Research activity information

• 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
• 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.
• Development of a Liquid Chromatography-Tandem Mass Spectrometry Method for Oxylipin Analysis and Its Application to Children's Plasma.
  Yonghan Li; Siddabasave Gowda B Gowda; Divyavani Gowda; Atsuko Ikeda; Yu Ait Bamai; Rahel Mesfin Ketema; Reiko Kishi; Hitoshi Chiba; Shu-Ping Hui
  Diagnostics (Basel, Switzerland), 15, 15, 25 Jul. 2025, [International Magazine]
  English, Scientific journal, Background/Objectives: Oxylipins, a family of oxygenated natural products derived from polyunsaturated fatty acids (PUFAs), play crucial roles in various physiological processes. Evaluating their levels in vivo helps to reveal their roles in health and disease. Because of the numerous isomers of oxylipins, it is essential to develop efficient and precise analytical methods for their identification and quantification. The objective of this study is to establish a quantitative method for oxylipin analysis and its application to the assessment of oxylipins in children's plasma, with potential implications for diagnostic use in pediatric populations. Methods: A liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed to quantify 64 oxylipins and four precursor PUFAs within 36 min. The limits of quantification ranged from 0.25 to 50 pg, with most analytes showing recoveries and matrix effects between 85 and 110% and between 90 and 110%, respectively. Intra- and inter-day precision values were within 15%. The established method was applied to plasma samples from children aged 9-12 years (boys = 181; girls = 161) in Hokkaido, Japan, to assess the relation between plasma oxylipin and PUFA levels and age, sex, and body mass index. Results: There was no significant correlation between oxylipin levels and age, sex, or body mass index. However, among the PUFAs, boys had higher eicosapentaenoic acid and arachidonic acid levels than those of girls, with a significant increase in eicosapentaenoic acid levels in the overweight group compared with those in the underweight group. Conclusions: We successfully developed a simple and highly selective method for the analysis of oxylipins in preadolescent children's plasma samples. Thus, this study provides a foundation for broader application of the developed method to different biological samples in future studies.
• Association of Phthalate Exposure with Respiratory and Allergic Symptoms and Type 2 and Non-Type 2 Inflammation: The Hokkaido Study.
  Ketema RM; Ait Bamai Y; Goudarzi H; Yamaguchi T; Zeng Y; Yasuda A; Marsela M; Konno S; Kishi R; Ikeda A
  Environmental science & technology, 08 Apr. 2025
  Scientific journal, Phthalate exposure is linked to asthma and allergic symptoms, yet their individual and combined effects on symptoms and inflammatory biomarkers, type 2 (T2) and non-T2, remain unexplored. This study examined the association of phthalate metabolites with allergic symptoms (wheeze, allergic rhinoconjunctivitis, and eczema), T2 biomarker (fraction of exhaled nitric oxide (FeNO), blood eosinophil count, and total immunoglobulin E (IgE)), and non-T2 biomarker (absolute neutrophil count (ANC)) and also their association with oxidative stress biomarkers, such as 4-hydroxynonenal, hexanoyl-lysine, and 8-hydroxy-2-deoxyguanosine. Ten urinary phthalate metabolites were measured using UPLC-MS/MS in 421 children (aged 9-12 years) from The Hokkaido Cohort, Japan. Symptoms were defined using the International Study of Asthma and Allergies in Childhood questionnaire, and biomarkers were measured in blood. Logistic regression assessed individual metabolites, while quantile-g computation and Bayesian kernel machine regression analyzed mixture effects on binary outcomes. Individual analysis showed that MnBP (mono-n-butyl phthalate) was positively associated with allergic rhinoconjunctivitis and eosinophil ≥ 300 cells/μL, while ∑DBP (dibutyl phthalate) and OH-MiNP (mono-hydroxy-isononyl phthalate) were linked with FeNO ≥ 35 ppb. DEHP (di(2-ethylhexyl) phthalate) metabolites were associated with a high prevalence of blood eosinophils ≥ 300 cells/μL. We found a positive association between phthalates and oxidative stress markers, but no link was observed between oxidative stress and inflammatory markers. Mixture analysis identified MnBP as a major contributor to the high FeNO level, with di-n-butyl phthalate (DnBP) and DEHP metabolites contributing to eosinophil count ≥ 300 cells/μL and ANC ≥ 4400 cells/μL. These findings suggest that phthalate exposure from DnBP and DEHP is associated with immune dysregulation by triggering both T2 and non-T2 inflammatory responses.
• 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
• 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.
• Application of Liquid Chromatography/Tandem Mass Spectrometry for Quantitative Analysis of Plasmalogens in Preadolescent Children—The Hokkaido Study
  Yifan Chen; Siddabasave Gowda B. Gowda; Divyavani Gowda; Jayashankar Jayaprakash; Lipsa Rani Nath; Atsuko Ikeda; Yu Ait Bamai; Rahel Ketema; Reiko Kishi; Hitoshi Chiba; Shu-Ping Hui
  Diagnostics, Mar. 2025
  Scientific journal
• Association between prenatal exposure to maternal metal and trace elements and Streptococcus infection: A prospective birth cohort in the Japan Environment and Children’s Study
  Hiroyoshi Iwata; Atsuko Ikeda; Mariko Itoh; Rahel Mesfin Ketema; Naomi Tamura; Takeshi Yamaguchi; Keiko Yamazaki; Rieko Yamamoto; Maki Tojo; Yu Ait Bamai; Yasuaki Saijo; Yoshiya Ito; Reiko Kishi
  PLOS ONE, 20, 2, e0319356, e0319356, Public Library of Science (PLoS), 27 Feb. 2025
  Scientific journal, Background
  
