rates of all anomalies classified as birth defects, including those identified before the 22nd gestational week, are limited in published reports, including those from the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). In our birth cohort study, we collected the data for all birth defects after 12 weeks of gestation. METHODS: Subjects in this study comprised 19,244 pregnant women who visited one of 37 associated hospitals in the Hokkaido Prefecture from 2003 through 2012, and completed follow-up. All birth defects after 12 weeks of gestation, including 55 marker anomalies associated with environmental chemical exposures, were recorded. We examined parental risk factors for birth defects and the association between birth defects and risk of growth retardation. RESULTS: Prevalence of all birth defects was 18.9/1,000 births. The proportion of patients with birth defects delivered between 12 and 21 weeks of gestation was approximately one-tenth of all patients with birth defects. Among those with congenital malformation of the nerve system, 39% were delivered before 22 weeks of gestation. All patients with anencephaly and encephalocele were delivered before 22 weeks of gestation. We observed different patterns of parental risk factors between birth defect cases included in ISBDSR and cases not included. Cases included in ISBDSR were associated with an increased risk of preterm birth. Cases not included in ISBDSR were associated with an increased risk of being small for gestational age at term. CONCLUSIONS: Data from our study complemented the data from ICBDSR. We recommend that birth defects not included in ICBDSR also be analyzed to elucidate the etiology of birth defects.
• Different Risk Factors for Very Low Birth Weight, Term-Small-for-Gestational-Age, or Preterm Birth in Japan.
  Naomi Tamura; Tomoyuki Hanaoka; Kumiko Ito; Atsuko Araki; Chihiro Miyashita; Sachiko Ito; Hisanori Minakami; Kazutoshi Cho; Toshiaki Endo; Kazuo Sengoku; Katsuhiko Ogasawara; Reiko Kishi
  International journal of environmental research and public health, 15, 2, 21 Feb. 2018, [International Magazine]
  English, Scientific journal, From 1985 to 2013, the mean birth weight of infants in Japan decreased from 3120 g to 3000 g, and the low-birth-weight rate among live births increased from 6.3% to 9.6%. No prospective study has elucidated the risk factors for poor fetal growth and preterm birth in recent Japanese parents, such as increased parental age, maternal body figure, assisted reproductive technology (ART), and socioeconomic status. Participants were mother-infant pairs (n = 18,059) enrolled in a prospective birth cohort in Hokkaido, Japan from 2002 to 2013. Parental characteristics were obtained via self-reported questionnaires during pregnancy. Medical records helped identify very-low-birth-weight (VLBW; <1500g), term-small-for-gestational-age (term-SGA), and preterm-birth (PTB; <37 weeks) infants. We calculated relative risks (RRs) for PTB, VLBW, and term-SGA birth based on parental characteristics. The prevalence of PTB, VLBW, and term-SGA was 4.5%, 0.4%, and 6.5%, respectively. Aged parents and ART were risk factors for PTB and VLBW. Maternal alcohol drinking during pregnancy increased the risk; a parental educational level of ≥16 years reduced risk of term-SGA. Maternal pre-pregnancy BMI of <18.5 kg/m² increased the risk of PTB and term-SGA. The RR for low BMI was highest among mothers who have low educational level. Among various factors, appropriate nutritional education to maintain normal BMI is important to prevent PTB and term-SGA in Japan.
• Association of prenatal exposure to PCDD/Fs and PCBs with maternal and infant thyroid hormones: The Hokkaido Study on Environment and Children's Health.
  Toshiaki Baba; Sachiko Ito; Motoyuki Yuasa; Eiji Yoshioka; Chihiro Miyashita; Atsuko Araki; Seiko Sasaki; Sumitaka Kobayashi; Jumboku Kajiwara; Tsuguhide Hori; Shizue Kato; Reiko Kishi
  The Science of the total environment, 615, 1239, 1246, 15 Feb. 2018, [International Magazine]
  English, Scientific journal, Polychlorinated dibenzo-p-dioxins (PCDDs), dibenzofurans (PCDFs) and biphenyls (PCBs) are persistent organic pollutants that are universally detected. Some congeners of PCDDs, PCDFs or PCBs have dioxin-like toxicity, whereas non-dioxin-like PCBs are considered to have different toxicity. Reports of the relationships between prenatal exposure to PCDDs, PCDFs or PCBs and thyroid homeostasis in pregnant women and infants have been inconsistent. The aim of this study was to investigate the effect of maternal serum PCDD/F or PCB levels on maternal and neonatal thyroid hormone (TH) levels in a prospective cohort. Of the 514 subjects in the prospective cohort, 386 mothers and 410 infants were included for analysis. Fifteen dioxins and seventy PCBs in maternal blood collected between 23 and 41weeks of gestation were measured using high-resolution gas chromatography and high-resolution mass spectrometry. Blood samples to measure thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from mothers at an early gestational stage (median ten weeks), and from infants between four and seven days of age, respectively. Multiple linear regression analysis was conducted. Median concentration of total PCBs, PCB 153 were 104,700, and 20,500pg/g lipid, respectively. Median total dioxin-TEQ was 13.8pg/g lipid. Total dioxin-TEQ, coplanar PCBs were positively associated with neonatal FT4 (beta=0.224, 0.206, respectively). The association was stronger in boys (beta=0.299, 0.282, respectively). Several PCDD/F and PCB isomers were also positively associated with neonatal FT4. Total PCBs or non-dioxin-like PCBs were not associated with any maternal or neonatal THs. No DLC grouping or congeners were associated with neonatal TSH. Non-ortho PCBs were positively associated with maternal FT4. Three PCB congeners had significant positive association(s) with maternal THs. In conclusion, the results of our study suggest that perinatal exposure to background-level DLCs increases neonatal FT4, especially in boys.
• Birth cohorts in Asia: The importance, advantages, and disadvantages of different-sized cohorts.
  Reiko Kishi; Atsuko Araki; Machiko Minatoya; Sachiko Itoh; Houman Goudarzi; Chihiro Miyashita
  The Science of the total environment, 615, 1143, 1154, 15 Feb. 2018, [International Magazine]
  English, Scientific journal, Asia contains half of the world's children, and the countries of Asia are the most rapidly industrializing nations on the globe. Environmental threats to the health of children in Asia are myriad. Several birth cohorts were started in Asia in early 2000, and currently more than 30 cohorts in 13 countries have been established for study. Cohorts can contain from approximately 100-200 to 20,000-30,000 participants. Furthermore, national cohorts targeting over 100,000 participants have been launched in Japan and Korea. The aim of this manuscript is to discuss the importance of Asian cohorts, and the advantages and disadvantages of different-sized cohorts. As for case, one small-sized (n=514) cohort indicate that even relatively low level exposure to dioxin in utero could alter birth size, neurodevelopment, and immune and hormonal functions. Several Asian cohorts focus prenatal exposure to perfluoroalkyo substances and reported associations with birth size, thyroid hormone levels, allergies and neurodevelopment. Inconsistent findings may possibly be explained by the differences in exposure levels and target chemicals, and by possible statistical errors. In a smaller cohort, novel hypotheses or preliminary examinations are more easily verifiable. In larger cohorts, the etiology of rare diseases, such as birth defects, can be analyzed; however, they require a large cost and significant human resources. Therefore, conducting studies in only one large cohort may not always be the best strategy. International collaborations, such as the Birth Cohort Consortium of Asia, would cover the inherent limitation of sample size in addition to heterogeneity of exposure, ethnicity, and socioeconomic conditions.
• Association between prenatal bisphenol A and phthalate exposures and fetal metabolic related biomarkers: The Hokkaido study on Environment and Children's Health.
