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.
Biomarkers/blood* ; Child ; Child Health ; Child, Preschool ; Cohort Studies ; Environmental Exposure/adverse effects* ; Environmental Health ; Environmental Pollutants/adverse effects* ; Female ; Fetal Blood/chemistry* ; Follow-Up Studies ; Growth/drug effects* ; Humans ; Hypersensitivity/etiology* ; Infant ; Japan/epidemiology* ; Male ; Neurodevelopmental Disorders/etiology* ; Pregnancy ; Prenatal Exposure Delayed Effects/etiology* ; Prevalence ; Smoking/adverse effects*

OBJECTIVE: To study the association of exposure to polycyclic aromatic hydrocarbons (PAH) during pregnancy and autism spectrum disorder (ASD)-related behaviors in toddlers. METHODS: A total of 348 toddlers who had accepted the measurement of PAH-DNA adduct in umbilical cord blood and evaluation of behavior problems at the age of 36 months were enrolled in this birth cohort study. Child Behavior Checklist (CBCL) and Autism Behavior Checklist (ABC) were used to evaluate behavior problems at the age of 36 months. The correlation of the concentration of PAH-DNA adduct in umbilical cord blood with CBCL and ABC scores at the age of 36 months were analyzed. RESULTS: The detection rate of PAH-DNA adduct in umbilical cord blood was 52.3%, and the median concentration was 0.68 ng/mL. The median total scores of CBCL and ABC scales were 23 and 8 respectively. In children aged 36 months, the concentration of PAH-DNA adduct was positively correlated with the score of social withdrawal in the CBCL scale (r=0.205, P<0.05), the total score of the ABC scale (r=0.412, P<0.05), and the self-care score of the ABC scale (r=0.355, P<0.05). The concentration of PAH-DNA adduct was closely associated with the total score of the ABC scale in children aged 36 months (β=0.122, P<0.05). CONCLUSIONS PAH exposure during pregnancy may be a risk factor for ASD-related behaviors in toddlers. Effective reduction of PAH exposure during pregnancy and detection of PAH-DNA adduct in neonatal umbilical cord blood are of vital importance for early prevention, screening and intervention of ASD.
Autism Spectrum Disorder ; chemically induced ; Child Behavior ; Child, Preschool ; Cohort Studies ; Female ; Fetal Blood ; Humans ; Polycyclic Aromatic Hydrocarbons ; adverse effects ; Pregnancy ; Prenatal Exposure Delayed Effects ; chemically induced

BACKGROUND: There have been inconsistent findings reported on maternal passive smoking during pregnancy and child risk of ADHD. In this study, ADHD symptoms at pre-school age children in association with prenatal passive and active tobacco smoke exposure determined by maternal plasma cotinine levels in the third trimester were investigated. METHODS: This was a follow-up study of the birth cohort: the Hokkaido Study on Environment and Children's Health. Children whose parents answered Strengths and Difficulties Questionnaire (SDQ) to identify child ADHD symptoms (hyperactivity/inattention and conduct problems) and total difficulties at age 5 years with available maternal plasma cotinine level at the third trimester were included (n = 3216). Cotinine levels were categorized into 4 groups; ≦ 0.21 ng/ml (non-smoker), 0.22-0.51 ng/ml (low-passive smoker), 0.52-11.48 ng/ml (high-passive smoker), and ≧ 11.49 ng/ml (active smoker). RESULTS: Maternal cotinine levels of active smokers were significantly associated with an increased risk of total difficulties (OR = 1.67) and maternal low- and high-passive smoking also increased the risk (OR = 1.11, 1.25, respectively) without statistical significance. Similarly, maternal cotinine levels of active smokers were associated with an increased risk of hyperactivity/inattention (OR = 1.49). Maternal low- and high-passive smoking and active smoking increased the risk of hyperactivity/inattention (OR = 1.45, 1.43, and OR = 1.59, respectively) only in boys. CONCLUSION Our findings suggested that maternal active smoking during pregnancy may contribute to the increased risk of child total difficulties and hyperactivity/inattention at pre-school age. Pregnant women should be encouraged to quit smoking and avoid exposure to tobacco smoke.
Adult ; Attention Deficit Disorder with Hyperactivity ; epidemiology ; etiology ; physiopathology ; psychology ; Child, Preschool ; Cotinine ; blood ; Female ; Follow-Up Studies ; Humans ; Japan ; epidemiology ; Male ; Maternal Exposure ; adverse effects ; Mothers ; Pregnancy ; Pregnancy Trimester, Third ; Prenatal Exposure Delayed Effects ; epidemiology ; etiology ; Risk ; Sex Factors ; Tobacco Smoking ; adverse effects ; epidemiology