  Streptococcus infection is a common and potentially severe bacterial infection which remains a global public health challenge, underscoring the necessity of investigating potential risk factors.
  
  Aims
  
  The present study aims to assess the association between metal and trace element exposure and Streptococcus infection using a prospective nationwide birth cohort, the Japan Environment and Children’s Study (JECS).
  
  Methods
  
  The JECS obtained data from over 100,000 pregnancies through 15 Regional Centres across Japan. We assessed toxic metal and trace element levels among pregnant mothers and Streptococcus infection among their children, born between 2011 and 2014, at age three to four. Analysis was performed using univariable and multivariable logistic regressions, as well as Quantile g-computation. We also conducted quartile regressions to assess the effects of higher serum selenium levels and potential interactions between selenium and mercury.
  
  Results
  
  Among 74,434 infants and their mothers, univariable and multivariable regression analyses found that selenium and mercury each had an inverse association with Streptococcus infection incidence. Quantile g-computation analysis yielded results consistent with the primary regression analyses. Quartile regression suggested that serum selenium levels above the third quartile were inversely associated with later Streptococcus infection incidence, but no interaction between selenium and mercury was found.
  
  Conclusions
  
  These findings imply that maternal selenium exposure may have protective effects on Streptococcus infection among children. Further studies should explore the role of pediatric selenium in immune responses to infectious diseases, especially Streptococcus infection.
• The Potential Health Risks of Exposure to Environmental Chemicals – Global Implications for Future Generations
  Reiko KISHI; Atsuko IKEDA; Rahel Mesfin KETEMA
  Jan. 2025, [Peer-reviewed], [Last author]
• 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.
• Quantitative determination of plasma cholesteryl ester levels in Japanese preadolescents from the Hokkaido study using liquid chromatography/tandem mass spectrometry.
  Divyavani Gowda; Siddabasave Gowda B Gowda; Atsuko Ikeda; Rahel Mesfin Ketema; Yu Ait Bamai; Reiko Kishi; Hitoshi Chiba; Shu-Ping Hui
  Steroids, 211, 109498, 109498, Nov. 2024, [International Magazine]
  English, Scientific journal, Cholesteryl esters (CE) are sterols comprising various fatty acyl chains attached to a cholesterol hydroxyl moiety. CEs are often considered plasma biomarkers of liver function; however, their absolute concentrations in the plasma of Japanese preadolescents have not been well explored. This study aimed to determine the plasma CE levels in Japanese preadolescents of different sexes, ages, and body weights living in Hokkaido, Japan using targeted liquid chromatography/tandem mass spectrometry. The analysis was performed on the non-fasting plasma of preadolescents aged 9-12 years (n = 339 healthy volunteers; 178 boys and 161 girls) from Sapporo, Hokkaido, Japan. The analysis results showed that the total CE levels in boys and girls were 871 ± 153 and 862 ± 96 pmol/μL, respectively. CE 18:2 (41 ± 2.9 %) was found to be the most abundant species followed by CE 18:1 (16 ± 1.5 %) and CE 16:0 (13 ± 1.1 %). The ω-3 fatty acid-containing CEs such as CE 18:3 and CE 20:5 were significantly lower in girls than in boys. Despite the different ages, CEs were tightly regulated in the plasma of children's, and the total CEs ranged between 844 and 906 pmol/μL in boys and 824 and 875 pmol/μL in girls. The participants were further classified into three groups based on their body mass index underweight (n = 237), normal weight (n = 94), and overweight (n = 8). Most of the quantified CEs were accumulated in the overweight group. Interestingly, CE 18:3 was significantly upregulated in the overweight group compared to that in the normal range, and the area under the receiver operating characteristic curve was 0.73, suggesting that it could be a possible marker for obesity. This study marks the initial investigation of absolute CE levels in the plasma of children and can help elucidate the relationship between CEs and childhood obesity.
