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山口　健史 (ヤマグチ　タケシ)

環境健康科学研究教育センター特任准教授

研究者基本情報

■ 学位
  • 博士, 北海道大学, 2020年03月
■ URL
researchmap URL■ ID 各種
研究者番号
  • 80894972
ORCID IDJ-Global ID■ 研究キーワード・分野
研究分野
  • ライフサイエンス, 衛生学、公衆衛生学分野：実験系を含む
  • ライフサイエンス, 代謝、内分泌学
  • ライフサイエンス, 胎児医学、小児成育学

経歴

■ 経歴
経歴
  • 2024年04月 - 現在
    北海道大学, 環境健康科学研究教育センター, 副センター長
  • 2023年10月 - 現在
    北海道大学, 環境健康科学研究教育センター, 特任准教授
  • 2016年04月 - 現在
    北海道大学病院, 小児科
  • 2021年01月 - 2023年09月
    北海道大学, 環境健康科学研究教育センター, 特任講師
学内役職歴
  • 環境健康科学研究教育副センター長, 2024年4月1日 - 2025年3月31日

研究活動情報

■ 受賞
  • 2022年, 日本医師会, 2022年度日本医師会 医学研究奨励賞
    「思春期における肥満形成基盤の解明とコロナ禍による生活習慣変容の影響の検討」
■ 論文
  • 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, 2026年07月
    研究論文（学術雑誌）
  • Relationship between pre-pregnancy body mass index and postpartum depression, and the mediation effects of cesarean delivery, low birth weight, child anomaly, and breastfeeding: a prospective birth cohort in the Japan environment and children’s study
    Yasuaki Saijo; Yukihiro Sato; Hiroyuki Shiotsuki; Tomoki Ishikawa; Eiji Yoshioka; Kentaro Nakanishi; Yasuhito Kato; Ken Nagaya; Satoru Takahashi; Yoshiya Ito; Mariko Itoh; Hiroyoshi Iwata; Takeshi Yamaguchi; Reiko Kishi; Michihiro Kamijima; Shin Yamazaki; Maki Fukami; 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, 2026年05月27日, ［査読有り］
    英語, 研究論文（学術雑誌）
  • Postnatal growth trajectories of very preterm appropriate-for-gestational-age infants from term-equivalent age to 6 years.
    Akinori Moriichi; Yumi Kono; Katsuaki Toyoshima; Yoshiya Ito; Kazutoshi Cho; Katsumi Mizuno; Yasuka Kimoto; Reiko Kushima; Nozomi Ishii; Takeshi Yamaguchi; Keiji Hashimoto; Yukari Yada
    Pediatric research, 2026年03月10日, ［国際誌］
    英語, 研究論文（学術雑誌）, BACKGROUND: Very preterm infants born before 32 weeks of gestation remain vulnerable to postnatal growth impairment. However, longitudinal data focusing on appropriate-for-gestational-age (AGA) infants are limited. Standard growth references may inadequately reflect the developmental trajectories of this population. METHODS: We constructed sex-specific growth curves for height, weight, body mass index, and head circumference from term-equivalent age to 6 years postmenstrual age in AGA infants born at <32 weeks of gestation without neurodevelopmental impairments. These trajectories were compared with Japanese national growth standards. RESULTS: Infants born before 28 weeks of gestation demonstrated significantly reduced growth relative to national standards, with the greatest deviation occurring between 40 and 60 weeks postmenstrual age. While gradual catch-up growth was observed thereafter, full alignment with standard curves was not achieved. Lower gestational age correlated with more pronounced deficits across all anthropometric parameters. Head circumference remained notably reduced among infants born before 25 weeks, raising concern for potential neurodevelopmental implications. CONCLUSIONS: Extremely preterm AGA infants experience persistent growth deficits through early childhood. These findings underscore the importance of long-term growth surveillance and early intervention strategies to support optimal physical and neurological outcomes in this high-risk population. IMPACT: Many extremely preterm infants grow more slowly than expected well into early childhood. Babies born earlier in pregnancy show more delayed physical growth across all measures. Infants born before 25 weeks may have a smaller head size, raising concerns for brain development.
  • 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
    BMC pregnancy and childbirth, 2026年03月06日, ［国際誌］
    英語, 研究論文（学術雑誌）
  • 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, 295, 123839, 123839, 2026年03月, ［国際誌］
    英語, 研究論文（学術雑誌）, PURPOSE: This study aimed to evaluate the associations of prenatal exposure to organophosphate pesticides (OPP) with eczema and allergic rhinoconjunctivitis (AR) in 4-year-old Japanese children. METHODS: The participants in this study were Sub-Cohorts of the Japan Environment and Children's Study (JECS). The maternal urinary OPP metabolite concentrations of six dialkylphosphates (DAPs) were measured by lipid chromatography coupled with tandem mass spectrometry, corrected by specific gravity. Eczema and AR cases were defined according to the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire for children at 4 years old. Multiple logistic regression analysis was used to examine the associations of DAPs with eczema and AR. Sub-group analyses were performed to explore the association between DAP metabolites and AR and eczema in children with elevated (≥170 IU/mL) and lower (<170 IU/mL) serum IgE levels. RESULTS: Data from 4218 participants were analyzed. The highest DAP concentration was observed in the dimethylthiophosphate (DMTP) (Median: 3.33 ng/ml). Out of the six measured OPP metabolites, only 3 could be used for the analyses. There were positive associations of dimethylphosphate (DMP) (adjusted OR = 1.30; 95%CI = 1.06-1.59; FDR-adjusted p = 0.048) with eczema. No associations were found with AR or IgE alone. Sub-group analysis revealed a positive association between DMTP and eczema in children with lower IgE levels (<170 IU/mL) (adjusted OR = 1.28; 95%CI = 1.04-1.57; p = 0.02). CONCLUSION: Prenatal DMP and DMTP were associated with an increased risk of eczema in children aged 4, with this association confined to children with DMTP and lower IgE levels, while no associations were found with AR or IgE levels.
  • Echinococcosis in Japan: Time to Reconsider a Neglected Endemic.
    Hiroyoshi Iwata; Takeshi Yamaguchi; Keitaro Makino; Reiko Kishi
    Internal medicine (Tokyo, Japan), 2025年12月25日, ［国内誌］
    英語, 研究論文（学術雑誌）
  • 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, 2025年12月15日, ［国際誌］
    英語, 研究論文（学術雑誌）, BACKGROUND: This study aimed to clarify the network structure of the Edinburgh Postnatal Depression Scale (EPDS) in postpartum women using data from the Japan Environment and Children's Study (JECS), a large-scale nationwide birth cohort. METHODS: Network analysis was performed on EPDS data from 89,151 participants at 1 and 6 months postpartum. Gaussian graphical models (GGM) were employed to estimate the direct relationships between EPDS items; predictability measures were used to assess the degree of variance in each item that could be explained by the network. Subgroup analyses were conducted for groups with high (≥9) and low (<9) EPDS scores based on the Japanese cutoff for postpartum depression screening. RESULTS: The EPDS network structure was well-preserved from 1 month to 6 months postpartum. In both periods, "Sad" and "Anxious" demonstrated high centrality, playing key roles in the psychological network. Strong associations between "Hard to sleep" and "Self-harm" were observed in the high-score group at 1 month postpartum, but not at 6 months. Overall predictability was lower in the high-score group, suggesting greater involvement of external factors such as social support, economic conditions, and childcare burden. CONCLUSIONS: This study provides the first insights into the EPDS network structure among postpartum women. Anxiety, sadness, and sleep disturbances emerged as key symptoms, underscoring the need for early intervention. Lower predictability in the high-score group suggests the influence of external factors, emphasizing the need for comprehensive support programs. Future research should consider other populations and time points, such as pregnancy and beyond 1 year postpartum.
  • 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, 18, 1, 7, 7, 2025年12月01日, ［国際誌］
    英語, 研究論文（学術雑誌）, BACKGROUND: Childhood obesity is a pressing public health and pediatric issue. Recently, epigenome-wide association study (EWAS) has received increasing research attention and revealed the association between cord blood methylation and pediatric health problems. However, the relationship between cord blood DNA methylation and childhood obesity remains incompletely understood. This study aimed to assess cord blood DNA methylation and its association with childhood obesity using an EWAS. RESULTS: The present study included 12-year-old children with obesity and control participants from the Hokkaido Study on Environment and Children's Health (the Hokkaido cohort), a prospective birth cohort study. The Hokkaido cohort study collected participants' cord blood samples at birth, which were evaluated using an EWAS. We conducted robust linear regression analysis for the differentially methylated positions (DMPs). Thereafter, we also conducted differentially methylated region (DMR) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. As a result, our analysis involved 500 children, comprising 218 individuals with obesity and 282 controls with no obesity. After quality control, 428 high-quality samples remained (192 children with obesity and 236 controls). Although our DMP analysis did not produce statistically significant results with adjusted p-values with Bonferroni correction and local false discovery rate (FDR) correction, our DMP analysis identified potential candidate genes with a global FDR correction of < 0.05. Three differentially methylated cytosine-phosphate-guanine candidate sites (cg27093962 in dynein regulatory complex 1 [DRC1], cg25187049 in Potassium Voltage-Gated Channel Subfamily B Member 2 [KCNB2], and cg07817806 in Uromodulin [UMOD]) were found to be potentially associated with childhood obesity. Among them, KCNB2 and UMOD are implicated in metabolic and inflammatory pathways relevant to obesity. While DMR analysis did not produce statistically significant results, KEGG analysis revealed potential pathways associated with childhood obesity. CONCLUSION: The present study suggests three candidate DMPs and pathways that may explain the association between DNA methylation at birth and obesity at 12 years of age.