  Machiko Minatoya; Atsuko Araki; Chihiro Miyashita; Yu Ait Bamai; Sachiko Itoh; Jun Yamamoto; Yu Onoda; Kazuki Ogasawara; Toru Matsumura; Reiko Kishi
  Environmental research, 161, 505, 511, Feb. 2018, [International Magazine]
  English, Scientific journal, Bisphenol A and phthalates are widely detected in human urine, blood, breast milk, and amniotic fluid. Both bisphenol A and phthalates have been suggested as playing a role in obesity epidemics. Exposure to these chemicals during fetal development, and its consequences should be concerning because they can cross the placenta. Thus, this study aimed to assess the association between prenatal exposure to bisphenol A and phthalates, and cord blood metabolic-related biomarkers. Maternal serum was used during the first trimester, to determine prenatal exposure to bisphenol A and phthalates. Levels of metabolic-related biomarkers in the cord blood were also determined. Linear regression models were applied to the 365 participants with both, exposure and biomarker assessments, adjusted for maternal age, pre-pregnancy body mass index, parity, education, and sex of the child. The level of bisphenol A was negatively associated with the leptin level (β = -0.06, 95% confidence interval [CI]: -0.11, -0.01), but was positively associated with the high-molecular-weight adiponectin level, with marginal significance (β = 0.03, 95%CI: 0.00, 0.06). The mono-isobutyl phthalate (MiBP), mono-n-butyl phthalate (MnBP), mono-(2-ethylhexyl) phthalate (MEHP), and summation of MEHP and MECPP to represent DEHP exposure (∑DEHPm) levels were inversely associated with the leptin levels (β=-0.14, 95%CI: -0.27, -0.01; β = -0.12, 95%CI: -0.24, 0.00 with marginal significance; β=0.08, 95%CI: -0.14, -0.03; and β = -0.09, 95%CI: -0.16, -0.03, respectively). The present study provided some evidence that prenatal exposure to bisphenol A and certain phthalates may modify fetal adiponectin and leptin levels.
• Association between Fetal Adipokines and Child Behavioral Problems at Preschool Age: The Hokkaido Study on Environment and Children's Health.
  Machiko Minatoya; Sachiko Itoh; Atsuko Araki; Naomi Tamura; Keiko Yamazaki; Chihiro Miyashita; Reiko Kishi
  International journal of environmental research and public health, 15, 1, 11 Jan. 2018, [International Magazine]
  English, Scientific journal, Studies have suggested associations between maternal obesity and mental health problems of their children. However, the underlying mechanism is largely unknown. A possible mechanism can be via inflammatory states and the other possible mechanism is metabolic hormone-induced programming. Cross-talk between adipokines, including inflammatory cytokines and metabolic hormones secreted from adipose tissue and the central nervous system needs to be further investigated to elucidate the mechanism. Thus, the aim of this study was to investigate the association between fetal adipokine levels and child behavioral problems at preschool age. Cord blood adiponectin, leptin, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels were measured and child behavioral problems were assessed using the Strengths and Difficulties Questionnaire at preschool age. Logistic regression models adjusted by related maternal factors were performed to examine the association between cord blood adipokines and child behavioral problems. Three hundred and sixty-one children were included in the final analysis. A significant association between decreased hyperactivity/inattention and increased leptin was found (OR = 0.22, 95% CI: 0.06-0.89). Cord blood adiponectin, TNF-α and IL-6 levels were not associated with child behavioral problems. Our findings suggested that cord blood adipokines, particularly, leptin level, may be a predictor of hyperactivity/inattention problems at preschool age.
• Prenatal exposure to dioxin-like compounds is associated with decreased cord blood IgE and increased risk of wheezing in children aged up to 7years: The Hokkaido study.
  Chihiro Miyashita; Yu Ait Bamai; Atsuko Araki; Sachiko Itoh; Machiko Minatoya; Sumitaka Kobayashi; Jumboku Kajiwara; Tsuguhide Hori; Reiko Kishi
  The Science of the total environment, 610-611, 191, 199, 01 Jan. 2018, [International Magazine]
  English, Scientific journal, INTRODUCTION: In utero exposure to dioxin-like compounds (DLCs) may cause imbalance of immune development in early infancy. However, there are few epidemiological studies into the effects of in utero exposure to DLCs on allergies and infections during childhood. This study evaluates associations between concentrations of maternal DLCs and cord blood immunoglobulin (Ig) E, as well as allergies and infections during childhood. METHOD: We recruited 514 pregnant women in a maternity hospital in Sapporo, Japan, and measured concentrations of DLCs in 426 maternal blood samples using high-resolution gas chromatography/high-resolution mass spectrometry. We examined the relationship between concentrations of maternal DLCs and cord blood IgE at birth (n=239), as well as for allergies and infections in children at 3.5 (n=327) and 7 (n=264) years, using regression analysis adjusted for confounding variables. RESULTS: We found a positive association between maternal DLC concentrations and frequency of wheezing in children aged up to 7years [odds ratio (OR); 7.81 (95% confidence interval (CI), 1.42 to 42.9)]. At 3.5years, boys showed inverse associations between maternal DLC concentrations and cord blood IgE [partial regression coefficient; -0.87 (95% CI), -1.68 to -0.06], and frequency of wheezing [OR; 0.03 (95% CI), 0.00 to 0.94] but girls did not. DISCUSSION: As one reason for the significant association observed at 7 but absent at 3.5years, we suggest that allergic symptoms are more obvious in older children due to matured immune function. CONCLUSION: The findings suggest that prenatal exposure to DLCs may modify offspring immune responses and result in increased risk of allergy among children of school age.
• Prenatal organochlorine pesticide exposure and the disruption of steroids and reproductive hormones in cord blood: The Hokkaido study.
  Atsuko Araki; Chihiro Miyashita; Takahiko Mitsui; Houman Goudarzi; Futoshi Mizutani; Youichi Chisaki; Sachiko Itoh; Seiko Sasaki; Kazutoshi Cho; Kimihiko Moriya; Nobuo Shinohara; Katsuya Nonomura; Reiko Kishi
  Environment international, 110, 1, 13, Jan. 2018, [International Magazine]
  English, Scientific journal, Certain organochlorine pesticides (OCPs) are designated as persistent organic pollutants and are regulated in many countries. The effects of OCPs on pediatric endocrinology are a concern; however, only limited data exist from human studies on maternal OCP exposure and its effects on infants' hormone levels. This study was conducted as part of the Hokkaido Study Sapporo Cohort, a prospective birth cohort study in Japan. Participants included 514 women who enrolled at 23-35weeks of gestation between 2002 and 2005; maternal blood samples were collected in late pregnancy, and 29 OCPs were measured. Reproductive and steroid hormone levels in cord blood were also determined. Characteristics of mothers and their infants were obtained from self-administered questionnaires and medical records. Ultimately, 232 samples with both OCP and hormone data were analyzed. Fifteen of 29 investigated OCPs were detected in over 80% of the samples, with p,p'-dichlorodiphenyldichloroethylene showing the highest concentration (median value: 619pg/g-wet). The association between OCPs and sex hormone levels varied by sex. Linear regression models after sex stratification showed that chlordanes, cis-hexachlorobenzene, heptachlor epoxide, Mirex, and toxaphenes in maternal blood were inversely associated with testosterone, cortisol, cortisone, sex hormone-binding globin, prolactin, and androstenedione-dehydroepiandrosterone (DHEA) and testosterone-androstenediones ratios among boys. Furthermore, these OCPs were positively correlated with DHEA, follicle stimulating hormone (FSH), and adrenal androgen-glucocorticoid and FSH-inhibin B ratios among boys. In categorical quartile models, testosterone and DHEA were inversely and positively associated with OCPs, respectively. Estradiol-testosterone and adrenal androgen-glucocorticoid ratios tended to increase with increasing OCP concentrations in the higher quartile, while the testosterone-androstenedione ratio tended to decrease. Sex hormone-binding globulin and prolactin showed an inverse association with OCPs. Among girls, the linear regression model showed that only p,p'-dichlorodiphenyltrichloroethane was inversely associated with the level of DHEA and the adrenal androgen-glucocorticoid ratio, but was positively associated with cortisone levels. However, no associations were observed using the quartile categorical model. These results suggest that prenatal exposure to OCPs disrupt reproductive hormones of fetuses in utero among boys, even at relatively low levels.
• [Importance of Two Birth Cohorts (n=20,926 and n=514): 15 Years' Experience of the Hokkaido Study on Environment and Children's Health: Malformation, Development and Allergy].