• Determination of plasma lysophosphatidylethanolamines (lyso-PE) by LC-MS/MS revealed a possible relation between obesity and lyso-PE in Japanese preadolescent children: the Hokkaido study.
  Nao Inoue; Siddabasave Gowda B Gowda; Divyavani Gowda; Toshihiro Sakurai; Atsuko Ikeda-Araki; Yu Ait Bamai; Rahel Mesfin Ketema; Reiko Kishi; Hitoshi Chiba; Shu-Ping Hui
  Annals of clinical biochemistry, 45632241280352, 45632241280352, 21 Aug. 2024, [International Magazine]
  English, Scientific journal, BACKGROUND: Lysophosphatidylethanolamines (lyso-PEs) are the partial hydrolysis products of phosphatidylethanolamine. Although lyso-PEs are important biomarkers in various diseases, their determination is limited by the lack of simple and efficient quantification methods. This study aims to develop an improved quantitative method for the determination of lyso-PEs and its application to an epidemiological study. METHODS: Single reaction monitoring channels by collision-induced dissociation for seven lyso-PEs were established using liquid chromatography-tandem mass spectrometry. Plasma lyso-PEs were extracted with a single-phase method using an isotopically labeled internal standard for quantification. The proposed method was adopted to define lyso-PEs in plasma samples of children aged 9-12 years living in Sapporo, Japan. RESULTS: The limit of detection and limit of quantification for each lyso-PE ranged between 0.001-0.015 and 0.002-0.031 pmol/μL, respectively. Recoveries were found to be > 91% for all the species. The analysis results of children's plasma showed that the total lyso-PE concentrations in boys (n = 181) and girls (n = 161) were 11.53 and 11.00 pmol/μL (median), respectively. Participants were further classified by the percentage of overweight and subgrouped as underweight (n = 12), normal range (n = 292), or overweight (n = 38). Interestingly, the reduction of lyso-PE 16:0 and increased lyso-PE 22:6 were observed in overweight children compared with normal range (Fold change: 0.909 and 1.174, respectively). CONCLUSIONS: This study successfully established a simple quantitative method to determine lyso-PE concentrations. Furthermore, our method revealed the possible relation between plasma lyso-PEs and overweight status.
• Alterations in plasma short-chain fatty acids in preadolescence children: The Hokkaido study
  Yonghan Li; Siddabasave Gowda B. Gowda; Divyavani Gowda; Atsuko Ikeda; Yu Ait Bamai; Rahel Mesfin Ketema; Reiko Kishi; Hitoshi Chiba; Shu-Ping Hui
  Journal of Chromatography B, 1242, 124191, 124191, Elsevier BV, Jul. 2024
  Scientific journal
• 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.
• 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, Elsevier BV, Jan. 2024
  Scientific journal
• 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, Elsevier BV, Nov. 2023
  Scientific journal
• Exposure Trends to the Non-phthalate Plasticizers DEHTP, DINCH, and DEHA in Children from 2012 to 2017: The Hokkaido Study.
  Rahel Mesfin Ketema; Monika Kasper-Sonnenberg; Yu Ait Bamai; Chihiro Miyashita; Holger M Koch; Claudia Pälmke; Reiko Kishi; Atsuko Ikeda
  Environmental science & technology, 57, 32, 11926, 11936, 15 Aug. 2023, [International Magazine]
  English, Scientific journal, Phthalates owing to their endocrine-disrupting effects are regulated in certain products, leading to their replacement with substitutions such as di-2-ethylhexyl terephthalate (DEHTP), 1,2-cyclohexane dicarboxylic acid di(isononyl) ester (DINCH), and di(2-ethylhexyl) adipate (DEHA). However, information on human exposure to these substitutes, especially in susceptible subpopulations such as children, is limited. Thus, we examined the levels and exposure trends of DEHTP, DINCH, and DEHA metabolites in 7 year-old Japanese school children. In total, 180 urine samples collected from 2012 to 2017 were used to quantify 10 DEHTP, DINCH, and DEHA metabolites via isotope dilution liquid chromatography with tandem mass spectrometry. DEHTP and DINCH metabolites were detected in 95.6 and 92.2% of the children, respectively, and