  • 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, 2025年11月26日, ［国際誌］
    英語, 研究論文（学術雑誌）, 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.
  • 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
    The Science of the total environment, 1006, 180895, 180895, 2025年11月10日, ［国際誌］
    英語, 研究論文（学術雑誌）, BACKGROUND: Urinary tract infections (UTIs) are common bacterial infections in young children and can lead to long-term renal complications. While established risk factors exist, the effect of prenatal exposure to toxic metals and trace elements on UTI risk remains unclear. We examined the association between maternal blood levels of these elements and UTI risk in early childhood. METHODS: This study is based on a nationwide birth cohort, the Japan Environment and Children's Study (JECS), which obtained data from over 100,000 pregnancies through 15 Regional Centres across Japan. Maternal blood samples were collected during mid-late pregnancy and the concentrations of selenium, manganese, lead, cadmium, and mercury were measured. Child UTI diagnoses during the first 2 years of life were assessed by caregiver questionnaires. Multivariable logistic regression models examined associations between log2-transformed level of metals and trace elements and UTI. RESULTS: Overall, 79,161 mother-child pairs were analyzed. During the first 2 years, 877 (1.1 %) children were diagnosed with UTI. Higher maternal selenium levels were associated with increased UTI risk (Odds ratio for a twofold increase in selenium: 1.58, 95 % CI: 1.06-2.35) after adjusting for covariates. The adjusted odds ratios (95 % CI) of other elements were 0.97 (0.82-1.14) in manganese, 1.01 (0.88-1.15) in lead, 0.94 (0.84-1.05) in cadmium, and 1.02 (0.93-1.11) in mercury. CONCLUSIONS: Elevated maternal selenium levels may increase susceptibility to UTIs during the first 2 years of life. Further studies are needed to investigate long-term effects, including bladder and kidney dysfunction.
  • 出生体重500gごとの成長曲線 エコチル調査より
    山口 健史; 田村 菜穂美; 岩田 啓芳; 中村 明枝; 伊藤 善也; 山内 太郎; 岸 玲子
    日本成長学会雑誌, 31, 2, 65, 65, 日本成長学会, 2025年11月
    日本語
  • Cord Blood Mitochondrial DNA Copy Number and Physical Growth in Infancy and Toddlerhood: A Birth Cohort Analysis
    Hisanori Fukunaga; Takeshi Yamaguchi; Hiroyoshi Iwata; Atsuko Ikeda
    Children, 12, 10, 2025年10月10日, ［国際誌］
    英語, 研究論文（学術雑誌）, Background/Objectives: Cord blood mitochondrial DNA copy number (mtDNAcn) has been proposed as a biomarker reflecting environmental influences during fetal life, with reported associations with perinatal outcomes such as birth weight and length. Within the framework of the Developmental Origins of Health and Disease (DOHaD) theory, this study aimed to investigate whether cord blood mtDNAcn is related to postnatal physical growth in early childhood. Methods: We analyzed data from 150 newborns (68 females and 82 males) enrolled in the Tohoku Medical Megabank Birth and Three-Generation Cohort Study in Japan. Cord blood mtDNAcn was quantified using real-time PCR, and standard deviation scores for weight and height were assessed at 1, 2-3, 4-6, 18-24, and 36-48 months of age. Correlation analyses were conducted separately by sex. Results: Cord blood mtDNAcn showed no significant associations with body weight or height at any of the postnatal time points up to 48 months of age. Growth trajectories of infants with higher or lower mtDNAcn values at birth tended to converge toward the population mean during infancy and toddlerhood. Conclusions: Although no significant relationships were observed, this exploratory, hypothesis-generating study provides a foundation for future investigations. Larger cohorts with extended follow-up are needed to clarify the potential significance of cord blood mtDNAcn in early-life research on child growth and health.
  • Small for gestational age as a predictor of developmental coordination disorders: Exploring early risk from Japan birth cohort consortium.
    Hiroyoshi Iwata; Maki Tojo; Kenji J Tsuchiya; Mami Ishikuro; Geng Chen; Satoshi Suyama; Akio Nakai; Naomi Tamura; Toshio Yoshikawa; Toyoki Yamagata; Tomoko Nishimura; Takeshi Yamaguchi; Keiko Yamazaki; Taku Obara; Kazue Ishitsuka; Naho Morisaki; Keitaro Makino; Shinichi Kuriyama; Reiko Kishi
    Brain & development, 47, 5, 104435, 104435, 2025年10月, ［国際誌］
    英語, 研究論文（学術雑誌）, BACKGROUND: Small for gestational age (SGA) and developmental coordination disorder (DCD) are receiving increasing attention in pediatric development. Understanding the risk of DCD, particularly in relation to SGA, would support children's health and development. However, the relationship between SGA and DCD remains unveiled beyond single-cohort studies. OBJECTIVES: This study aimed to integrate findings on DCD from different cohorts within the nationwide prospective Japanese Birth Cohort Consortium (JBiCC). STUDY DESIGN AND SUBJECTS: DCD was assessed in children aged 4 to 7 years from three birth cohorts participating in the JBiCC: the Hokkaido Study on Environment and Children's Health (Hokkaido Study), the Hamamatsu Birth Cohort for Mothers and Children (HBC Study), and the Tohoku Medical Megabank Project Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study). OUTCOME MEASURES: DCD was assessed using either the Developmental Coordination Disorder Questionnaire Japanese Version (DCDQ-J) or the Ages and Stages Questionnaires Third Edition (ASQ-3). Logistic regression was used to assess the association between SGA and DCD in each cohort. Second, meta-analysis of the association between SGA and DCD defined by DCDQ-J, and individual patient data (IPD) meta-analysis of the association between SGA and DCDQ-J scores were conducted with two cohorts. RESULTS AND CONCLUSIONS: The analysis included 14,233 children in three cohorts. The individual cohort analyses did not explore statistical significance, except for the TMM BirThree Cohort Study. Meta-synthesis of the Hokkaido and HBC studies showed a β-coefficient of -2.63, 95 % CI [-5.22, -0.03]. IPD analysis of linear regression showed a β-coefficient of -2.76, 95 % CI [-5.38, -0.15]. Our results suggest that SGA may be a potential risk factor for DCD.
  • 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 : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology, 34, 4, 226, 239, 2025年10月, ［国内誌］
    英語, 研究論文（学術雑誌）, Growth charts are essential tools for monitoring the physical development of children. We analyzed data from a nationwide Japanese birth cohort of 98,987 participants to create eight growth charts stratified by birth weight in 500-gram increments. Infants with birth weight < 2,500 g showed significant improvements in height and weight standard deviation (SD) scores by 4 yr of age. Boys and girls weighing 500-999 g at birth had average length/height SD scores of -6.40 and -8.20, which improved to -1.26 and -1.17 by 4 yr of age, respectively. Conversely, infants with birth weight ≥ 3,500 g showed decreased height and weight SD scores by 4 yr of age. Boys and girls weighing ≥ 4,000 g had average length/height SD scores of 1.87 and 2.10 at birth, which decreased to 0.34 and 0.51 by 4 yr of age, respectively. These findings reveal distinct growth patterns for different birth weight categories, highlighting the impact of birth weight on early childhood growth trajectories. The growth charts developed here serve as a valuable tool for evaluating children born small or large. These charts enable a more accurate monitoring of children's growth and can be useful in both clinical and public health settings.
  • 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), 2025年09月, ［国際誌］
    英語, 研究論文（学術雑誌）, 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.
  • Effects of maternal occupation on low birth weight and preterm birth: A prospective birth cohort study in the first trimester, the Japan environment and Children's study.