  Reiko Kishi; Atsuko Araki; Chihiro Miyashita; Sachiko Itoh; Machiko Minatoya; Sumitaka Kobayashi; Keiko Yamazaki; Yu Ait Bamai; Ryu Miura; Naomi Tamura
  Nihon eiseigaku zasshi. Japanese journal of hygiene, 73, 2, 164, 177, 2018, [Domestic magazines]
  Japanese, Scientific journal, Since "Our Stolen Future" by Theo Colborn was published in 1996, global interest on the impact of chemical substances, such as the endocrine-disrupting action of chemicals, has increased. In Japan, "The Hokkaido Study on Environment and Children's Health: Malformation, Development and Allergy" was launched in 2001. It was a model of Japan Environment and Children's Study of the Ministry of the Environment. In a large-scale, Hokkaido cohort, we obtained the consent of 20,926 mothers at the organogenesis stage with the cooperation of 37 obstetrics clinics in Hokkaido. We tracked the effects of endocrine disruptors on developmental disorders. In a small-scale Sapporo cohort, we observed in detail the neuropsychiatric development of children with the consent of 514 mothers in their late pregnancy. We examined how prenatal exposure to low concentrations of environmental chemicals affect the development of organs and the postnatal development of children. Maternal exposure to POPs, such as PCB/dioxins and perfluorinated alkyl substances, has affected not only children's birth size, thyroid functions, and sex hormone levels, but also postnatal neurodevelopment, infection, and allergy among others. The associations of short-half-life substances, such as DEHP and BPA, with obesity, ASD, and ADHD have been investigated. Gene-environment interactions have been found for smoking, caffeine, folic acid, and PCB/dioxin. In 2015, our center was officially designated as the WHO Collaborating Centre for Environmental Health and Prevention of Chemical Hazards, and we continue to the contribute to the global perspectives of child health.
• [Environmental Chemical Exposure and Its Effects on Infants' Reproductive Hormones].
  Atsuko Araki; Sachiko Itoh; Chihiro Miyashita; Machiko Minatoya; Reiko Kishi
  Nihon eiseigaku zasshi. Japanese journal of hygiene, 73, 3, 313, 321, 2018, [Domestic magazines]
  Japanese, Scientific journal, In recent years, the birthrate has been continuously declining in Japan. The main causes of the decline are social factors. On the other hand, there is increasing evidence that many environmental chemicals show endocrine disrupting properties. Thus, we hypothesized that exposure to these chemicals would also be a causal for the fertility crisis. In this review, we examined current evidence that focused on environmental chemical exposure in utero and its association with reproductive hormones in children. We have included the findings from a prospective birth cohorts, the Hokkaido Study on Environment and Children's Health Sapporo cohort. According to the literature, environmental chemical levels in utero, such as polychlorinated biphenyl, dioxins, perfluorinated chemical substances, phthalates, and bisphenol A were somewhat associated with the levels of reproductive hormones, such as testosterone, estradiol, progesterone, inhibin B, and insulin-like factor-3 in cord blood, in early childhood and adolescence. The literature also suggests the association between exposure to these chemicals and brain-sexual differentiation or the anogenital distance, which suggests the disruption of androgen shower during the developmental stage in the fetal period. There are still knowledge gaps on whether these hormones at an early stage affect the pubertal development and reproductive functions in later life. In addition, alternative chemicals are produced after banning one type. The health effects of alternative chemicals should be evaluated. Effects of exposure to a mixture of the chemicals should also be examined in future studies. In conclusion, the prevention of environmental chemical hazards in relation to human reproductive function is important. It would be one of the countermeasures to the falling birthrate caused by fertility issues.
• Cord Blood Bisphenol A Levels and Reproductive and Thyroid Hormone Levels of Neonates: The Hokkaido Study on Environment and Children's Health.
  Machiko Minatoya; Seiko Sasaki; Atsuko Araki; Chihiro Miyashita; Sachiko Itoh; Jun Yamamoto; Toru Matsumura; Takahiko Mitsui; Kimihiko Moriya; Kazutoshi Cho; Keita Morioka; Hisanori Minakami; Nobuo Shinohara; Reiko Kishi
  Epidemiology (Cambridge, Mass.), 28 Suppl 1, S3-S9, Oct. 2017, [International Magazine]
  English, Scientific journal, BACKGROUND: Bisphenol A (BPA) is widely used and BPA exposure is nearly ubiquitous in developed countries. While animal studies have indicated adverse health effects of prenatal BPA exposure including reproductive dysfunction and thyroid function disruption possibly in a sex-specific manner, findings from epidemiologic studies have not been enough to prove these adverse effects. Given very limited research on human, the aim of this study was to investigate associations between cord blood BPA levels and reproductive and thyroid hormone levels of neonates and whether associations differed by neonate sex. METHODS: The study population included 514 participants of the Hokkaido study recruited from 2002 to 2005 at one hospital in Sapporo, Japan. The BPA level in cord blood was determined by ID-LC/MS/MS, and the limit of quantification was 0.040 ng/ml. We measured nine types of reproductive hormone levels in cord blood, and thyroid hormone levels were obtained from neonate mass screening test data. There were 283 subjects, who had both BPA and hormone levels measurements, included for the final analyses. RESULTS: The geometric mean of cord blood BPA was 0.051 ng/ml. After adjustment, BPA level was negatively associated with prolactin (PRL) (β = -0.38). There was an interaction between infant sex and BPA levels on PRL; a weak negative association was found in boys (β = -0.12), whereas a weak positive association was found in girls (β = 0.14). BPA level showed weak positive association with testosterone, estradiol, and progesterone levels in boys. No association was found between BPA and thyroid hormone levels. CONCLUSIONS: Our findings suggested that fetal BPA levels might be associated with changes in certain reproductive hormone levels of neonates in a sex-specific manner, though further investigations are necessary.
• Prenatal exposure to perfluoroalkyl acids and prevalence of infectious diseases up to 4years of age.
  Houman Goudarzi; Chihiro Miyashita; Emiko Okada; Ikuko Kashino; Chi-Jen Chen; Sachiko Ito; Atsuko Araki; Sumitaka Kobayashi; Hideyuki Matsuura; Reiko Kishi
  Environment international, 104, 132, 138, Jul. 2017, [International Magazine]
  English, Scientific journal, Perfluoroalkyl acids (PFAAs) are synthetic chemicals with ability to repel oils and water, and have been widely used in many industrial and household applications such as adhesives and water- and stain-repellent surfaces to nonstick coatings. Animal studies have shown that PFAAs have immunotoxic effects. However, few epidemiological studies have investigated the effects of PFAAs on infectious diseases occurrence. We examined the relationship between prenatal exposure to PFAAs and prevalence of infectious diseases up to 4years of life. A total of 1558 mother-child pairs, who were enrolled in the Hokkaido Study on Environment and Children's Health, were included in this data analysis. Eleven PFAAs were measured in maternal plasma taken at 28-32weeks of gestation using ultra-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry. Participant characteristics were obtained from medical birth records and self-administered questionnaires during pregnancy and after delivery. Physicians' diagnosis of common infectious diseases including otitis media, pneumonia, respiratory syncytial virus infection, and varicella up to 4years were extracted from the mother-reported questionnaires. The number of children who developed infectious diseases up to 4years of age was as follows: otitis media, 649 (41.4%); pneumonia, 287 (18.4%); respiratory syncytial virus infection, 197 (12.6%); varicella 589 (37.8%). A total of 1046 (67.1%) children had at least one of the diseases defined as total infectious diseases. After adjusting for appropriate confounders, PFOS levels in the highest quartile were associated with increased odds ratios (ORs) of total infectious diseases (Q4 vs. Q1 OR: 1.61; 95% CI: 1.18, 2.21; p for trend=0.008) in all children. In addition, perfluorohexane sulfonate (PFHxS) was associated with a higher risk of total infectious diseases only among girls (Q4 vs. Q1 OR: 1.55, 95% CI: 0.976, 2.45; p for trend=0.045). We found no association between infectious diseases and other examined PFAAs. Our findings suggest that prenatal exposure to PFOS and PFHxS may associated with infectious diseases occurrence in early life. Therefore, prenatal exposure to PFAAs may be immunotoxic for the immune system in offspring.
• Association of prenatal exposure to perfluoroalkyl substances with cord blood adipokines and birth size: The Hokkaido Study on environment and children's health.