DEHA was not detected. This study, annually conducted between 2012 and 2017, revealed a significant (p < 0.05) 5-fold increase in DEHTP metabolites and a 2-fold increase in DINCH metabolites. However, the maximum estimated internal exposures were still below the health-based guidance and toxicological reference values. Exposure levels to DEHTP and DINCH have increased considerably in Japanese school children. DEHA is less relevant. Future studies are warranted to closely monitor the increasing trend in different aged and larger populations and identify the potential health effects and sources contributing to increasing exposure and intervene if necessary.
• E-waste in Vietnam: a narrative review of environmental contaminants and potential health risks.
  Kritika Poudel; Rahel Mesfin Ketema; Hien Thi Thu Ngo; Atsuko Ikeda; Machiko Minatoya
  Reviews on environmental health, 09 Feb. 2023, [International Magazine]
  English, Scientific journal, Informal electronic waste (e-waste) dismantling activities contribute to releasing hazardous compounds in the environment and potential exposure to humans and their health. These hazardous compounds include persistent organic pollutants (POPs), polycyclic aromatic hydrocarbons (PAHs) and heavy metals. This review searched papers addressing hazardous compounds emitted from e-waste recycling activities and their health effects in Vietnam. Based on the keywords searched in three electronic databases (PubMed, Psych Info, and Google scholar), we found 21 relevant studies in Vietnam. The review identifies extensive e-waste dismantling activities in Vietnam in the northern region. To measure the environmental exposure to hazardous compounds, samples such as e-waste recycling workshop dust, soil, air, and sediments were assessed, while human exposure levels were measured using participants' hair, serum, or breast milk samples. Studies that compared levels of exposure in e-waste recycling sites and reference sites indicated higher levels of PBDEs, PCBs, and heavy metals were observed in both environmental and human samples from participants in e-waste recycling sites. Among environmental samples, hazardous chemicals were the most detected in dust from e-waste recycling sites. Considering both environmental and human samples, the highest exposure difference observed with PBDE ranged from 2-48-fold higher in e-waste processing sites than in the reference sites. PCBs showed nearly 3-fold higher levels in e-waste processing sites than in reference sites. In the e-waste processing sites, age-specific higher PCB levels were observed in older recycler's serum samples. Among the heavy metals, Pb was highly detected in drinking water, indoor soil and human blood samples. While high detection of Ni in cooked rice, Mn in soil and diet, Zn in dust and As in urine were apparent. Exposure assessment from human biomonitoring showed participants, including children and mothers from the e-waste processing areas, had higher carcinogenic and non-carcinogenic risks than the reference sites. This review paper highlights the importance of further comprehensive studies on risk assessments of environmentally hazardous substances and their association with health outcomes at e-waste processing sites.
• Nonylphenol exposure in 7-year-old Japanese children between 2012 and 2017- Estimation of daily intakes based on novel urinary metabolites.
  Benedikt Ringbeck; Daniel Bury; Atsuko Ikeda-Araki; Yu Ait Bamai; Rahel Mesfin Ketema; Chihiro Miyashita; Thomas Brüning; Reiko Kishi; Holger M Koch
  Environment international, 161, 107145, 107145, Mar. 2022, [International Magazine]