    Sumitaka Kobayashi; Hiroyoshi Iwata; Takeshi Yamaguchi; Naomi Tamura; Mariko Itoh; Maki Tojo; Keiko Yamazaki; Yasuaki Saijo; Yoshiya Ito; Reiko Kishi
    International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics, 172, 2, 991, 1008, 2025年08月11日, ［国際誌］
    英語, 研究論文（学術雑誌）, OBJECTIVE: Although there are some reports that maternal occupation during pregnancy decreases birth size, the results are inconsistent. Hence, we examined the association of maternal occupation during pregnancy with infant low birth weight (LBW) and preterm birth (PB). METHODS: We used data from 53 932 participants of the prospective birth cohort of the Japan Environment and Children's Study. During the first trimester, information on maternal occupational major and minor groups, type of employment, and average weekly working hours was obtained using a self-administered questionnaire. Information on LBW and PB was obtained from medical records transcribed by physicians, midwives/nurses, and/or research coordinators at birth. Associations between maternal occupation and birth outcomes were examined using logistic regression models adjusted for confounding factors. RESULTS: In the major occupational group, the odds ratio (95% confidence interval) of LBW in administrative and managerial workers (0.52; 0.32-0.84) was lower than that in professional and engineering workers. Among administrative and managerial workers, the percentages of LBW among management government officials (4.6%), officers of companies and organizations (4.0%), and management staff of companies and organizations (7.1%) were lower than the overall average of 8.2%. Similar results were found for LBW at full-term (Term-LBW; ≥37 weeks of gestational age). However, there were no associations between the maternal major occupational groups on PB. We observed the association of maternal occupation in the first trimester on infant LBW and Term-LBW. CONCLUSION: The results suggest that medical professionals need to advise considering maternal occupation when performing pregnancy checkups.
  • Associations between urinary phthalate metabolites and reproductive, adrenal, and gonadotropic hormones in peripubertal children: the Hokkaido study
    Ayaka Yasuda; Yu Ait Bamai; Takeshi Yamaguchi; Rahel Mesfin Ketema; Yi Zeng; Megasari Marsela; Yoshinori Ikenaka; Akie Nakamura; Takeya Kitta; Masafumi Kon; Atsushi Manabe; Reiko Kishi; Hiroyuki Kojima; Atsuko Ikeda
    Environmental Research, 276, 121535, 121535, 2025年07月, ［国際誌］
    英語, 研究論文（学術雑誌）, Phthalates have raised concerns regarding the disruption of hormone synthesis and signaling. The purpose of this study was to investigate the associations between urinary phthalate metabolites and 18 hormones, including reproductive, adrenal, and gonadotropic hormones, in peripubertal children. The study comprised a cross-sectional analysis of participants in the Hokkaido Birth Cohort Study. We collected data from 429 school children aged 9-12 living in Sapporo, Japan. Ten phthalate metabolites and 14 steroid hormones were analyzed using LC-MS/MS, whereas four peptide hormones were detected using immunoassays. Multivariable linear regression, quantile-based g-computation (qg-computation), and Bayesian kernel machine regression (BKMR) were used to investigate the associations between the individual phthalate metabolites and the phthalate mixtures with hormone levels, as well as with puberty based on hormone levels. In girls, we found that higher phthalate metabolite levels, as well as phthalate mixtures, were significantly associated with lower dehydroepiandrostenedione-sulfate (DHEA-S) and higher (androstenedione + testosterone)/DHEA-S. The higher phthalate mixture showed lower levels of LH, FSH, and cortisol levels among girls, whereas higher 11-deoxycortisol levels. In boys, a higher phthalates mixture was significantly associated with a higher estradiol/testosterone ratio, whereas lower levels of insulin-like factor-3 (INSL3), testosterone, (androstenedione + testosterone)/DHEA-S, testosterone/androstenedione, and cortisol/cortisone. Higher phthalate mixtures were associated with lower prevalence of puberty in girls. These findings indicate that phthalate exposure may disrupt the hormones in children during puberty.
  • Association of Phthalate Exposure with Respiratory and Allergic Symptoms and Type 2 and Non-Type 2 Inflammation: The Hokkaido Study
    Rahel Mesfin Ketema; Yu Ait Bamai; Houman Goudarzi; Takeshi Yamaguchi; Yi Zeng; Ayaka Yasuda; Megasari Marsela; Satoshi Konno; Reiko Kishi; Atsuko Ikeda
    Environmental Science & Technology, 59, 15, 7541, 7549, 2025年04月22日, ［国際誌］
    英語, 研究論文（学術雑誌）, 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.
  • Adiposity rebound and body mass index in Japanese patients with congenital hypothyroidism.
    Kanako Nakayama; Naoya Kaneko; Nozomi Hishimura; Takeshi Yamaguchi; Shuntaro Morikawa; Isao Yokota; Hotaka Kamasaki; Keisuke Nagasaki; Yukihiro Hasegawa; Akie Nakamura
    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology, 34, 2, 121, 130, 2025年04月, ［国内誌］
    英語, 研究論文（学術雑誌）, The long-term prognosis of congenital hypothyroidism (CH) has become apparent since the introduction of newborn screening programs; however, the risk of obesity in patients with CH remains unclear. Early adiposity rebound (AR) is one of the predictors of obesity in adults. This study evaluated AR and the adolescent body mass index (BMI) in Japanese patients with CH. We longitudinally collected anthropometric measurements from 288 patients aged 1-10 yr and plotted their BMI curves to determine the age at onset of AR. We also evaluated the effects of thyroid function, presence of distal femoral epiphysis (DFE) ossification, and disease type on AR age and adolescent BMI. The mean AR ages were determined to be 5.5 ± 1.4 yr in boys and 5.9 ± 1.5 yr in girls. There were no significant differences in AR age or adolescent BMI according to thyroid-stimulating hormone or free T4 levels before treatment initiation or according to disease type. However, at the last visit, more than half of the boys without DFE ossification had higher BMI SD scores than those with DFE ossification. These findings raise the possibility that severe prolonged fetal hypothyroidism may have a lasting influence after birth despite early treatment initiation.
  • 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, 2025年04月, ［国際誌］
    英語, 研究論文（学術雑誌）, Although per- and polyfluoroalkyl substances (PFAS) have raised global concern due to their adverse effects on children's development, the association between prenatal exposure to PFAS and the achievement of developmental milestones in preschool children remains unclear. This study aimed to examine the individual and cumulative associations between prenatal PFAS and developmental delay in 4-year-old children. We used data from 15,131 mothers (15,175 children) in the Japan Environment and Children Study (JECS), an ongoing nationwide prospective birth cohort. Among 28 PFAS measured in maternal plasma, eight with detection frequencies ≥ 60 % were analyzed. Developmental delays were assessed using the Japanese version of the Ages and Stages Questionnaires third edition (JASQ-3), a self-administered screening tool, with suspicion of developmental delay indicated by total scores falling below the Japanese version cutoffs for the five JASQ-3 domains (communication, gross motor, fine motor, problem solving, and personal-social). Univariate and multivariable logistic regression analysis and quantile g-computation were applied. Findings revealed that these eight PFAS were not significantly associated with higher odds of developmental delay across any JASQ-3 domain, nor did their combined effects. However, the effects of PFAS substances not measured in this study and the impact of continued postnatal exposure to PFAS on developmental delays remain a concern. Continuous investigation of the effects of PFAS on development throughout the lifespan is necessary.
  • 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, 135, 108905, 108905, Elsevier BV, 2025年04月, ［国際誌］
    英語, 研究論文（学術雑誌）, Prenatal passive and active smoking and oxidative stress are of concern because of their adverse effects on infant birth sizes. This study aimed to examine the mediation of maternal cotinine and 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels during pregnancy on infant birth size by occupation. The study used data from 72,544 participants of the Japan Environment and Children's Study (JECS), an ongoing nationwide prospective birth cohort. We used maternal cotinine in urine as a biomarker for prenatal passive and active smoking and maternal 8-OHdG as a biomarker for prenatal oxidative stress. In all participants, multiple linear regression analysis adjusted for covariates showed birth weight (95 % confidence interval; CI) at cotinine level 5 (active smoker level) decreased by 140 (127, 152) g compared to birth weight at cotinine level 1 (non-smoker level), and birth weight at the fourth quartile of 8-OHdG level decreased by 18 (12, 25) g compared to birth weight at the first quartile of 8-OHdG level. When stratified by maternal occupation, no association was found between the cotinine levels of maternal passive smoking exposure and birth size. The association between cotinine levels and decreased birth size in all the participants was mediated by 8-OHdG. The results showed that there was a maternal cotinine levels during pregnancy on birth size in infants.
  • 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, 2025年03月18日, ［国際誌］
    英語, 研究論文（学術雑誌）, 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.
