Keiko Yamazaki

The Hokkaido Birth Cohort Study on Environment and Children's Health : cohort profile -- updated 2017

The Hokkaido Study on Environment and Children’s Health is an ongoing study consisting of two birth cohorts of different population sizes: the Sapporo cohort and the Hokkaido cohort. Our primary study goals are (1) to examine the effects of low-level environmental chemical exposures on birth outcomes, including birth defects and growth retardation; (2) to follow the development of allergies, infectious diseases, and neurobehavioral developmental disorders and perform a longitudinal observation of child development; (3) to identify high-risk groups based on genetic susceptibility to environmental chemicals; and (4) to identify the additive effects of various chemicals, including tobacco smoking. The purpose of this report is to update the progress of the Hokkaido Study, to summarize the recent results, and to suggest future directions. In particular, this report provides the basic characteristics of the cohort populations, discusses the population remaining in the cohorts and those who were lost to follow-up at birth, and introduces the newly added follow-up studies and case-cohort study design. In the Sapporo cohort of 514 enrolled pregnant women, various specimens, including maternal and cord blood, maternal hair, and breast milk, were collected for the assessment of exposures to dioxins, polychlorinated biphenyls, organochlorine pesticides, perfluoroalkyl substances, phthalates, bisphenol A, and methylmercury. As follow-ups, face-to-face neurobehavioral developmental tests were conducted at several different ages. In the Hokkaido cohort of 20,926 enrolled pregnant women, the prevalence of complicated pregnancies and birth outcomes, such as miscarriage, stillbirth, low birth weight, preterm birth, and small for gestational age were examined. The levels of exposure to environmental chemicals were relatively low in these study populations compared to those reported previously. We also studied environmental chemical exposure in association with health outcomes, including birth size, neonatal hormone levels, neurobehavioral development, asthma, allergies, and infectious diseases. In addition, genetic and epigenetic analyses were conducted. The results of this study demonstrate the effects of environmental chemical exposures on genetically susceptible populations and on DNA methylation. Further study and continuous follow-up are necessary to elucidate the combined effects of chemical exposure on health outcomes.

Cord blood BPA level and child neurodevelopment and behavioral problems: The Hokkaido Study on Environment and Children's Health

Abstract Background Bisphenol A (BPA) is a ubiquitous environmental chemical which has been detected in various populations. There have been concerns that endocrine disrupting property of BPA may cause adverse health effects on neurodevelopmental and behavioral problems. Yet findings from prospective cohort studies to assess influence of prenatal exposure to BPA on child neural development were not conclusive. Especially, with relatively lower levels of exposure and its influence was not examined. Thus, the aim of this study was to evaluate child mental, psychomotor and behavioral problems at different ages in association with prenatal BPA exposures in the prospective birth cohort study. Method BPA level in cord blood was determined by ID-LC/MS/MS. Bayley Scales of Infant Development 2nd Edition was used to assess mental and motor development at 6 and 18 month of age. Kaufman Assessment Battery for Children to assess intelligence and Child Behavior Checklist (CBCL) to assess behavioral problems were used at 42 month of age. Out of 514 subjects in Sapporo cohort, 285 mother-child pairs with BPA measurement and child developmental assessments were included in this study. Results The median level of cord blood BPA was 0.051ng/ml. No association was found between BPA level and either mental or psychomotor development at 6 and 18 month of age. BPA level was positively associated with total, internalizing and externalizing problem scores of CBCL, respectively (β=4.77, 95% CI: -0.28, 9.82, β=4.35, 95% CI: -0.48, 9.18, β=4.33, 95% CI: -0.86, 9.25) with marginal significance. Cord blood BPA concentration was positively associated with development problems score (β=2.60, 95% CI: 0.15, 5.06) with significance. Conclusion Our findings suggested no association between cord blood BPA level and child mental, psychomotor, however, cord blood BPA level may be associated with child behavioral problems at early age.