  English, Scientific journal, Nonylphenol (NP) has been under scrutiny for decades due to its endocrine-disrupting properties and its ubiquity in the environment. Despite its widespread occurrence, robust and reliable exposure data are rare. In this study, we used human biomonitoring (HBM) measuring the novel urinary alkyl-chain-oxidized biomarkers OH-NP and oxo-NP to determine NP exposure in 7-year-old Japanese children. The new biomarkers are advantageous over measuring unchanged NP because they are not prone to external contamination. We analyzed 180 first morning void urine samples collected between 2012 and 2017. OH-NP and oxo-NP were detected in 100% and 66% of samples at median concentrations of 2.69 and 0.36 µg/L, respectively. 10-fold concentration differences between OH-NP and oxo-NP are in line with recent findings on human NP metabolism. Based on OH-NP we back-calculated median and maximum NP daily intakes (DI) of 0.14 and 0.95 µg/(kg bw*d). These DIs are rather close to but still below the current provisional tolerable daily intake of 5 µg/(kg bw*d) by the Danish Environmental Protection Agency. Between 2012 and 2017 the DIs decreased by an average of 4.7% per year. We observed no seasonal changes or gender differences and questionnaire data on food consumption, housing characteristics or pesticide use showed no clear associations with NP exposure. Urinary OH-NP was weakly associated with the oxidative stress (lipid peroxidation) biomarkers N-ε-hexanoyl-lysine (HEL) and trans-4-hydroxy-2-nonenal (HNE) (Spearman ρ = 0.30 and 0.22, respectively), but not with 8-hydroxy-2'-deoxyguanosine (8-OHdG). Further research is needed to identify and understand the major sources of NP exposure and to investigate a potential role in oxidative stress. This study is the first to investigate NP exposure in Japanese children based on robust and sensitive HBM data. It is a first step to fill the long-standing gap in quantitative human NP exposure monitoring and risk assessment.
• Phthalates mixture on allergies and oxidative stress biomarkers among children: The Hokkaido study.
  Rahel Mesfin Ketema; Yu Ait Bamai; Chihiro Miyashita; Takeshi Saito; Reiko Kishi; Atsuko Ikeda-Araki
  Environment international, 160, 107083, 107083, Feb. 2022, [International Magazine]
  English, Scientific journal, BACKGROUND: Exposure to individual phthalates and the mediation effect of oxidative stress in association with asthma and allergic symptoms have been studied previously. Little is known about the mixture effect of phthalates on health outcomes. Thus, we investigated the effect of a mixture of ten phthalate metabolites in association with wheeze, rhino-conjunctivitis, and eczema. The mediating effect of three oxidative stress biomarkers was also assessed. METHODS: Levels of 10 phthalate metabolites and 3 oxidative stress biomarkers were measured in 386 urine samples from 7-year-old children. Parents reported demographic and allergic symptoms using ISAAC questionnaires. Logistic regression for individual metabolites and mixture analysis weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) were fitted to examine the association between phthalate metabolite exposure and health outcomes. Baron and Kenny's regression approach was used for mediation analysis. RESULTS: In logistic regression model showed mono (2-ethyl-5-carboxypentyl) phthalate (MECPP) (OR = 1.41, 95% CI 1.02-1.97) and mono carboxy-isononyl phthalate (cx-MINP) (OR = 1.40, 95% CI 1.07-1.86) were associated with wheeze. The WQS index had a significant association (OR = 1.46, 95% CI 1.09-1.96) with wheeze and (OR = 1.40, 95% CI 1.07-1.82) with eczema. Mono-isononyl phthalate (MINP) and mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP) were the most highly weighted metabolites. In the BKMR model, diisononyl phthalate (DINP) metabolites showed the highest group posterior inclusion probability (PIP). Among DINP metabolites, MINP in wheeze, cx-MINP in rhino-conjunctivitis and OH-MINP in eczema showed the highest conditional PIPs. The overall metabolites mixture effect was associated with eczema. We did not find any mediation of oxidative stress in the association between phthalates and symptoms. No significant association between phthalate metabolites and oxidative stress was observed in this study. CONCLUSION: Mixture of phthalate metabolites were associated with wheeze and eczema. The main contributors to the association were DEHP and DINP metabolites. No mediation of oxidative stress was observed.
• 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, Springer Science and Business Media {LLC}, Dec. 2021
  English, Scientific journal, Abstract
  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.
  