  • 胎児期フタル酸エステル類混合曝露と前思春期の性ホルモンとの関連 北海道スタディ
    安田 彩夏; アイツバマイ ゆふ; 山口 健史; ケテマ・ラヒルメスフィン; 曾 怡; 池中 良徳; メガサリ・マルセラ; 岸 玲子; 小島 弘幸; 池田 敦子
    日本衛生学雑誌, 80, Suppl., S233, S233, (一社)日本衛生学会, 2025年03月
    日本語
  • 妊婦における社会経済要因・喫煙と妊娠前の低体重・肥満との関連(エコチル調査)
    西條 泰明; 吉岡 英治; 佐藤 遊洋; 九里 優輝; 金谷 智子; 中西 研太郎; 加藤 育民; 長屋 健; 高橋 悟; 伊藤 善也; 岩田 啓芳; 山口 健史; 宮下 ちひろ; 伊藤 佐智子; 岸 玲子
    日本衛生学雑誌, 80, Suppl., S255, S255, (一社)日本衛生学会, 2025年03月
    日本語
  • 妊婦における社会経済要因・喫煙と妊娠前の低体重・肥満との関連(エコチル調査)
    西條 泰明; 吉岡 英治; 佐藤 遊洋; 九里 優輝; 金谷 智子; 中西 研太郎; 加藤 育民; 長屋 健; 高橋 悟; 伊藤 善也; 岩田 啓芳; 山口 健史; 宮下 ちひろ; 伊藤 佐智子; 岸 玲子
    日本衛生学雑誌, 80, Suppl., S255, S255, (一社)日本衛生学会, 2025年03月
    日本語
  • 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), 2025年02月27日, ［国際誌］
    英語, 研究論文（学術雑誌）, 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.
  • Effects of the Maternal Work Environment on Psychological Distress During Pregnancy
    Sumitaka Kobayashi; Yasuaki Saijo; Mariko Itoh; Naomi Tamura; Maki Tojo; Hiroyoshi Iwata; Takeshi Yamaguchi; Yoshiya Ito; Reiko Kishi
    Journal of Occupational & Environmental Medicine, 2025年02月
    研究論文（学術雑誌）
  • Sick building syndrome, multiple chemical sensitivity, and related factors: A cross-sectional analysis from the Japan Environment and Children's Study.
    Yasuaki Saijo; Eiji Yoshioka; Yukihiro Sato; Hiroyuki Shiotsuki; Kentaro Nakanishi; Yasuhito Kato; Ken Nagaya; Satoru Takahashi; Yoshsiya Ito; Atsuko Ikeda; Hiroyoshi Iwata; Takeshi Yamaguchi; Reiko Kishi
    PloS one, 20, 6, e0324562, 2025年, ［国際誌］
    英語, 研究論文（学術雑誌）, Sick building syndrome (SBS) is caused by having unhealthy indoor environments. Multiple chemical sensitivity (MCS) is a chronic condition that is potentially triggered by low-level chemical exposure. Demographic factors, lifestyle factors, and comorbidities have been reported as potential risk factors of both conditions; however, studies on these factors involving large populations in Japan are limited. The aim of this study was to investigate whether demographics, lifestyle, and comorbidities were associated with MCS and SBS in a large Japanese population, and whether autistic traits (Japanese version of the Autism-Spectrum Quotient Short Form, AQ-10-J), psychological distress (Japanese version of the Kessler 6-Item Psychological Distress Scale, K6), and serum total and allergen-specific immunoglobulin E (IgE) levels were related to the outcomes. The participants included 92,387 pregnant women and 48,451 partners. The outcomes were self-reported physician-diagnosed SBS, MCS, and SBS and/or MCS (combined outcome [CO]). Age-adjusted odds ratios (ORs) of total and antigen-specific IgE levels, demographic factors, and lifestyle factors were determined. The proportions of pregnant women with SBS, MCS, and CO were 307 (0.33%), 128 (0.14%), and 415 (0.45%), respectively, while those of their partners were 85 (0.18%), 30 (0.06%), and 112 (0.23%), respectively. Allergic diseases, psychiatric diseases, migraine, and higher psychological distress were associated with significantly higher ORs for SBS, MCS, and CO. Among pregnant women, autoimmune diseases, cancer, kidney diseases, higher physical activity, autistic traits, and total and specific IgE levels were associated with significantly higher ORs for SBS, MCS, and CO. Clinicians should consider common comorbid disorders when treating patients with SBS and MCS, and their protective and deteriorating lifestyles and demographic factors should be clarified.
  • Association between small for gestational age and neurodevelopmental disability at 5 years in the Hokkaido study.
    Satoshi Suyama; Mariko Itoh; Naomi Tamura; Hiroyoshi Iwata; Takeshi Yamaguchi; Sumitaka Kobayashi; Chihiro Miyashita; Takuya Saito; Reiko Kishi
    Pediatrics international : official journal of the Japan Pediatric Society, 67, 1, e70137, 2025年, ［国際誌］
    英語, 研究論文（学術雑誌）, BACKGROUND: Low birth weight is a known risk factor for delayed growth and disability in children. It is assessed using a measure called small for gestational age (SGA). SGA children have an increased risk of neurodevelopmental disabilities, regardless of gestational age. We conducted this study to evaluate the effects of SGA on neurodevelopmental disability, particularly in SGA full-term newborns (term-SGA). METHODS: This study was conducted using a prospective birth cohort from the Hokkaido Study on Environment and Children's Health. The mothers of 4851 children who reached the age of 5 years between April 2008 and November 2011 received questionnaires, including the strengths and difficulties questionnaire (SDQ). Neurodevelopmental disability was assessed using the SDQ. SGA infants, including term-SGA, were assessed by referring to the birth weight database of the Japan Pediatric Society. RESULTS: We received 3484 responses from the parents. Univariate analysis revealed a significant difference in hyperactivity/inattention and the total difficulties score (TDS) between groups defined as normal and borderline/clinical based on the TDS, for both SGA and term-SGA infants. In the multivariate analysis, sex, household income, and SGA and term-SGA status were significantly associated with TDS (term-SGA: odds ratio [OR] = 1.72; 95% confidence interval [CI], 1.07-2.76; SGA, OR = 1.75; 95% CI: 1.10-2.78). However, SGA and term-SGA status were not associated with hyperactivity/inattention. CONCLUSIONS: SGA, even at term, may predispose children to neurodevelopmental disability.
  • 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, 2024年12月26日, ［国際誌］
    英語, 研究論文（学術雑誌）, 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.
  • Association between the occupation of pregnant women’s partners and risks of infant low birth weight and preterm birth in a prospective birth cohort: the Japan Environment and Children’s Study
    Sumitaka Kobayashi; Yasuaki Saijo; Hiroyoshi Iwata; Takeshi Yamaguchi; Naomi Tamura; Mariko Itoh; Maki Tojo; Yoshiya Ito; Reiko Kishi
    Journal of Occupational & Environmental Medicine, 67, 3, 161, 170, 2024年11月19日, ［国際誌］
    英語, 研究論文（学術雑誌）, OBJECTIVE: We examined the association between the occupations of pregnant women's partners and infant low birth weight (LBW) and preterm birth (PB). METHODS: Birth outcome data were collected from 46,540 participants enrolled in the Japan Environment and Children's Study. Participants were recruited from January 2011 to March 2014. Associations between the occupations of pregnant women's partners and birth outcomes were examined using logistic regression models adjusted for confounding factors. RESULTS: LBW and PB incidences were 7.5% and 4.1%, respectively. In the major occupational group, the odds ratios (95% confidence intervals) of LBW for clerical (1.19; 1.03-1.37) and service workers (1.21; 1.05-1.39) were higher than those for professional and engineering workers. However, no associations existed between the major occupational groups of the pregnant women's partners and PB. CONCLUSIONS: Partner's employment in clerical and service works increases the risk for LBW.
  • Association between small for gestational age and motor coordination difficulties in children aged 5-6 years: Insights from the Hokkaido Study on Environment and Children's Health.