  Machiko Minatoya; Sachiko Itoh; Chihiro Miyashita; Atsuko Araki; Seiko Sasaki; Ryu Miura; Houman Goudarzi; Yusuke Iwasaki; Reiko Kishi
  Environmental research, 156, 175, 182, Jul. 2017, [International Magazine]
  English, Scientific journal, Perfluoroalkyl substances (PFASs) are synthetic chemicals that persist in the environment and in humans. There is a possible association between prenatal PFASs exposure and both neonate adipokines and birth size, yet epidemiological studies are very limited. The objective of this study was to examine associations of prenatal exposure to PFASs with cord blood adipokines and birth size. We conducted birth cohort study, the Hokkaido Study. In this study, 168 mother-child pairs were included. Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in maternal blood were determined by liquid chromatography tandem mass spectrometry. Cord blood adiponectin and leptin levels were measured by ELISA and RIA, respectively. Birth weight and ponderal index (PI) were obtained from birth record. The median maternal PFOS and PFOA were 5.1 and 1.4ng/mL, respectively. The median total adiponectin and leptin levels were 19.4μg/mL and 6.2ng/mL, respectively. Adjusted linear regression analyses found that PFOS level was positively associated with total adiponectin levels (β=0.12, 95% CI:0.01, 0.22), contrary was negatively associated with PI (β=-2.25, 95% CI: -4.01, -0.50). PFOA level was negatively associated with birth weight (β=-197, 95% CI: -391, -3). Leptin levels were not associated with PFASs levels. PFOS and adiponectin levels showed marginal dose-response relationship and both PFOS and PFOA and birth size showed significant dose-response relationships. Results from this study suggested that prenatal PFASs exposure may alter cord blood adiponectin levels and may decrease birth size.
• The Hokkaido Birth Cohort Study on Environment and Children's Health: cohort profile-updated 2017.
  Reiko Kishi; Atsuko Araki; Machiko Minatoya; Tomoyuki Hanaoka; Chihiro Miyashita; Sachiko Itoh; Sumitaka Kobayashi; Yu Ait Bamai; Keiko Yamazaki; Ryu Miura; Naomi Tamura; Kumiko Ito; Houman Goudarzi
  Environmental health and preventive medicine, 22, 1, 46, 46, 18 May 2017, [International Magazine]
  English, Scientific journal, The Hokkaido Study on Environment and Children's Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary study goals are (1) to examine the effects of low-level environmental chemical exposures on birth outcomes, including birth defects and growth retardation; (2) to follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders and perform a longitudinal observation of child development; (3) to identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) to identify the additive effects of various chemicals, including tobacco smoking. The purpose of this report is to update the progress of the Hokkaido Study, to summarize the recent results, and to suggest future directions. In particular, this report provides the basic characteristics of the cohort populations, discusses the population remaining in the cohorts and those who were lost to follow-up at birth, and introduces the newly added follow-up studies and case-cohort study design. In the Sapporo cohort of 514 enrolled pregnant women, various specimens, including maternal and cord blood, maternal hair, and breast milk, were collected for the assessment of exposures to dioxins, polychlorinated biphenyls, organochlorine pesticides, perfluoroalkyl substances, phthalates, bisphenol A, and methylmercury. As follow-ups, face-to-face neurobehavioral developmental tests were conducted at several different ages. In the Hokkaido cohort of 20,926 enrolled pregnant women, the prevalence of complicated pregnancies and birth outcomes, such as miscarriage, stillbirth, low birth weight, preterm birth, and small for gestational age were examined. The levels of exposure to environmental chemicals were relatively low in these study populations compared to those reported previously. We also studied environmental chemical exposure in association with health outcomes, including birth size, neonatal hormone levels, neurobehavioral development, asthma, allergies, and infectious diseases. In addition, genetic and epigenetic analyses were conducted. The results of this study demonstrate the effects of environmental chemical exposures on genetically susceptible populations and on DNA methylation. Further study and continuous follow-up are necessary to elucidate the combined effects of chemical exposure on health outcomes.
• Associated factors of behavioural problems in children at preschool age: the Hokkaido study on environment and children's health
  M. Minatoya; S. Itoh; A. Araki; N. Tamura; K. Yamazaki; S. Nishihara; C. Miyashita; R. Kishi
  CHILD CARE HEALTH AND DEVELOPMENT, 43, 3, 385, 392, May 2017, [Peer-reviewed]
  English, Scientific journal
• Effects of prenatal perfluoroalkyl acid exposure on cord blood IGF2/H19 methylation and ponderal index: The Hokkaido Study.
  Sachiko Kobayashi; Kaoru Azumi; Houman Goudarzi; Atsuko Araki; Chihiro Miyashita; Sumitaka Kobayashi; Sachiko Itoh; Seiko Sasaki; Mayumi Ishizuka; Hiroyuki Nakazawa; Tamiko Ikeno; Reiko Kishi
  Journal of exposure science & environmental epidemiology, 27, 3, 251, 259, May 2017, [International Magazine]
  English, Scientific journal, Prenatal exposure to perfluoroalkyl acids (PFAAs) influences fetal growth and long-term health. However, whether PFAAs affect offspring DNA methylation patterns to influence health outcomes is yet to be evaluated. Here, we assessed effect of prenatal PFAA exposure on cord blood insulin-like growth factor 2 (IGF2), H19, and long interspersed element 1 (LINE1) methylation and its associations with birth size. Mother-child pairs (N=177) from the Hokkaido Study on Environment and Children's Health were included in the study. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) levels in maternal serum were measured by liquid chromatography-tandem mass spectrometry. IGF2, H19, and LINE1 methylation in cord blood DNA was determined by pyrosequencing. After full adjustment in multiple linear regression models, IGF2 methylation showed a significant negative association with log-unit increase in PFOA (partial regression coefficient=-0.73; 95% confidence interval: -1.44 to -0.02). Mediation analysis suggested that reduced IGF2 methylation explained ~21% of the observed association between PFOA exposure and reduced ponderal index of the infant at birth. These results indicated that the effects of prenatal PFOA exposure could be mediated through DNA methylation. Further study will be required to determine the potential for long-term adverse health effects of reduced IGF2 methylation induced by PFOA exposure.
• Prenatal di(2-ethylhexyl) phthalate exposure and disruption of adrenal androgens and glucocorticoids levels in cord blood: The Hokkaido Study.
  Atsuko Araki; Takahiko Mitsui; Houman Goudarzi; Tamie Nakajima; Chihiro Miyashita; Sachiko Itoh; Seiko Sasaki; Kazutoshi Cho; Kimihiko Moriya; Nobuo Shinohara; Katsuya Nonomura; Reiko Kishi
  The Science of the total environment, 581-582, 297, 304, 01 Mar. 2017, [International Magazine]
  English, Scientific journal, Di(2-ethylhexyl) phthalate (DEHP) is known for its endocrine disrupting properties. We previously demonstrated that prenatal DEHP exposure is associated with decreased progesterone levels and testosterone/estradiol ratio in the cord blood. However, evidence of the effects of prenatal DEHP exposure on adrenal androgen and glucocorticoids in infants is scarce. Thus, the objectives of this study were to investigate the association between prenatal DEHP exposure and adrenal androgen and glucocorticoids, and to discuss its effects on steroid hormone profiles in infants. This is part of a birth cohort study: The Hokkaido Study on Environment and Children's Health, Sapporo Cohort. Among the 514 participants, 202 mother-infant pairs with available data on maternal mono(2-ethylhexyl) phthalate (MEHP), adrenal androgen (dehydroepiandrostenedione [DHEA] and androstenedione) and glucocorticoid (cortisol and cortisone) cord blood levels were included in this study. After adjusting for potential confounders, a linear regression analysis showed that maternal MEHP levels were associated with reduced cortisol and cortisone levels and glucocorticoid/adrenal androgen ratio, whereas increased DHEA levels and DHEA/androstenedione ratio. In a quartile model, when comparing the adjusted least square means in the 4th quartile of MEHP with those in the 1st quartile, cortisol and cortisone levels and glucocorticoid/adrenal androgen ratio decreased, whereas DHEA/androstenedione and cortisol/cortisone ratios increased. Significant p-value trends for cortisol and cortisone levels, cortisol/cortisone ratio, and glucocorticoid/adrenal androgen ratio were observed. In combination with the previous results of reduced progesterone levels and testosterone/estradiol ratio, prenatal exposure to DEHP altered the steroid hormone profiles of infants. Further studies investigating the long-term effects of DEHP exposure on growth, neurodevelopment, and gonad and reproductive function are required.