Associated factors of behavioural problems in children at preschool age: the Hokkaido study on environment and children's health

BACKGROUND Finding associated factors with childhood behavioural problems as early as preschool age is important. Studies have revealed several factors including socioeconomic factors, which may vary among different cultural background and population. However, investigation in general Japanese population of preschool age has not been well demonstrated. Thus, the objective of this study was to examine associated factors of childhood behavioural problems using Strengths and Difficulties Questionnaire (SDQ) in a prospective birth cohort study. METHODS Total 3813 SDQ were distributed between October 2014 and December 2015 to the subpopulation of prospective birth cohort study, the Hokkaido Study on Environment and Childrens Health. The subpopulation consisted of participants who had reached age 5 and were born between April 2008 and December 2010. Baseline questionnaire filled at recruitment and birth record were used to obtain participant information. Children with total difficulties score ≧ 13 were defined as likelihood of behavioural problems. A total of 2553 children with valid answers were included into the analysis. The response rate was 67.1%. RESULTS Number of children with likelihood of behavioural problems was 521 (20.4%). Boys showed more problematic scores than girls. Multivariate analysis found that maternal pre-pregnancy BMI ≧ 30 kg/m2 , primipara, maternal education lower than high school, family income during pregnancy < 3 million yen/year and boy gender were the factors associated with increased odds ratio of likelihood of child behavioural problems. CONCLUSIONS This study found that prenatal socioeconomic factors were associated with likelihood of child behavioural problems at preschool age in Japan.

Association between Fetal Adipokines and Child Behavioral Problems at Preschool Age: The Hokkaido Study on Environment and Children’s Health

Studies have suggested associations between maternal obesity and mental health problems of their children. However, the underlying mechanism is largely unknown. A possible mechanism can be via inflammatory states and the other possible mechanism is metabolic hormone-induced programming. Cross-talk between adipokines, including inflammatory cytokines and metabolic hormones secreted from adipose tissue and the central nervous system needs to be further investigated to elucidate the mechanism. Thus, the aim of this study was to investigate the association between fetal adipokine levels and child behavioral problems at preschool age. Cord blood adiponectin, leptin, tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6) levels were measured and child behavioral problems were assessed using the Strengths and Difficulties Questionnaire at preschool age. Logistic regression models adjusted by related maternal factors were performed to examine the association between cord blood adipokines and child behavioral problems. Three hundred and sixty-one children were included in the final analysis. A significant association between decreased hyperactivity/inattention and increased leptin was found (OR = 0.22, 95% CI: 0.06–0.89). Cord blood adiponectin, TNF-α and IL-6 levels were not associated with child behavioral problems. Our findings suggested that cord blood adipokines, particularly, leptin level, may be a predictor of hyperactivity/inattention problems at preschool age.

Association between prenatal exposure to organochlorine pesticides and the mental and psychomotor development of infants at ages 6 and 18 months: The Hokkaido Study on Environment and Children’s Health

&NA; Organochlorine pesticides (OCPs) are environmental contaminants that persist in the environment and bioaccumulate through the food chain in humans and animals. Although previous studies have shown an association between prenatal OCP exposure and subsequent neurodevelopment, the levels of OCPs included in these studies were inconsistent. A hospital‐based prospective birth cohort study was conducted to examine the associations between prenatal exposure to relatively low levels of OCPs and neurodevelopment in infants at 6 (n = 164) and 18 (n = 115) months of age. Blood samples were analyzed using gas chromatography/mass spectrometry techniques to quantify 29 OCPs. The Bayley Scales of Infant Development 2nd edition (BSID‐II) was used to assess the Mental and Psychomotor Developmental Index. After controlling for confounders, we found an inverse association between prenatal exposure to cis‐heptachlor epoxide and the Mental Developmental Index at 18 months of age. Furthermore, infants born to mothers with prenatal concentrations of cis‐heptachlor epoxide in the highest quartile had Mental Developmental Index scores −9.8 (95% confidence interval: −16.4, −3.1) lower than that recorded for infants born to mothers with concentrations of cis‐heptachlor epoxide in the first quartile (p for trend <0.01). These results support the hypothesis that prenatal exposure to OCPs, especially cis‐heptachlor epoxide, may have an adverse effect on the neurodevelopment of infants at specific ages, even at low levels.