    Maki Tojo; Hiroyoshi Iwata; Naomi Tamura; Takeshi Yamaguchi; Kenji J Tsuchiya; Satoshi Suyama; Taku Obara; Akio Nakai; Toshio Yoshikawa; Toyoki Yamagata; Mariko Itoh; Keiko Yamazaki; Sumitaka Kobayashi; Reiko Kishi
    Brain & development, 47, 1, 104296, 104296, 2024年11月14日, ［国際誌］
    英語, 研究論文（学術雑誌）, BACKGROUND: Developmental coordination disorder (DCD) presents motor skill delays in early childhood and has been associated with later maladaptation, necessitating early intervention. However, research on the potential risk factors, particularly in preschool-aged children, remains scarce. AIMS: We aimed to explore the association between small for gestational age (SGA) and other factors and motor coordination problems in 5-6-year-olds from the Hokkaido Study on Environment and Children's Health Cohort. STUDY DESIGN: Prospective. SUBJECTS: We analyzed data from >3500 participants from the Hokkaido Study, a prospective birth cohort, and assessed children aged 5-6 years. OUTCOME MEASURES: Participants underwent assessment with the Developmental Coordination Disorder Questionnaire Japanese version (DCDQ-J). We conducted linear regression analyses adjusted for variables such as the child's sex, maternal age, and maternal smoking history during pregnancy, while also examining the independent associations of each risk factor. RESULTS: Among the 3883 children analyzed for SGA, children with SGA exhibited significantly lower DCDQ-J total scores than non-SGA children (mean difference: -2.25, 95 % confidence interval [-4.19, -0.30], p = 0.02). On the subscales, children with SGA demonstrated significantly lower "Control During Movement" scores than non-SGA children (mean difference: -0.96, 95 % confidence interval [-1.78, -0.13], p = 0.02). Furthermore, the child's sex, maternal smoking, maternal age, and preterm birth were independently associated with DCD. CONCLUSIONS: SGA was shown to be one of the risk factors for the manifestation of motor coordination difficulties in 5-6-years old children. In combination with other factors, screening for motor coordination difficulties in SGA children will be an important means of initiating appropriate interventions.
  • 研究と報告 低出生体重児における日本語版ASQ®-3の妥当性
    橋本 圭司; 盛一 享徳; 九島 令子; 豊島 勝昭; 木本 裕香; 石井 のぞみ; 廣瀬 悦子; 七條 了宣; 和田 友香; 水野 克己; 伊藤 善也; 長 和俊; 山口 健史; 河野 由美
    総合リハビリテーション, 52, 11, 1223, 1230, 株式会社医学書院, 2024年11月10日
  • Post-Discharge Growth Among Extremely Preterm Infants With or Without Bronchopulmonary Dysplasia.
    Yasuka Kimoto; Katsuya Hirata; Shinya Hirano; Kazuko Wada; Akinori Moriichi; Yoshiya Ito; Kazutoshi Cho; Katsumi Mizuno; Katsuaki Toyoshima; Reiko Kushima; Nozomi Ishii; Takeshi Yamaguchi; Keiji Hashimoto; Yukari Yada; Yumi Kono
    Pediatric pulmonology, 2024年11月08日, ［国際誌］
    英語, 研究論文（学術雑誌）, OBJECTIVE: This study aimed to evaluate whether bronchopulmonary dysplasia (BPD) and home respiratory care (HRC) after discharge, including home oxygen therapy (HOT) or home mechanical ventilation (HMV), were associated with the growth of extremely preterm infants. STUDY DESIGN: This secondary study uses data from a study on the infant and early childhood development survey of low-birth-weight infants in the Health, Labor, and Welfare Science Research. We enrolled 788 singleton extremely preterm infants appropriate for gestational age (GA). BPD was defined as the requirement of supplemental oxygen or respiratory support at 36 weeks corrected GA. We compared trends of anthropometric measurements from age 0 to 5 years among infants with non-BPD, BPD without HRC, and BPD with HRC. RESULTS: We obtained 4113 weight and length measurements. At age 0-5 years, the BPD with the HRC group weighed less and was shorter than the other two groups. Lower GA and BPD status were significantly associated with growth failure of weight at 3 and 5 years after adjustment for potential risk factors. Lower GA was significantly associated with growth failure of length at 3 and 5 years. Conversely, although BPD status was significantly associated with growth failure of length at 3 years, it was not at 5 years. CONCLUSION: Among extremely preterm infants, BPD with HRC was associated with a significant growth delay at 0-5 years compared with non-BPD and BPD without HRC. However, the effect of different severities of BPD on growth failure of length was attenuated with age.
  • Transforming Large Birth Cohorts and Graduate Education: Challenges and Strategies.
    Hiroyoshi Iwata; Takeshi Yamaguchi; Reiko Kishi
    Internal medicine (Tokyo, Japan), 64, 9, 1448, 1448, 2024年09月11日, ［国内誌］
    英語, 研究論文（学術雑誌）
  • 前思春期の学童における血中性・ステロイドホルモン濃度 北海道スタディ
    安田 彩夏; 山口 健史; 池中 良徳; アイツバマイ ゆふ; 岸 玲子; 小島 弘幸; 池田 敦子
    日本成長学会雑誌, 30, 2, 86, 86, 日本成長学会, 2024年09月
    日本語
  • 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, 2024年08月03日
    研究論文（学術雑誌）
  • 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, 2024年05月
    研究論文（学術雑誌）
  • 前思春期のフタル酸エステル類曝露とステロイドホルモン値との関連 北海道スタディ
    安田 彩夏; アイツバマイ ゆふ; 山口 健史; ケテマ・ラヒルメスフィン; 曾 怡; 池中 良徳; 宮下 ちひろ; マルセラ・メガサリ; 岸 玲子; 小島 弘幸; 池田 敦子
    日本衛生学雑誌, 79, Suppl., S209, S209, (一社)日本衛生学会, 2024年03月
    日本語
  • 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年, ［国際誌］
    英語, 研究論文（学術雑誌）, 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.
  • Adipsic hypernatremia with marked hyperprolactinemia and GH deficiency in a 9-year-old boy.
    Hisato Segoe; Akie Nakamura; Kimiaki Uetake; Nozomi Hishimura; Naoya Kaneko; Shuntaro Morikawa; Akari Nakamura-Utsunomiya; Takeshi Yamaguchi
    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology, 33, 3, 163, 168, 2024年, ［国内誌］
    英語, 研究論文（学術雑誌）
  • 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年, ［国内誌］
    英語, 研究論文（学術雑誌）
  • 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年, ［国際誌］
    英語, 研究論文（学術雑誌）
  • Maternal pre-pregnancy body mass index and related factors: A cross-sectional analysis from the Japan Environment and Children's Study.
    Yasuaki Saijo; Eiji Yoshioka; Yukihiro Sato; Yuki Kunori; Tomoko Kanaya; Kentaro Nakanishi; Yasuhito Kato; Ken Nagaya; Satoru Takahashi; Yoshiya Ito; Hiroyoshi Iwata; Takeshi Yamaguchi; Chihiro Miyashita; Sachiko Itoh; Reiko Kishi
    PloS one, 19, 6, e0304844, 2024年, ［国際誌］
    英語, 研究論文（学術雑誌）
  • 北海道における小学２年生の口腔内調査 ： エコチル調査の札幌地区での検討
    菊池媛美; 武藤麻未; 中西康; 保浦七愛; 笠井満知子; 伊藤佐智子; 小林澄貴; 山口健史; 遠藤諒俊; 春藤彩花; 柴田真友子; 鈴木悠人; 齋藤紫; 岸玲子; 佐藤嘉晃
    北海道矯正歯科学会雑誌, 51, 1, 1, 6, 北海道矯正歯科学会, 2023年12月, ［査読有り］, ［国内誌］
    日本語, 研究論文（学術雑誌）
  • Hokkaido birth cohort study in Japan on the growth trajectory of children born with low birth weight until 7 years of age
    Kritika Poudel; Sumitaka Kobayashi; Hiroyoshi Iwata; Maki Tojo; Takeshi Yamaguchi; Keiko Yamazaki; Naomi Tamura; Mariko Itoh; Taku Obara; Shinichi Kuriyama; Reiko Kishi
    Early Human Development, 189, 105925, 105925, Elsevier BV, 2023年12月
    研究論文（学術雑誌）
  • 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, 2023年11月11日, ［国際誌］
    英語, 研究論文（学術雑誌）
  • 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, 95, 7, 1875, 1882, 2023年10月19日, ［国際誌］
    英語, 研究論文（学術雑誌）
  • 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, 168, 107448, 107448, 2022年08月04日, ［国際誌］
    英語, 研究論文（学術雑誌）
  • Adrenal function during long-term ACTH therapy for patients with developmental and epileptic encephalopathy.
    Yuki Ueda; Shuta Fujishige; Takeru Goto; Shuhei Kimura; Noriko Namatame; Masashi Narugami; Sachiko Nakakubo; Midori Nakajima; Kiyoshi Egawa; Naoya Kaneko; Kanako Nakayama; Nozomi Hishimura; Takeshi Yamaguchi; Akie Nakamura; Hideaki Shiraishi
    Epilepsia open, 7, 1, 194, 200, 2022年03月, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）
  • 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, 2022年01月15日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）
  • Functional analysis of PAX8 variants identified in patients with congenital hypothyroidism in situ
    Khishigjargal Batjargal; Toshihiro Tajima; Eriko Fujita-Jimbo; Takeshi Yamaguchi; Akie Nakamura; Takanori Yamagata
    Clinical Pediatric Endocrinology, 31, 4, 234, 241, 2022年
    研究論文（学術雑誌）
  • 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, 2021年10月18日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）
  • 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
    International Journal of Environmental Research and Public Health, 18, 19, 10103, 10103, MDPI AG, 2021年09月26日, ［査読有り］
    研究論文（学術雑誌）
  • Successful kidney transplantation in a patient with neonatal-onset ILNEB.