• The Association of Prenatal Exposure to Perfluorinated Chemicals with Glucocorticoid and Androgenic Hormones in Cord Blood Samples: The Hokkaido Study.
  Houman Goudarzi; Atsuko Araki; Sachiko Itoh; Seiko Sasaki; Chihiro Miyashita; Takahiko Mitsui; Hiroyuki Nakazawa; Katsuya Nonomura; Reiko Kishi
  Environmental health perspectives, 125, 1, 111, 118, Jan. 2017, [International Magazine]
  English, Scientific journal, BACKGROUND: Perfluorinated chemicals (PFCs) disrupt cholesterol homeostasis. All steroid hormones are derived from cholesterol, and steroid hormones such as glucocorticoids and androgenic hormones mediate several vital physiologic functions. However, the in utero effects of PFCs exposure on the homeostasis of these steroid hormones are not well understood in humans. OBJECTIVES: We examined the relationship between prenatal exposure to perfluorooctane sulfonate (PFOS)/perfluorooctanoate (PFOA) and cord blood levels of glucocorticoid and androgenic hormones. METHODS: We conducted a hospital-based birth cohort study between July 2002 and October 2005 in Sapporo, Japan (n = 514). In total, 185 mother-infant pairs were included in the present study. Prenatal PFOS and PFOA levels in maternal serum samples were measured using liquid chromatography-tandem mass spectrometry (LC-MS-MS). Cord blood levels of glucocorticoid (cortisol and cortisone) and androgenic hormones [dehydroepiandrosterone (DHEA) and androstenedione] were also measured in the same way. RESULTS: We found a dose-response relationship of prenatal PFOS, but not PFOA, exposure with glucocorticoid levels after adjusting for potential confounders. Cortisol and cortisone concentrations were -23.98-ng/mL (95% CI: -0.47.12, -11.99; p for trend = 0.006) and -63.21-ng/mL (95% CI: -132.56, -26.72; p for trend < 0.001) lower, respectively, in infants with prenatal PFOS exposure in the fourth quartile compared with those in the first quartile. The highest quartile of prenatal PFOS exposure was positively associated with a 1.33-ng/mL higher DHEA level compared with the lowest quartile (95% CI: 0.17, 1.82; p for trend = 0.017), whereas PFOA showed a negative association with DHEA levels (quartile 4 vs. quartile 1: -1.23 ng/mL, 95% CI: -1.72, -0.25; p for trend = 0.004). We observed no significant association between PFCs and androstenedione levels. CONCLUSIONS: Our results indicate that prenatal exposure to PFCs is significantly associated with glucocorticoid and DHEA levels in cord blood. Citation: Goudarzi H, Araki A, Itoh S, Sasaki S, Miyashita C, Mitsui T, Nakazawa H, Nonomura K, Kishi R. 2017. The association of prenatal exposure to perfluorinated chemicals with glucocorticoid and androgenic hormones in cord blood samples: the Hokkaido Study. Environ Health Perspect 125:111-118; http://dx.doi.org/10.1289/EHP142.
• Effects of prenatal exposure to perfluoroalkyl acids on prevalence ofallergic diseases among 4-year-old children.
  Houman Goudarzi; Chihiro Miyashita; Emiko Okada; Ikuko Kashino; Sumitaka Kobayashi; Chi-Jen Chen; Sachiko Ito; Atsuko Araki; Hideyuki Matsuura; Yoichi M Ito; Reiko Kishi
  Environment international, 94, 124, 132, Sep. 2016, [International Magazine]
  English, Scientific journal, Perfluoroalkyl acids (PFAAs) are ubiquitous chemicals extremely resistant and widespread throughout the environment, frequently being detected in human blood samples. Animal studies have revealed that exposure to PFAAs results in immunotoxicity. However, the association between PFAAs, especially long-chain PFAAs, and allergies in humans is not well established. We examined whether prenatal exposure to PFAAs is associated with allergic diseases among 4-year-old children in a large-scale prospective birth cohort in Hokkaido, Japan. In total, 1558 mother-child pairs were included in this study and prenatal levels of eleven PFAAs were measured in maternal plasma samples obtained between 28 and 32weeks of pregnancy by using ultra-performance liquid chromatography-tandem mass spectrometry. Participant demographic and characteristic information were obtained from self-administered pre- and postnatal questionnaires and medical birth records. Infant allergies were assessed using the Japanese version of the International Study of Asthma and Allergies in Childhood (ISAAC) Phase Three questionnaire, which was administered 4years post-delivery. Symptoms included eczema, wheezing and rhinoconjunctivitis with a prevalence of 19.0%, 18.7%, and 5.4%, respectively. Associations of PFAA quartiles with allergic outcomes were examined using logistic models. Adjusted odds ratios (ORs) in the 4th quartile vs. 1st quartile (Q4 vs. Q1) for total allergic diseases (including at least one allergic outcome) significantly decreased for perfluorododecanoic acid (PFDoDa) (Q4 vs. Q1 OR: 0.621; 95% confidence interval (CI): 0.454, 0.847) and perfluorotridecanoic acid (PFTrDA) (Q4 vs. Q1 OR: 0.712; 95% CI: 0.524, 0.966) in all children. We obtained similar results when examining the association between PFAAs and eczema. The adjusted OR (Q4 vs. Q1) for wheezing in relation to higher maternal PFHxS levels was 0.728 (95% CI: 0.497, 1.06) in all children. In conclusion, prenatal exposure to long-chain PFAAs, such as PFDoDa and PFTrDA may have an immunosuppressive effect on allergic diseases in 4-year-old children.
• Effects of adrenal androgens during the prenatal period on the second to fourth digit ratio in school-aged children.
  Takahiko Mitsui; Atsuko Araki; Houman Goudarzi; Chihiro Miyashita; Sachiko Ito; Seiko Sasaki; Takeya Kitta; Kimihiko Moriya; Kazutoshi Cho; Keita Morioka; Reiko Kishi; Nobuo Shinohara; Masayuki Takeda; Katsuya Nonomura
  Steroids, 113, 46, 51, Sep. 2016, [International Magazine]
  English, Scientific journal, OBJECTIVES: We investigated the relationship between the levels of adrenal steroid hormones in cord blood and the second to fourth digit ratio (2D/4D), which is regarded as an indirect method to investigate the putative effects of prenatal exposure to androgens, in school-aged children. MATERIALS AND METHODS: Of the 514 mother-child pairs who participated in the prospective cohort study of birth in Sapporo between 2002 and 2005, the following adrenal steroid hormone levels in 294 stored cord blood samples (135 males and 159 females) were measured; cortisol, cortisone, androstenedione and dehydroepiandrosterone (DHEA). A total of 190 out of 350 children who were currently school-aged and contactable for this survey sent back photocopies of their palms for 2D/4D measurements. RESULTS: 2D/4D in all right hands, left hands, and mean values was significantly lower in males than in females (p<0.01). DHEA levels were significantly higher in females. A multivariate regression model showed that 2D/4D negatively correlated with DHEA in males only (p<0.01). No correlations were observed in the other adrenal steroid hormones tested in males or in any adrenal steroid hormones in females. CONCLUSION: DHEA is mainly secreted in large amounts by the adrenal gland and is transformed into active sex-steroid hormones in peripheral tissues. The present study demonstrated that sex differences in digits were influenced by adrenal androgens during the prenatal period, possibly through intracrinological processes for androgen receptors located in fetal cartilaginous tissues.
• Association of perfluorinated chemical exposure in utero with maternal and infant thyroid hormone levels in the Sapporo cohort of Hokkaido Study on the Environment and Children's Health.