Objective: To study the dose-response relationship between maternal thyroid hormone levels in the first twenty weeks of pregnancy and the infant physical and neuropsychological development. Methods: In this prospective cohort study, a total of 945 women and their children were included. Maternal serum samples during first half of the pregnancy were collected and analyzed for levels of thyroid hormones by using the electro-chemiluminescence immunoassay. Maternal social demographic information was collected by using the a self-administered questionnaire. Physical measurements of newborns and neuropsychological evaluation of infants were performed by doctors of maternal and child health care. Results: The differences in newborns' birth length and head circumference were significant among the newborns of mothers with different percentiles of maternal serum (thyroid-stimulating hormone, TSH) levels (P<0.05). Newborns with maternal TSH level ≥P(95) or <P(5) had significantly lower birth length and birth head circumference, compared with the newborns with maternal TSH level between P(25)-P(75) (P<0.05). Newborns' birth head circumferences showed an inverted U-shaped association with maternal serum TSH level (Y=33.940+0.003X-0.109X(2), F=4.685, P=0.009). The difference in mental development index (MDI) of the infants at 18-30 months were significant among the infants of mothers with different percentiles of maternal serum TSH level (P<0.05). Infants with maternal TSH level ≥P(90) showed lower MDI (6.39, 95%CI: 2.29-10.49, P=0.002) compared with the infants with maternal TSH level between P(25)-P(75). Infant's MDI at 18- 30 months also showed an inverted U-shaped association with maternal serum TSH level (Y=103.249-1.524X-0.939X(2), F=6.616, P=0.001). Conclusions: Maternal TSH level was associated with newborn's birth length, birth head circumference and infant's MDI at 18-30 months. Newborn's birth head circumference and infant's MDI at 18-30 months showed an inverted U-shaped association with maternal serum TSH-Z score.
Birth Weight/physiology* ; Child ; Child Development/physiology* ; China ; Female ; Fetal Blood/metabolism* ; Humans ; Infant ; Infant, Newborn/blood* ; Pregnancy ; Prenatal Exposure Delayed Effects/blood* ; Prospective Studies ; Thyroid Gland/physiology* ; Thyroid Hormones/metabolism* ; Thyrotropin/blood*

Alkanesulfonic Acids ; toxicity ; Animals ; Female ; Fluorocarbons ; toxicity ; Humans ; Male ; Mice ; Neovascularization, Physiologic ; drug effects ; Pedigree ; Placenta ; blood supply ; drug effects ; metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects ; genetics ; metabolism ; physiopathology ; RNA, Long Noncoding ; genetics ; metabolism

BACKGROUND: Studies reported adverse behavioral development including internalizing and externalizing problems in association with prenatal exposure to bisphenol A (BPA) and phthalates; however, findings were not sufficient due to using different assessment tools and child ages among studies. This study aimed to examine associations between maternal serum levels of BPA and phthalate metabolites and behavioral problems at preschool age. METHODS: The Strengths and Difficulties Questionnaire (SDQ) was used to assess behavioral problems at 5 years of age. BPA and phthalate metabolite levels in the first trimester maternal serum was determined by LC-MS/MS for 458 children. Variables used for adjustment were parental ages, maternal cotinine levels, family income during pregnancy, child sex, birth order, and age at SDQ completed. RESULTS: The median concentrations of BPA, MnBP, MiBP, MEHP, and MECPP, primary and secondary metabolites of phthalates, were 0.062, 26.0, 7.0, 1.40, and 0.20 ng/ml, respectively. MECPP level was associated with increase conduct problem risk (OR = 2.78, 95% CI 1.36-5.68) overall and the association remained after child sex stratification, and odds ratios were increased with wider confidence interval (OR = 2.85, 95% CI 1.07-7.57 for boys, OR = 4.04, 95% CI 1.31-12.5 for girls, respectively). BPA, ∑DBP (MnBP + MiBP), and ∑DEHP (MEHP+MECPP) levels were not associated with any of the child behavioral problems. CONCLUSIONS Our analyses found no significant association between BPA or summation of phthalate metabolite levels and any of the behavioral problems at 5 years of age but suggested possible association between MECPP levels and increased risk of conduct problems.
Adult ; Age Factors ; Benzhydryl Compounds ; blood ; Child, Preschool ; Environmental Exposure ; analysis ; Female ; Humans ; Male ; Phenols ; blood ; Phthalic Acids ; blood ; Pregnancy ; Prenatal Exposure Delayed Effects ; epidemiology ; Problem Behavior ; Smoking ; epidemiology ; Socioeconomic Factors

Rats were exposed to 1 or 10 μg/mL bisphenol A (BPA) in water during pregnancy and lactation. Offspring rats were given normal water and a standard diet from weaning to postnatal day (PND) 50. Perinatal exposure to BPA resulted in significantly increased body weight, visceral adipose tissue, abnormal serum lipids, and lower adiponectin (ADP) levels in both female and male offspring rats. Liver adipose triglyceride lipase (Atgl) mRNA levels and ADP protein in visceral adipose tissue were significantly decreased in BPA-exposed offspring rats. In both female or male offspring rats, obesity and dyslipidemia induced by perinatal exposure to BPA were associated with down regulation of Atgl mRNA in liver and ADP protein in visceral adipose tissue.
Adiponectin ; metabolism ; Adipose Tissue ; metabolism ; Animals ; Benzhydryl Compounds ; adverse effects ; metabolism ; Body Weight ; Dyslipidemias ; enzymology ; etiology ; metabolism ; physiopathology ; Female ; Humans ; Lipase ; genetics ; metabolism ; Lipids ; blood ; Male ; Obesity ; enzymology ; etiology ; metabolism ; physiopathology ; Phenols ; adverse effects ; metabolism ; Pregnancy ; Prenatal Exposure Delayed Effects ; enzymology ; etiology ; metabolism ; physiopathology ; Rats ; Rats, Sprague-Dawley