    Takayuki Okamoto; Akie Nakamura; Asako Hayashi; Takeshi Yamaguchi; Yayoi Ogawa; Ken Natsuga; Kumiko Yanagi; Kiyohiko Hotta
    Pediatric transplantation, 25, 5, e13971, 2021年08月, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）
  • Genotype-phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling.
    Yasuki Ishihara; Yasuhisa Ohata; Shinji Takeyari; Taichi Kitaoka; Makoto Fujiwara; Yukako Nakano; Kenichi Yamamoto; Chieko Yamada; Katsusuke Yamamoto; Toshimi Michigami; Hiroyo Mabe; Takeshi Yamaguchi; Katsuyuki Matsui; Izumi Tamada; Noriyuki Namba; Akiko Yamamoto; Junya Etoh; Azusa Kawaguchi; Rieko Kosugi; Keiichi Ozono; Takuo Kubota
    Bone, 153, 116135, 116135, 2021年07月30日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）
  • 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, 2021年05月22日, ［査読有り］, ［国際誌］
    英語
  • A case undergoing cocktail therapy for cardiac involvement in Barth syndrome.
    Jiro Abe; Takeshi Yamaguchi; Maki Matsuzawa; Ichiro Kobayashi; Atsuhito Takeda
    Pediatrics international : official journal of the Japan Pediatric Society, 62, 12, 1393, 1395, 2020年12月, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）
  • Targeted next-generation sequencing for congenital hypothyroidism with positive neonatal TSH screening.
    Takeshi Yamaguchi; Akie Nakamura; Kanako Nakayama; Nozomi Hishimura; Shuntaro Morikawa; Katsura Ishizu; Toshihiro Tajima
    The Journal of clinical endocrinology and metabolism, 105, 8, E2825, E2833, 2020年05月27日, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）
  • Case of miliaria rubra histologically showing neutrophilic eccrine hidradenitis due to hyperhidrosis induced by a catecholamine-producing neuroblastoma.
    Sho Katayama; Hiroaki Iwata; Yukiko Nomura; Akie Nakamura; Takeshi Yamaguchi; Nozomi Hishimura; Kanako Nakayama; Kahoko Hashimoto; Shohei Honda; Hiroshi Shimizu
    The Journal of dermatology, 47, 3, e92-e93, 2020年03月, ［査読有り］, ［国際誌］
    英語
  • Hypoglycemia in type 1A diabetes can develop before insulin therapy: A retrospective cohort study.
    Takeshi Yamaguchi; Rumi Hachiya; Sayaka Watanabe-Yamamoto; Kentaro Sawano; Shuntaro Morikawa; Akie Nakamura; Yukihiro Hasegawa
    Diabetes research and clinical practice, 147, 87, 92, 2019年01月, ［査読有り］, ［国際誌］
    英語, 研究論文（学術雑誌）, AIMS: There are as yet no cohort studies of hypoglycemia in type 1 diabetes before starting insulin therapy. Our aim was to determine the frequency and clinical features of hypoglycemia in patients with type 1A diabetes prior to commencing insulin therapy. METHODS: Eighty-seven patients with type 1A diabetes were enrolled, and a retrospective chart review of the patients was conducted. RESULTS: Hypoglycemia before insulin therapy occurred in six of 87 patients (6.9%). The HbA1c levels at the diagnosis of type 1A diabetes in the hypoglycemia group were lower than in the non-hypoglycemia group (median: 7.3% (56 mmol/mol) vs. 11.9% (106 mmol/mol), p < 0.0001). Similarly, the 24-hour urinary C-peptide (UCPR) levels of the former group were higher than those of the latter group (16.5 μg/day/m2 vs. 7.0 μg/day/m2, p = 0.0075). Hypoglycemic episodes occurred mostly in the postprandial period and gradually disappeared with a decrease in insulin secretion. CONCLUSIONS: We demonstrated that some patients with type 1A diabetes experience hypoglycemic episodes before insulin therapy. Patients with early-stage type 1A diabetes with relatively low HbA1c or high UCPR have a risk of hypoglycemia. These findings may impact when and how insulin is introduced in the treatment of early-stage type 1A diabetes.
  • A Japanese patient with congenital central hypothyroidism caused by a novel IGSF1 mutation.
    Takeshi Yamaguchi; Tomoyuki Hothubo; Shuntaro Morikawa; Akie Nakamura; Toshihiko Mori; Toshihiro Tajima
    Journal of pediatric endocrinology & metabolism : JPEM, 31, 3, 355, 359, 2018年03月28日, ［査読有り］, ［国際誌］
    英語, BACKGROUND: IGSF1 abnormality causes diverse symptoms, including congenital central hypothyroidism (CCH), prolactin hyposecretion, testicular enlargement and delayed puberty. CASE PRESENTATION: Here, we report a case of a male patient who visited our hospital with a chief complaint of abdominal pain and short stature, in whom we identified a novel IGSF1 mutation. He was closely examined because of chronic constipation since infancy, persistent abdominal pain at 14 years of age and marked short stature (-4.7 standard deviation [SD] for normal Japanese boys). He was diagnosed with CCH. Decreased prolactin (PRL) secretion was also observed. IGSF1 analysis revealed a novel mutation at the splicing donor site (c.2065+1G>A) in intron 11. In silico analysis predicted this mutation to be a non-functional splice donor site. After thyroid hormone replacement, his thyroid function, constipation and growth rate improved. CONCLUSIONS: This is the first report of a patient in whom constipation and short stature led to a diagnosis of CCH with a novel IGSF1 mutation.
  • Two siblings with congenital central hypothyroidism caused by a novel mutation in the IGSF1 gene.
    Makiko Oguma; Mizuki Kobayashi; Masayo Yamazaki; Koji Yokoyama; Shuntaro Morikawa; Takeshi Yamaguchi; Takanori Yamagata; Toshihiro Tajima
    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology, 27, 2, 95, 100, 2018年, ［査読有り］, ［国内誌］
    英語, 研究論文（学術雑誌）, Genetic defects in the immunoglobulin superfamily member 1(IGSF1) protein are the cause of congenital central hypothyroidism (C-CH). Here we report two Japanese siblings with C-CH due to a novel IGSF1 mutation. The youngest brother showed a failure to thrive, hypothermia, and neonatal icterus six days after birth. Further endocrine evaluations led to the diagnosis of C-CH. In addition, PRL deficiency was later detected. In contrast, the elder brother did not show symptoms of severe hypothyroidism during the neonatal period, but he had been followed up by doctors due to psychomotor developmental delays since the age of 1 yr. At the age of 3 yr, he had low thyroxine and PRL levels and was also diagnosed with C-CH. Because of the C-CH and PRL deficiency, an IGSF1 deficiency was suspected. Sequence analysis of the IGSF1 gene identified a novel hemizygous mutation of p.Trp1173GlyfsTer8 (NM_001170961.1:c.3517del) in both siblings. In conclusion, the phenotypic severity of C-CH is different, even in siblings. Importantly, an IGSF1 deficiency may result in severe hypothyroidism during the neonatal period.