  Shizue Kato; Sachiko Itoh; Motoyuki Yuasa; Toshiaki Baba; Chihiro Miyashita; Seiko Sasaki; Sonomi Nakajima; Akiko Uno; Hiroyuki Nakazawa; Yusuke Iwasaki; Emiko Okada; Reiko Kishi
  Environmental health and preventive medicine, 21, 5, 334, 344, Sep. 2016, [International Magazine]
  English, Scientific journal, OBJECTIVES: Perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) have been widely used as industrial products, and are persistent organic pollutants due to their chemical stability. Previous studies suggested that PFOS and PFOA might disrupt thyroid hormone (TH) status. Although TH plays an important role in fetal growth during pregnancy, little attention has been paid to the relationships between maternal exposure to perfluorocarbons and TH statuses of mothers and fetuses. We investigated the effects of low levels of environmental PFOS and PFOA on thyroid function of mothers and infants. METHODS: Of the eligible subjects in a prospective cohort, 392 mother-infant pairs were selected. Concentration of maternal serum PFOS and PFOA was measured in samples taken during the second and third trimesters or within 1 week of delivery. Blood samples for measuring thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from mothers at early gestational stage (median 11.1 weeks), and from infants between 4 and 7 days of age, respectively. RESULTS: Median concentrations of PFOS and PFOA were 5.2 [95 % confidence interval (CI) 1.6-12.3] and 1.2 (95 % CI limitation of detection-3.4) ng/mL, respectively. Maternal PFOS levels were inversely correlated with maternal serum TSH and positively associated with infant serum TSH, whereas maternal PFOA showed no significant relationship with TSH or FT4 among mothers and infants. CONCLUSIONS: These findings suggest that PFOS may independently affect the secretion and balances of maternal and infant TSH even at low levels of environmental exposure.
• Association of perfluoroalkyl substances exposure in utero with reproductive hormone levels in cord blood in the Hokkaido Study on Environment and Children's Health.
  Sachiko Itoh; Atsuko Araki; Takahiko Mitsui; Chihiro Miyashita; Houman Goudarzi; Seiko Sasaki; Kazutoshi Cho; Hiroyuki Nakazawa; Yusuke Iwasaki; Nobuo Shinohara; Katsuya Nonomura; Reiko Kishi
  Environment international, 94, 51, 59, Sep. 2016, [International Magazine]
  English, Scientific journal, BACKGROUND: Exposure to perfluoroalkyl substances (PFASs) may disrupt reproductive function in animals and humans. Although PFASs can cross the human placental barrier, few studies evaluated the effects of prenatal PFAS exposure on the fetus' reproductive hormones. OBJECTIVE: To explore the associations of prenatal exposure to perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) with cord blood reproductive hormones. METHODS: In the prospective birth cohort (Sapporo cohort of the Hokkaido study), we included 189 mother-infant pairs recruited in 2002-2005 with both prenatal maternal and cord blood samples. PFOS and PFOA levels in maternal blood after the second trimester were measured via liquid chromatography-tandem mass spectrometry. We also measured cord blood levels of the fetuses' reproductive hormones, including estradiol (E2), total testosterone (T), progesterone (P4), inhibin B, insulin-like factor 3, steroid hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone, and prolactin (PRL). RESULTS: The median PFOS and PFOA levels in maternal serum were 5.2ng/mL and 1.4ng/mL, respectively. In the fully adjusted linear regression analyses of the male infants, maternal PFOS levels were significantly associated with E2 and positively, and T/E2, P4, and inhibin B inversely; PFOA levels were positively associated with inhibin B levels. Among the female infants, there were significant inverse associations between PFOS levels and P4 and PRL levels, although there were no significant associations between PFOA levels and the female infants' reproductive hormone levels. CONCLUSIONS: These results suggest that the fetal synthesis and secretion of reproductive hormones may be affected by in utero exposure to measurable levels of PFOS and PFOA.
• Prenatal exposure to perfluorinated chemicals and neurodevelopment in early infancy: The Hokkaido Study.
  Houman Goudarzi; Sonomi Nakajima; Tamiko Ikeno; Seiko Sasaki; Sachiko Kobayashi; Chihiro Miyashita; Sachiko Ito; Atsuko Araki; Hiroyuki Nakazawa; Reiko Kishi
  The Science of the total environment, 541, 1002, 1010, 15 Jan. 2016, [International Magazine]
  English, Scientific journal, Perfluorinated chemicals (PFCs) are ubiquitous and persistent pollutants widely detected in blood samples of animals and humans across the globe. Although animal studies have shown the potential neurotoxicity of PFCs, there are few epidemiological studies regarding neurological effects of PFCs in humans, and those studies have had inconclusive results. In this study, we conducted a hospital-based prospective birth cohort study between 2002 and 2005 (n=514) to examine the associations between prenatal perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) exposures and the neurodevelopment of infants at 6 (n=173) and 18 (n=133) months of age. Using the second edition of the Bayley Scales of Infant Development (BSID II), the Mental and Psychomotor Developmental Indices (MDI and PDI, respectively) were assessed. PFOS and PFOA were measured in maternal serum samples by liquid chromatography-tandem mass spectrometry. After controlling for confounders, prenatal PFOA concentrations were associated with the MDI of female (but not male) infants at 6 months of age (β=-0.296; 95% confidence interval (CI): -11.96, -0.682). Furthermore, females born to mothers with prenatal concentrations of PFOA in the fourth quartile had MDI scores -5.05 (95% CI: -10.66 to 0.55) lower than females born to mothers with concentrations of PFOA in the first quartile (p for trend=0.045). However, PFOA concentrations were not significantly associated with neurodevelopmental indices at 18 months of age. In addition, we did not observe any significant association between PFOS concentrations and neurodevelopmental outcomes in early infancy. In conclusion, our results suggest that prenatal PFOA exposure may affect female mental scales of neurodevelopment at 6 months of age. Further studies with larger sample sizes and longer observation periods are required to clarify sex difference of the neurodevelopmental effects.
• The Relationship between the Second-to-Fourth Digit Ratio and Behavioral Sexual Dimorphism in School-Aged Children.
  Takahiko Mitsui; Atsuko Araki; Chihiro Miyashita; Sachiko Ito; Tamiko Ikeno; Seiko Sasaki; Takeya Kitta; Kimihiko Moriya; Kazutoshi Cho; Keita Morioka; Reiko Kishi; Nobuo Shinohara; Masayuki Takeda; Katsuya Nonomura
  PloS one, 11, 1, e0146849, 2016, [International Magazine]
  English, Scientific journal, Sexually dimorphic brain development and behavior are known to be influenced by sex hormones exposure in prenatal periods. On the other hand, second-to forth digit ratio (2D/4D) has been used as an indirect method to investigate the putative effects of prenatal exposure to androgen. In the present study, we herein investigated the relationship between gender-role play behavior and the second-to-fourth digit ratio (2D/4D), which has been used as an indirect method to investigate the putative effects of prenatal exposure to androgens, in school-aged children. Among 4981 children who became 8 years old by November 2014 and were contactable for this survey by The Hokkaido Study of Environment and Children's Health, 1631 (32.7%), who had data for 2D/4D and Pre-school Activities Inventory (PSAI) as well as data for the survey at baseline, were available for analysis. Parents sent reports of PSAI on the sex-typical characteristics, preferred toys, and play activities of children, and black and white photocopies of the left and right hand palms via mail. PSAI consisted of 12 masculine items and 12 feminine items, and a composite score was created by subtracting the feminine score from the masculine score, with higher scores representing masculine-typical behavior. While composite scores in PSAI were significantly higher in boys than in girls, 2D/4D was significantly lower in boys than in girls. Although the presence or absence of brothers or sisters affected the composite, masculine, and feminine scored of PSAI, a multivariate regression model revealed that 2D/4D negatively correlated with the composite scores of PSAI in boys, whereas no correlation was found in girls. Although 2D/4D negatively correlated with the masculine score in boys and girls, no correlation was observed between 2D/4D and the feminine score. In conclusion, although social factors, such as the existence of brother or sisters, affect dimorphic brain development and behavior in childhood, the present study revealed that the prenatal hormonal environment was an important factor influencing masculine-typical dimorphic brain development and behavior in school-aged children.
• Effects of in utero exposure to polychlorinated biphenyls, methylmercury, and polyunsaturated fatty acids on birth size.