• Secular trends of urinary phthalate metabolites in 7-year old children and association with building characteristics: Hokkaido study on environment and children's health
  Rahel Mesfin Ketema; Yu Ait Bamai; Atsuko Ikeda-Araki; Takeshi Saito; Reiko Kishi
  International Journal of Hygiene and Environmental Health, 234, 113724, 113724, Elsevier {BV}, May 2021
  English, Scientific journal
• Lifestyle behaviors and home and school environment in association with sick building syndrome among elementary school children: a cross-sectional study
  Rahel Mesfin Ketema; Atsuko Araki; Yu Ait Bamai; Takeshi Saito; Reiko Kishi
  Environmental Health and Preventive Medicine, 25, 1, Springer Science and Business Media {LLC}, Dec. 2020
  English, Scientific journal, Abstract
  Background
  Sick building syndrome (SBS) refers to the combination of symptoms experienced by occupants of specific building characteristics. This study investigated the associations of children’s lifestyle behaviors, allergies, home, and school environment with SBS symptoms.
  
  Methods
  A total of 4408 elementary school children living in Sapporo City, Japan participated in this study. SBS was determined on parental answers to MM080 standardized school questionnaires on symptoms that were weekly experienced by these children, and if the symptom is attributed to their home or school environment. The Japanese version of the International Study of Asthma and Allergies in Childhood questionnaire was used to assess wheeze, rhino-conjunctivitis, and eczema. A logistic regression analysis was conducted to evaluate the associations between SBS symptoms and variables by controlling the potential confounders (gender, grade, school, and parental history of allergies). A stepwise backward elimination was conducted to assess independent variables related to SBS.
  
  Results
  Participants revealed mucosal (6.9%), skin (2.0%), and general (0.8%) symptoms. The presence of one or more allergy was associated with increased mucosal and skin symptoms. Children who skipped breakfast, displayed faddiness (like/dislike of food), had constipation, have insufficient sleep, did not feel refreshed after sleep, and lacked deep sleep showed significantly high odds ratios with SBS symptoms. The stepwise analysis showed faddiness for mucosal symptoms and not feeling refreshed after sleep for mucosal and skin symptoms, whereas constipation and lacking deep sleep for general symptoms were independent variables in increasing the symptoms. We found no significant relationship between SBS in children and schools. Considering children’s home, old building, no ventilation, wall-to-wall carpet, and heavy nearby traffic were associated with elevated mucosal symptom, while living in a multifamily home increased general symptoms. Home dampness was an independent variable in increasing all SBS symptoms.
  