The study objectives were to investigate the relationship between early exposure to genistein and obesity in young adulthood and to evaluate changes in reproductive health during puberty and adulthood following in utero exposure to genistein. Thirty-two female rats were randomized into four groups; low dose 400 mg genistein/kg diet group (LG), mid-dose 1200 mg genistein/kg diet group (MG), high dose 3600 mg genistein/kg diet group (HG), and control group without genistein diet (CON). Rats were fed genistein at the beginning of pregnancy along with a high-fat diet. Pups were sacrificed at week 4 and week 8 after birth. High performance liquid chromatography (HPLC) results showed a correlation between maternal genistein intake and genistein concentration in pups' plasma. Compared to CON, body weight reduced significantly in male HG group at week 8. No statistical differences were found in plasma estradiol (E2), testosterone (T), interleukin (IL)-6, and C-reactive protein (CRP) levels with early genistein exposure. Furthermore, uterine histopathology showed notable changes in groups HG and MG compared with CON at week 4 and week 8. In conclusion, maternal genistein supplement could reduce body weight in male pups and alter uterine histopathology in female pups.
Animal Nutritional Physiological Phenomena ; Animals ; Body Weight ; drug effects ; Dietary Fats ; administration & dosage ; Female ; Genistein ; administration & dosage ; blood ; pharmacology ; Male ; Maternal Nutritional Physiological Phenomena ; Pregnancy ; Prenatal Exposure Delayed Effects ; Random Allocation ; Rats ; Uterus ; growth & development

Our objective was to evaluate the relationship between intrauterine exposure to cadmium and the presence of atopic dermatitis in infants 6 months of age, adjusted for covariates including exposure to other heavy metals. The present research is a component of the Mothers' and Children's Environmental Health (MOCEH) study, a multi-center birth cohort project conducted in Korea. Study subjects were restricted to pregnant women in whom cadmium and lead levels were measured at delivery and whose infants were assessed for the presence of atopic disease at 6 months of age. The odds ratio (OR) for the presence of atopic dermatitis in 6-month-old infants whose cord blood had elevated cadmium levels, after adjustment for other covariates, was 2.350 (95% CI, 1.126-4.906). The OR for the presence of atopic dermatitis in infants whose cord blood had elevated lead levels was not significant. In the present study, the cord blood cadmium level was significantly associated with the presence of atopic dermatitis in 6-month-old infants; this was not true of the cord blood lead level. To the best of our knowledge, this is the first prospective study to show a relationship between prenatal exposure to cadmium and atopic dermatitis in infancy.
Adult ; Cadmium/analysis ; Cadmium Poisoning/*complications ; Cohort Studies ; Dermatitis, Atopic/diagnosis/*etiology ; Female ; Fetal Blood/chemistry ; Gestational Age ; Humans ; Infant ; Lead/analysis/toxicity ; Male ; Odds Ratio ; Pregnancy ; Prenatal Exposure Delayed Effects

OBJECTIVETo study the effects of low pre-pregnant lead exposure level on the mobilization of lead and calcium in maternal skeleton during gestation and lactation in mice.

METHODSSeventy Kunming female mice were randomly divided into the lead exposure or control groups, 36 mice were exposed to lead by drinking water (50 mg/L) and 36 mice were exposed to deionized water for 4 weeks. The levels of calcium and lead in blood and femurs were measured on the 1st, 7th and 14th days during gestation and on the 1st,10th and 21st days during lactation with atomic absorption spectrophotometry using a heated graphite atomizer or flame atomic absorption spectrophotometry.

RESULTSAs compared with the pre-pregnant, at the end of lactation in exposure group the levels of calcium in blood and bones significantly decreased 18.5% and 17.75%, respectively, the levels of lead in blood significantly increased 65.22% and the levels of lead in bones significantly decreased 28.45% (P < 0.05). There was a significant negative correlation between the blood lead level and the bone lead level during gestation and lactation in exposure group (r = -0.904, P < 0.01). There were significant differences of lead and calcium levels during the gestation and lactation between exposure group and control group (P < 0.05).

CONCLUSIONThe lead mobilization in maternal bone occurred during gestation and lactation in mice, which could be accelerated by the low pre-pregnant lead exposure.

Animals ; Bone Remodeling ; drug effects ; Bone and Bones ; drug effects ; metabolism ; Calcium ; blood ; metabolism ; Calcium, Dietary ; Female ; Lactation ; Lead ; blood ; toxicity ; Mice ; Mice, Inbred Strains ; Pregnancy ; Prenatal Exposure Delayed Effects