  Chihiro Miyashita; Seiko Sasaki; Tamiko Ikeno; Atsuko Araki; Sachiko Ito; Jumboku Kajiwara; Takashi Todaka; Noriyuki Hachiya; Akira Yasutake; Katsuyuki Murata; Tamie Nakajima; Reiko Kishi
  The Science of the total environment, 533, 256, 65, 15 Nov. 2015, [International Magazine]
  English, Scientific journal, The adverse effects of in utero exposure to polychlorinated biphenyls (PCBs) or methylmercury (MeHg), and the beneficial effects of nutrients from maternal fish intake might have opposing influences on fetal growth. In this study, we assessed the effects of in utero exposure to PCBs and MeHg on birth size in the Japanese population, which is known to have a high frequency of fish consumption. The concentrations of PCBs and polyunsaturated fatty acids in maternal blood, and the total mercury in hair (as a biomarker of MeHg exposure) were measured during pregnancy and at delivery. Maternal intakes of fish (subtypes: fatty and lean) and shellfishes were calculated from a food frequency questionnaire administered at delivery. Newborn anthropometric measurement data were obtained from birth records. The associations between chemical exposures and birth size were analyzed by using multiple regression analysis with adjustment for confounding factors among 367 mother-newborn pairs. The birth weight was 3073±37 g (mean±SD). The incidence of babies small for gestational age (SGA) by weight was 4.9%. The median concentrations of total PCBs and hair mercury were 108 ng/g lipid and 1.41 μg/g, respectively. There was no overall association between mercury concentrations and birth weight, birth length, chest circumference, and head circumference. We observed that the risk of SGA by weight decreased with increasing mercury concentration in regression analyses with adjustment for polyunsaturated fatty acids. Our results suggest that the beneficial effect of essential nutrition may mask the adverse effects of MeHg on birth size. The concentrations of PCBs had no association with birth size.
• The Association of Prenatal Exposure to Perfluorinated Chemicals with Maternal Essential and Long-Chain Polyunsaturated Fatty Acids during Pregnancy and the Birth Weight of Their Offspring: The Hokkaido Study.
  Reiko Kishi; Tamie Nakajima; Houman Goudarzi; Sachiko Kobayashi; Seiko Sasaki; Emiko Okada; Chihiro Miyashita; Sachiko Itoh; Atsuko Araki; Tamiko Ikeno; Yusuke Iwasaki; Hiroyuki Nakazawa
  Environmental health perspectives, 123, 10, 1038, 45, Oct. 2015, [International Magazine]
  English, Scientific journal, BACKGROUND: Fatty acids (FAs) are essential for fetal growth. Exposure to perfluorinated chemicals (PFCs) may disrupt FA homeostasis, but there are no epidemiological data regarding associations of PFCs and FA concentrations. OBJECTIVES: We estimated associations between perfluorooctane sulfonate (PFOS)/perfluorooctanoate (PFOA) concentrations and maternal levels of FAs and triglyceride (TG) and birth size of the offspring. METHODS: We analyzed 306 mother-child pairs in this birth cohort between 2002 and 2005 in Japan. The prenatal PFOS and PFOA levels were measured in maternal serum samples by liquid chromatography-tandem mass spectrometry. Maternal blood levels of nine FAs and TG were measured by gas chromatography-mass spectrometry and TG E-Test Wako kits, respectively. Information on infants' birth size was obtained from participant medical records. RESULTS: The median PFOS and PFOA levels were 5.6 and 1.4 ng/mL, respectively. In the fully adjusted model, including maternal age, parity, annual household income, blood sampling period, alcohol consumption, and smoking during pregnancy, PFOS but not PFOA had a negative association with the levels of palmitic, palmitoleic, oleic, linoleic, α-linolenic, and arachidonic acids (p < 0.005) and TG (p-value = 0.016). Female infants weighed 186.6 g less with mothers whose PFOS levels were in the fourth quartile compared with the first quartile (95% CI: -363.4, -9.8). We observed no significant association between maternal levels of PFOS and birth weight of male infants. CONCLUSIONS: Our data suggest an inverse association between PFOS exposure and polyunsaturated FA levels in pregnant women. We also found a negative association between maternal PFOS levels and female birth weight.
• Effects of prenatal Leydig cell function on the ratio of the second to fourth digit lengths in school-aged children.
  Takahiko Mitsui; Atsuko Araki; Ayako Imai; Sakiko Sato; Chihiro Miyashita; Sachiko Ito; Seiko Sasaki; Takeya Kitta; Kimihiko Moriya; Kazutoshi Cho; Keita Morioka; Reiko Kishi; Katsuya Nonomura
  PloS one, 10, 3, e0120636, 2015, [International Magazine]
  English, Scientific journal, Prenatal sex hormones can induce abnormalities in the reproductive system and adversely impact on genital development. We investigated whether sex hormones in cord blood influenced the ratio of the second to fourth digit lengths (2D/4D) in school-aged children. Of the 514 children who participated in a prospective cohort study on birth in Sapporo between 2002 and 2005, the following sex hormone levels were measured in 294 stored cord blood samples (135 boys and 159 girls); testosterone (T), estradiol (E), progesterone, LH, FSH, inhibin B, and insulin-like factor 3 (INSL3). A total of 350 children, who were of school age and could be contacted for this survey, were then requested via mail to send black-and-white photocopies of the palms of both the left and right hands. 2D/4D was calculated in 190 children (88 boys and 102 girls) using photocopies and derived from participants with the characteristics of older mothers, a higher annual household income, higher educational level, and fewer smokers among family members. 2D/4D was significantly lower in males than in females (p<0.01). In the 294 stored cord blood samples, T, T/E, LH, FSH, Inhibin B, and INSL3 levels were significantly higher in samples collected from males than those from females. A multivariate regression model revealed that 2D/4D negatively correlated with INSL3 in males and was significantly higher in males with <0.32 ng/mL of INSL3 (p<0.01). No correlations were observed between other hormones and 2D/4D. In conclusion, 2D/4D in school-aged children, which was significantly lower in males than in females, was affected by prenatal Leydig cell function.
• Association between maternal exposure to di(2-ethylhexyl) phthalate and reproductive hormone levels in fetal blood: the Hokkaido study on environment and children's health.
  Atsuko Araki; Takahiko Mitsui; Chihiro Miyashita; Tamie Nakajima; Hisao Naito; Sachiko Ito; Seiko Sasaki; Kazutoshi Cho; Tamiko Ikeno; Katsuya Nonomura; Reiko Kishi
  PloS one, 9, 10, e109039, 2014, [International Magazine]
  English, Scientific journal, Prenatal di(2-ethylhexyl) phthalate (DEHP) exposure can produce reproductive toxicity in animal models. Only limited data exist from human studies on maternal DEHP exposure and its effects on infants. We aimed to examine the associations between DEHP exposure in utero and reproductive hormone levels in cord blood. Between 2002 and 2005, 514 pregnant women agreed to participate in the Hokkaido Study Sapporo Cohort. Maternal blood samples were taken from 23-35 weeks of gestation and the concentration of the primary metabolite of DEHP, mono(2-ethylhexyl) phthalate (MEHP), was measured. Concentrations of infant reproductive hormones including estradiol (E2), total testosterone (T), and progesterone (P4), inhibin B, insulin-like factor 3 (INSL3), steroid hormone binding globulin, follicle-stimulating hormone, and luteinizing hormone were measured from cord blood. Two hundred and two samples with both MEHP and hormones' data were included in statistical analysis. The participants completed a self-administered questionnaire regarding information on maternal characteristics. Gestational age, birth weight and infant sex were obtained from birth records. In an adjusted linear regression analysis fit to all study participants, maternal MEHP levels were found to be associated with reduced levels of T/E2, P4, and inhibin B. For the stratified analyses for sex, inverse associations between maternal MEHP levels T/E2, P4, inhibin B, and INSL3 were statistically significant for males only. In addition, the MEHP quartile model showed a significant p-value trend for P4, inhibin B, and INSL3 decrease in males. Since inhibin B and INSL3 are major secretory products of Sertoli and Leydig cell, respectively, the results of this study suggest that DEHP exposure in utero may have adverse effects on both Sertoli and Leydig cell development in males, which agrees with the results obtained from animal studies. Comprehensive studies investigating phthalates' exposure in humans, as well as their long-term effects on reproductive development are needed.