  • CLINICAL FEATURES OF TWO JAPANESE PATIENTS WITH MICRODUPLICATIONS OF 5Q35.2-Q35.3 ENCOMPASSING NSD1
    Sayaka Yamamoto; Akie Nakamura; Hayato Aoyagi; Satoru Shida; Yasuhiro Ueda; Takeshi Yamaguchi; Shuntaro Morikawa; Katsura Ishizu; Masayo Kagami; Maki Fukami; Toshihiro Tajima
    HORMONE RESEARCH IN PAEDIATRICS, 88, 382, 382, 2017年, ［査読有り］
    英語
  • Two novel mutations of the CYP11B2 gene in a Japanese patient with aldosterone deficiency type 1
    Eisuke Kondo; Akie Nakamura; Keiko Homma; Tomonobu Hasegawa; Takeshi Yamaguchi; Masahiko Narugami; Tetsuo Hattori; Hayato Aoyagi; Katsura Ishizu; Toshihiro Tajima
    Endocrine Journal, 60, 1, 51, 55, 2013年, ［査読有り］
    英語, 研究論文（学術雑誌）
■ その他活動・業績
■ 主な担当授業
  • 大学院共通授業科目（教育プログラム）：社会と健康, 2024年, 修士課程, 大学院共通科目
  • 発達障害学, 2024年, 学士課程, 医学部
  • 小児健康障害論, 2024年, 学士課程, 医学部
  • 一般臨床医学, 2024年, 学士課程, 医学部
■ 所属学協会
  • 日本成長学会
  • 日本DOHaD学会
  • 日本衛生学会
  • 日本小児内分泌学会
  • 日本内分泌学会
  • 日本小児科学会
■ 共同研究・競争的資金等の研究課題
  • プラスチック添加剤によるエピゲノム変化と健康影響：ヒトと細胞の融合的アプローチ
    科学研究費助成事業
    2025年04月01日 - 2029年03月31日
    池田 敦子; 曾 怡; 小島 弘幸; 池中 良徳; KETEMA RAHEL・MESFIN; MEGASARI MARSELA; 山口 健史; アイツバマイ ゆふ
    日本学術振興会, 基盤研究(A), 北海道大学, 25H01075
  • 妊娠中のビタミンD不足が児に与える長期的な影響の検討
    科学研究費助成事業
    2025年04月01日 - 2029年03月31日
    山口 健史
    日本学術振興会, 若手研究, 北海道大学, 25K20590
  • フタル酸エステル類曝露と体組成：幼児期から思春期の運動習慣を加味した長期縦断研究
    科学研究費助成事業
    2025年04月01日 - 2029年03月31日
    牧野 圭太郎; 山口 健史; アイツバマイ ゆふ
    日本学術振興会, 基盤研究(C), 北海道大学, 25K14858
  • 胎児期から続く化学物質によるリプロダクティブヘルスへの影響：分子機構の解明を含む
    科学研究費助成事業
    2025年04月01日 - 2029年03月31日
    岸 玲子; アイツバマイ ゆふ; 山口 健史; 伊藤 佐智子; 岩田 啓芳; 牧野 圭太郎; 田村 菜穂美; 馬場 剛; 齊藤 良玄; 江口 哲史; 今 雅史; 村西 雄貴; 平田 由里絵
    日本学術振興会, 基盤研究(A), 北海道大学, 25H01076
  • 有機フッ素化合物および新規類縁化合物の曝露実態と児の免疫系への健康影響の解明
    科学研究費助成事業
    2024年03月11日 - 2027年03月31日
    アイツバマイ ゆふ; 池田 敦子; 岸 玲子; 山口 健史; KETEMA RAHEL・MESFIN; MEGASARI MARSELA; 宮下 ちひろ
    2024年度は、これまでのレガシーPFAS14化合物に加え、PFASの代替化合物を含む新規PFASの追加のため、環境中あるいはヒト、野生生物からの検出が近年報告されているPFASに関する文献検索を実施した。その結果、新たに30化合物を追加し、全44化合物を分析対象項目とすることとした。分析対象の44種類のPFASについて、LC－MS/MS（ACQUITY UPLC H-Class/Xevo TQ-S micro）による一斉分析法の確立を進めた。分析対象のPFAS標準物質44種類とその内部標準物質24種類の全てのピークが検出可能であることを確認し、0.05－40 ng/mLの範囲で10点で作成した検量線について、ほぼ全ての化合物で0.05－0.1 ng/mLで検出可能であり、機器分析の最適化が完了した。
    北海道スタディの9-12歳の対面調査はすでに終了しており、参加者約700名についてISAAC（International Study of Asthma and Allergies in Childhood）質問票による喘息やアレルギーに関する情報および尿と血液を収集済みである。このうち約400名についてはすでに血中のサイトカイン（IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12(p70), IL-13, IL-17, G-CSF, GM-CSF, IFN-gamma, MCP-1(MCAF), MIP-1beta, TNF-alpha）の測定が完了しており、今年度は残りの約300名分のサイトカイン測定の準備を進めている。加えて、児の甲状腺ホルモン（TSH, FT4, FT3）の測定を実施した。今後はこれらの測定データとPFAS曝露濃度との関連について解析を実施する。
    日本学術振興会, 基盤研究(B), 北海道大学, 23K25013
  • 胎児期および生後の環境によるエピゲノム変化がASDの症状多様性に与える影響の解明
    科学研究費助成事業
    2023年06月30日 - 2026年03月31日
    岸 玲子; 宮下 ちひろ; 小林 澄貴; 伊藤 佐智子; 須山 聡; 山崎 圭子; 山口 健史; 岩田 啓芳; 東條 真希; RAHEL MESFIN・KETEMA
    Autism spectrum disorder (ASD)は少しずつ違った多様な症状（Spectrum）を呈する。遺伝的要因が発症に関与するとされるが、単独では疾患の発症を説明できず、近年は環境によるエピゲノム変化の関与が提唱されている。本研究では、継続して思春期・青年期以降まで追跡している出生コホートを用い、ASD症状を長期間観察した上で、発症年齢も含めたSpectrum様症状への胎児期および生後のエピゲノム変化による影響を明らかにする。
    臍帯血を用いた網羅的DNAメチル化解析(EWAS)にて、胎児期の環境影響によるエピゲノム変化を評価するケースコントロール研究を行う計画に対して、今年度は以下を実施した。①すでに取得している６歳および8歳時調査の日本語版SCQ(Social Communication Questionnaire)の結果の分布を基に、ケース群とコントロール群の選定の準備（必要なマッチングを行うための文献レビューを含む）を行った。②15歳を超える対象者のサンプル（唾液または血液）からDNAを採取し、網羅的DNAメチル化解析を行うための測定機器やプロトコールの準備や確認、過去に実施したEWAS解析の手順やスクリプトを確認した。③ASD発症後の経過観察および症状のスペクトラムとして解析するため、質問票あるいはADI-R/ADOS-2の可能性や実施フレームワークについて、最新の研究文献のレビューと、児童精神科医や心理士などの臨床の専門家、および疫学専門家で定期的な会議を通じて議論した。④これらの具体的な研究実施に向けた倫理審査申請の準備を行った。⑤バージョンアップされたInfinium MethylationEPIC v2.0の導入可能性について検討した。
    日本学術振興会, 挑戦的研究(開拓), 北海道大学, 23K17440
  • 化学物質の次世代影響-出生から青年期の脂質代謝やエピゲノムの作用機序
    科学研究費助成事業
    2023年04月01日 - 2026年03月31日
    宮下 ちひろ; 池田 敦子; 田村 菜穂美; 山口 健史; 惠 淑萍
    本研究では、出生前向きコホート研究に参加している母児の集団を対象として、出生時のカルテ情報から出生時体重、乳幼児健診、小学校入学時健診、年2回の学校健診の記録を収集し、出生時から学童期の体格と肥満・やせを評価した。臍帯血中の網羅的DNAメチル化率データを用いて、小学6年生の肥満傾向群218名と非肥満傾向群（コントロール群）282名の差異について、エピゲノムワイド関連解析（EWAS）を行った。
    小児の肥満傾向よるメチル化変化部位（differentially methylated position; DMP）は多変量解析（robust linear regression (Fox and Weisberg 2011)、および経験ベイズ法(Smyth 2004)）を用いて抽出した。多変量解析では、母の年齢、母の学歴、児の性別 および、メチル化値から推定した(Bakulski et al. 2016)細胞組成値で調整した。
    児の性別で層別化した解析も実施した。多重比較補正のために、False discovery rate (FDR）を0.05で設定して、FDR補正後のP値0.05未満をエピゲノムワイドの有意水準とした。全体、および男児ではp＜0.05に到達するメチル化部位は抽出されなかった。女児のみの解析でp ＜0.05を満たすメチル化部位が5か所、抽出された。児の成長に重要な脂質代謝物である母乳中のプロズマローゲンなどを測定した。胎児期の環境化学物質の曝露の評価としてすでに得られている有機フッ素化合物などの測定値を用いて、児の体格との関連を解析した。
    日本学術振興会, 基盤研究(C), 北海道大学, 23K09641