  Conclusions
  Allergies and lifestyle behaviors were associated with increased SBS in children, including skipping breakfast, displaying faddiness, constipation, insufficient sleep, not feeling refreshed after sleep, and the lack of deep sleep. Further, dampness at home was associated with increase in all SBS symptoms. Lifestyle (e.g., eating and sleeping habits) and home (i.e., dampness) improvements might alleviate SBS symptoms in children.
  
• Long-term effects of maternal resveratrol intake during lactation on cholesterol metabolism in male rat offspring
  Shojiro Yamasaki; Tomomi Tomihara; Goh Kimura; Yukako Ueno; Rahel Mesfin Ketema; Shin Sato; Yuuka Mukai; Tajuddin Sikder; Masaaki Kurasaki; Toshiyuki Hosokawa; Takeshi Saito
  International Journal of Food Sciences and Nutrition, 71, 2, 226, 234, Informa {UK} Limited, 17 Feb. 2020
  English, Scientific journal
• Polyphenol-enriched azuki bean (Vina angularis) extract reduces the oxidative stress and prevents DNA oxidation in the hearts of streptozotocin-induced early diabetic rats
  Tomomi Kita-Tomihara; Shin Sato; Shojiro Yamasaki; Yukako Ueno; Goh Kimura; Rahel M. Ketema; Tae Kawahara; Masaaki Kurasaki; Takeshi Saito
  International Journal of Food Sciences and Nutrition, 70, 7, 845, 855, Informa {UK} Limited, 03 Oct. 2019
  English, Scientific journal
• Associations between allergic symptoms and phosphate flame retardants in dust and their urinary metabolites among school children
  Atsuko Araki; Michiel Bastiaensen; Yu Ait Bamai; Nele Van den Eede; Toshio Kawai; Tazuru Tsuboi; Rahel Mesfin Ketema; Adrian Covaci; Reiko Kishi
  Environment International, 119, 438, 446, Elsevier {BV}, Oct. 2018
  English, Scientific journal
• Indoor environmental pollutants and their association with sick house syndrome among adults and children in elementary school
  Reiko Kishi; Rahel Mesfin Ketema; Yu Ait Bamai; Atsuko Araki; Toshio Kawai; Tazuru Tsuboi; Ikue Saito; Eiji Yoshioka; Takeshi Saito
  Building and Environment, 136, 293, 301, Elsevier {BV}, May 2018
  English, Scientific journal
• House Dust and Its Adverse Health Effects
  Atsuko ARAKI; Yu AIT BAMAI; Rahel Mesfin KETEMA; Reiko KISHI
  Nippon Eiseigaku Zasshi (Japanese Journal of Hygiene), 73, 2, 130, 137, Japanese Society for Hygiene, 2018
  English, Scientific journal
• 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; S. Sasaki; T. Ikeno; E. Okada; S. Nishihara; R. M. Ketema; T. Kita; I. Kashino; T. Baba; T. S. Braimoh; S. Minakami; K. Cho; N. Shinohara; K. Moriya; T. Mitsui; T. Saito; S. Suyama; T. Nomura; S. Konno; H. Matsuura; M. Ishizuka; T. Endo; T. Baba; F. Sata; K. Sengoku; Y. Saijo; E. Yoshioka; T. Miyamoto; M. Yuasa; J. Kajiwara; T. Hori; Y. Chisaki; T. Matsumura; F. Mizutani; J. Yamamoto; Y. Onoda; T. Kawai; T. Tsuboi
  Environmental Health and Preventive Medicine, 22, 1, 2017
  Scientific journal

• Indoor environmental quality and health risk toward healthier environment for all
  Kishi, Reiko; Norbäck, Dan; Araki, Atsuko
  Springer, 2020, 9789813291812, viii, 333 p., English

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