• Ten years of progress in the Hokkaido birth cohort study on environment and children's health: cohort profile--updated 2013.
  Reiko Kishi; Sachiko Kobayashi; Tamiko Ikeno; Atsuko Araki; Chihiro Miyashita; Sachiko Itoh; Seiko Sasaki; Emiko Okada; Sumitaka Kobayashi; Ikuko Kashino; Kumiko Itoh; Sonomi Nakajima
  Environmental health and preventive medicine, 18, 6, 429, 50, Nov. 2013, [International Magazine]
  English, Scientific journal, The Hokkaido Study on Environment and Children's Health is an ongoing cohort study that began in 2002. The study consists of two prospective birth cohorts, the Sapporo cohort (n = 514) and the Hokkaido large-scale cohort (n = 20,940). The primary goals of this study are to first examine the potential negative effects of perinatal environmental chemical exposures on birth outcomes, including congenital malformations and growth retardation; second, to evaluate the development of allergies, infectious diseases and neurodevelopmental disorders and perform longitudinal observations of the children's physical development to clarify the causal relationship between these outcomes and environmental chemicals; third, to identify individuals genetically susceptible to environmental chemicals; finally, to identify the additive effects of various environmental factors in our daily life, such as secondhand smoke exposure or low folate intake during early pregnancy. In this paper, we introduce our recent progress in the Hokkaido study with a cohort profile updated in 2013. For the last ten years, we followed pregnant women and their offspring, measuring various environmental chemicals, i.e., PCB, OH-PCB and dioxins, PFCs (Perfluorinated Compounds), Organochlorine pesticides, Phthalates, bisphenol A and mercury. We discovered that the concentration of toxic equivalents (TEQ) of dioxin and other specific congeners of PCDF or PCDD have effects on birth weight, infants' neurodevelopment and immune function. There were significant gender differences in these effects; our results suggest that male infants have more susceptibility to those chemical exposures than female infants. Interestingly, we found maternal genetic polymorphisms in AHR, CYP1A1 or GSTs that significantly modified the dioxin concentrations in maternal blood, suggesting different dioxin accumulations in the bodies of individuals with these genotypes, which would lead to different dioxin exposure levels. These genetic susceptibility factors influenced the body size of children born from mothers that either smoked or were passively exposed to tobacco smoke. Further studies investigating the correlation between epigenetics, the effects of intrauterine exposure to environmental chemicals and developmental factors related to health and disease are warranted.
• Biodistribution of aqueous suspensions of carbon nanotubes in mice and their biocompatibility.
  Shigeaki Abe; Sachiko Itoh; Daisuke Hayashi; Toshihisa Kobayashi; Takayuki Kiba; Tsukasa Akasaka; Motohiro Uo; Yasutaka Yawaka; Shin-Ichiro Sato; Fumio Watari; Tomoya Takada
  Journal of nanoscience and nanotechnology, 12, 1, 700, 6, Jan. 2012, [International Magazine]
  English, Scientific journal, In this study, we prepared two-types of water-dispersible carbon nanotubes (CNTs) and investigated their biodistribution in mice as well as bio-/cyto-compatibility. After administration, their organs were excised at various post-injection times, then observed using both optical and transmission electron microscopy (TEM). The color of the liver and lung markedly darkened, suggesting that administered CNTs reached these organs. By TEM observation, the CNTs were found in the liver and lung. They were observed even in the kidney and spleen, though their distributions in those organs were very low compared with that in liver and lung. Therefore, most of the administered CNTs would be accumulated in the liver or lung. However, the time profile of the body weight of CNT-administered mice was close to that of control mice. In addition, we estimated the cytocompatibility of the water-dispersible CNTs for hepatocytes. According to a TNF-alpha assay of the cells cultured with CNTs, the expression level was almost the same as that of the control. These results suggested that the water-dispersible CNTs have good bio-/cyto-compatibility under this condition.
• Highly sensitive detection and quantitative analysis of ultra low concentration of carbon nanotubes by absorptiometric method
  Sachiko Itoh; Yasutaka Yawaka; Fumio Watari
  Nano Biomedicine, 2, 2, 130, 138, 2010
  English, Scientific journal

• Editor’s Focus: Prenatal metal concentrations and physical abnormalities
  Yuichi Nakamura; Sumitaka Kobayashi; Kazutoshi Cho; Sachiko Itoh; Chihiro Miyashita; Takeshi Yamaguchi; Hiroyoshi Iwata; Naomi Tamura; Yasuaki Saijo; Yoshiya Ito; Yoshitaka Seto; Ryota Honjo; Akiko Ando; Yuta Furuse; Atsushi Manabe; Reiko Kishi; The Japan Environment and Children’s Study (JECS) Group, Pediatric Research, 95, 7, 1663, 1663, Jun. 2024, [Invited], [International Magazine]
  掲載論文（責任著者）が、Pediatric Research Volume 95 No.7 June 2024のEditor's Focusに選出され紹介された。掲載論文：Nakamura Y, Kobayashi S, et al. Prenatal metal concentrations and physical abnormalities in the Japan Environment and Children’s Study. Pediatric Research. 2024; 95 (7): 1875-1882. https://doi.org/10.1038/s41390-023-02851-4, Springer Sciences and Business Media LLC, English, Introduction scientific journal
• Editor’s Focus: Maternal Alcohol Use and Fetal Growth in Japan
  Kazutoshi Cho; Sumitaka Kobayashi; Atsuko Araki; Chihiro Miyashita; Sachiko Itoh; Yasuaki Saijo; Yoshiya Ito; Kazuo Sengoku; Tsuyoshi Baba; Hisanori Minakami; Yuichi Nakamura; Reiko Kishi; The Japan Environment and Children’s Study Group, Pediatric Research, 92, 1, 1, 1, Jul. 2022, [Invited], [International Magazine]
  掲載論文（責任著者）が、Pediatric Research volume 92 No. 1 July 2022のEditor’s Focusに選出され紹介された。掲載論文：Kazutoshi Cho, Sumitaka Kobayashi, et al. Prenatal alcohol exposure and adverse fetal growth restriction: findings from the Japan Environment and Children's Study. Pediatric Research. 2022; 92: 291-298. https://doi.org/10.1038/s41390-021-01595-3., Springer Science and Business Media LLC, English, Introduction scientific journal
• Childhood allergies and obesity relationship: Identification of novel non-invasive biomarkers
  Houman Goudarzi; Satoshi Konno; Atsuko Araki; Sachiko Ito; Yu Ait Bamai; Chihiro Miyashita; Reiko Kishi, EUROPEAN RESPIRATORY JOURNAL, 54, Sep. 2019
  English, Summary international conference
• LEVEL OF PRENATAL ADRENAL STEROIDS HORMONES AFFECTS BODY WEIGHT AT BIRTH
  Takahiko Mitsui; Atsuko Araki; Sachiko Ito; Chihiro Miyashita; Kimihiko Moriya; Takeya Kitta; Kazutoshi Cho; Keita Morioka; Nobuo Shinohara; Masayuki Takeda; Reiko Kishi; Katsuya Nonomura, JOURNAL OF UROLOGY, 197, 4, E475, E475, Apr. 2017
  English, Summary international conference

• The investigation of the impact of fetal exposure to POPs-induced neuroinflammation on ADHD symptoms in children.
  Grants-in-Aid for Scientific Research
  01 Apr. 2021 - 31 Mar. 2025
  Itoh Sachiko
  In recent years, fetal neuroinflammation has been suggested as a potential factor in the increasing incidence of attention-deficit/hyperactivity disorder (ADHD) in children. This study aimed to investigate whether cytokines mediate the relationship between maternal PFAS levels and ADHD symptoms at 6 years old by measuring the concentrations of cytokines (TNF-α, IL-6, Leptin) in umbilical cord blood from 290 mother-child pairs in the Hokkaido Study. A significant negative correlation was found between PFAS concentrations and ADHD symptoms, while higher Leptin concentrations were associated with a trend toward increased risk of ADHD, but no significant association was observed. Furthermore, no mediating effect of cytokines was detected. These findings suggest that other pathways may be involved in the development of ADHD due to fetal exposure to environmental chemicals.
  Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (C), Hokkaido University, 21K10390