  • 化学物質による青年期の生殖機能、抑うつ、NCDsへの影響：分子機構の解明を含めて
    科学研究費助成事業 基盤研究(A)
    2022年04月01日 - 2026年03月31日
    岸 玲子; 宮下 ちひろ; 小林 澄貴; 伊藤 佐智子; 山崎 圭子; アイツバマイ ゆふ; 山口 健史; 田村 菜穂美; 齊藤 卓弥
    本研究では20年間に渡り追跡している出生コーホート研究を用い、胎児期および生後の環境化学物質による曝露を含む環境要因による次世代影響の解明を目的として、将来の非感染性疾患（NCDs; Non-Communicable Diseases、循環器疾患や糖尿病など）や神経発達障害、不妊を含むリプロダクティブヘルス(性と生殖に関する健康)、若年層で深刻な社会問題であるうつ等の精神疾患の早期兆候と環境要因との関連を明らかにする。
    2023年度は、コーホートの参加者について12歳で第二次性徴に関する調査票1,030件、12歳で小学校の学校健診記録から転記する身長体重調査票1,012件、15歳で中学校の身長体重調査票1,183件、17歳のアレルギーと体格の質問票1,322件を発送した。回収数は、12歳第二次性徴686件（回収率66.6％）、12歳身長体重は672件（回収率66.4％）、14歳359件（回収率31.5％）、15歳611件（回収率51.6％）17歳757件（回収率57.3%）であった。郵送法で12歳の対象者から271件の尿試料を回収した。18歳の調査の本人の同意に関して1360件の発送を行い、667件（回収率51.6％）の返送があり、同意354件、不同意313件を得た。
    14-17歳の参加者39名を対象に、対面調査を実施した。参加者はアレルギーおよび身の周りの日用品の使用頻度等に関する調査票に回答し、採血、採尿を実施した。また、睡眠や活動量等を測定するため、Fitbitを着用して対面調査から1週間のデータ収集を実施した。
    日本学術振興会, 基盤研究(A), 北海道大学, 22H00489
  • 環境化学物質曝露による有害作用：ヒト疫学研究と動物実験による機序解明
    科学研究費助成事業 基盤研究(A)
    2021年04月05日 - 2025年03月31日
    池田 敦子; 小島 弘幸; 池中 良徳; Goudarzi Houman; 中村 明枝; アイツバマイ ゆふ; 惠 淑萍; 山口 健史; 増田 秀幸; POUDEL KRITIKA
    疫学研究では、「北海道スタディ」に参加する9-11歳の前思春期児から収集した血漿を用いて、購入したBio-Plex200 multiplexアッセイシステムによりTh1/Th2関連サイトカイン17種類およびエオタキシン、糖尿病マーカー10種類およびアディポネクチンとアディプシンを約420検体測定した。同様に、9-11歳の学童339人の血漿を用いて、独自に開発した内標準物質による定量LC/MS分析法を利用し、血中各種コレステリルエステル（CE）11化合物の濃度測定を行った。なお、CE濃度が他のパラメーター、例えば性別や年齢、体格と関連性については現在解析中である。一般集団の子どもにおけるT2バイオマーカー（総IgE、好酸球、呼気中一酸化窒素（FeNO））の基準値を求めた。喘鳴、鼻結膜炎、湿疹といったアレルギー症状に加えて、性別（男児）と喫煙がT2バイオマーカー値を説明していた。
    リン酸トリエステル類曝露とT2バイオマーカーである血中総IgE、好酸球、FeNO、および表現型としての喘鳴、湿疹、鼻結膜炎の症状との関連を解析し、リン酸トリエステル類ΣTBOEPとΣTPHP濃度が高いと喘息、好酸球およびFeNOのリスクが高くなることが明らかになった。
    妊娠ICRマウスに、水（対照群）、PFOA 0.3 mg/kg（低用量群）及びPFOA 3 mg/kg（高用量群）を妊娠期間中経口曝露した。それぞれ出生後７日目の仔マウス肝臓からmRNAを採取した。GeneChip解析を用いた網羅的遺伝子発現解析を行い、PFOA投与量に応じて変動遺伝子数の上昇を認めた。また、高用量群マウスから生まれた仔マウスの肝臓は肥大しており、PFOAが胎盤や母乳を介して仔に影響したと考えられた。
    日本学術振興会, 基盤研究(A), 北海道大学, 21H04843
  • 思春期肥満に着目した内分泌・代謝ネットワーク異常の病態解明
    科学研究費助成事業 若手研究
    2022年04月01日 - 2024年03月31日
    山口 健史
    思春期肥満は成人肥満に直結し、将来的なNon-communicable diseases (NCDs)のリスクとなる。近年、NCDsの病態を脂肪細胞機能から解明を目指す「アディポサイエンス」が提唱され、食欲やエネルギー調節機構における視床下部・消化管・膵臓・脂肪組織の臓器間ネットワークが注目されている。本研究では、大規模出生コーホートである「環境と子どもの健康に関する北海道スタディ（以下、北海道スタディ）」を用いて、思春期評価において重要なマイルストーンである9-12歳、15-18歳時を対象として、質問票による生活習慣などの情報、および対面調査による身体測定と、血液尿から網羅的にバイオマーカーを測定する。得られた結果から、各年齢の基準値を提供、思春期肥満におけるネットワーク異常の病態の考察を行う。
    令和4年度は、男児66名、女児95名、合計161名の15-18歳の対面調査を行い、令和3年度までとの合計では293名のデータを収集できた。質問票による生活習慣や、身長・体重・腹囲に加え、体脂肪率や筋肉量などの体組成、心拍数や血圧等のバイタルデータ、二次性徴Tanner分類、精巣容量・初潮発来時期などの情報に加え、血液尿サンプルの採取の実施を進めている。中間解析においては、体重、BMI、体組成計による体脂肪率と、血清脂質（総コレステロール、中性脂肪、LDL、HDL）やHbA１cの相関分析では、男女ともに体脂肪率とHDLの相関が特に強く認められ、体組成測定の重要性が確認された。
    日本学術振興会, 若手研究, 北海道大学, 22K17341
  • 胎児期POPs曝露による神経炎症が児のADHD症状へ与える影響の解明
    科学研究費助成事業 基盤研究(C)
    2021年04月01日 - 2024年03月31日
    伊藤 佐智子; 山崎 圭子; 須山 聡; 山口 健史
    有機フッ素化合物(PFAS)やPCBに代表される残留性有機汚染物質(POPs)は、その長い半減期から環境中や人体へ長期間蓄積し、製造規制後の現在も生活環境中に存在する。母から胎児への移行率が高いことから胎児への健康影響が懸念されており、これまで胎児期POPs曝露と子供の神経行動発達の関連が多数報告されてきた。これまで注意欠如多動症(Attention-deficit/hyperactivity disorder；ADHD)の発症は遺伝的要因に加え、母の妊娠中の栄養状態・喫煙・ストレス、感染症、社会経済状況等の胎児期環境や早産が要因の一部を担うと推測されてきたが、それらの環境因子に共通する要因としてサイトカインの関与が疑われていた。
    申請者らは近年、ADHD発症の機序として「胎児期の神経炎症」が提唱されていることから、本研究ではケースコントロールスタディで母児100組の母体血・臍帯血中サイトカイン濃度の測定を実施し、胎児期の内分泌攪乱作用を有する残留性有機汚染物質(POPs)曝露がもたらす児のADHD症状へ、POPsによる母児の炎症反応の介在影響を検討することを計画した。
    令和4年度は、令和3年度に引き続き出生前向きコホート「環境と子どもの健康に関する北海道スタディ(以下、北海道スタディ)」にてADHD-Rating scale（ADHD-RS）を含む6歳調査票
    および8歳調査票の回収結果から、ADHD-RSスコアの集計とカットオフ値の設定を実施した。また、保存血液検体からの炎症性バイオマーカー測定の予備検討を実施した。
    日本学術振興会, 基盤研究(C), 北海道大学, 21K10390
  • 網羅的エピゲノム解析による自閉スペクトラム症の分子機構の解明とバイオマーカー探索
    科学研究費助成事業 挑戦的研究(萌芽)
    2021年07月09日 - 2023年03月31日
    岸 玲子; 宮下 ちひろ; 伊藤 佐智子; 山口 健史; 須山 聡
    本研究の目的は、胎児期起源から発症後の縦断的なエピゲノム変化を前向きに解析し、あわせて末梢血中の慢性炎症マーカーなどに焦点を当て、ASD発症の分子機構およびその軌跡を明らかにすることを目的として、将来的な予防と早期発見、およびASD児のより良好な発達のための予防的介入法の開発に役立てることである。北海道スタディ札幌コーホートに参加している母児のうち、臍帯血検体を採取・保存しており、7歳まで追跡調査されている58名を対象とした。小児のASD傾向のスクリーニングとして、CBCL (Child Behavior Checklist)の３つの下位項目「ひきこもり」「社会性の問題」「思考の問題」のT得点の合計が180を超える小児をASD傾向のケースとして定義した。さらに、ASDの早期バイオマーカー検索を目的として、臍帯血中血清検体を用いてLC-TOFMS （液体クロマトグラフィ－飛行時間型質量分析計）により、メタボロミクス解析を実施した（ヒューマン・メタボローム・テクノロジーズ株式会社）。CBCLの下位3項目のT得点合計が180以上であったのは男女2名ずつ合計4名であった。ケースとコントロールの2群間T検定において、FDR有意水準であったのは、5-HEPE、Leukotriene B4-1、15-Deoxy-delta12,14-prostaglandin D2、13,14-Dihydro-15-keto-prostaglandin D2、およびFlavanoneであった。Leukotriene B4-1は炎症に関与するロイコトリエンで肥満マウスのインスリン抵抗性を促進することが報告されている。さらに今後は、臍帯血中DNAメチル化変化の解析も合わせて検討することで、小児のASDに関与するエピゲノム変異および、関与する代謝物質を明らかにする。
    日本学術振興会, 挑戦的研究(萌芽), 北海道大学, 21K19618