Associations between prenatal exposure to organochlorine pesticides and thyroid hormone levels in mothers and infants: The Hokkaido study on environment and children's health.

Organochlorine pesticides (OCPs) are environmental contaminants with potentially adverse effects on neurodevelopment. Previous findings on the association between prenatal exposure to OCPs and the maternal or infant thyroid hormone system are inconsistent. Moreover, the influence of exposure to multiple OCPs and other chemical compounds is not clearly understood. Our study therefore aimed to examine the association between OCP exposure and both maternal and infant thyroid hormone systems. We also explored multiple exposure effects of OCPs and the influence of each compound using weighted quantile sum (WQS) methods. The study population included 514 participants in the Hokkaido study, recruited from 2002 to 2005 at one hospital in Sapporo, Japan. To quantify 29 OCPs, maternal blood samples were analyzed using gas chromatography/mass spectrometry. Blood samples for measuring thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from mothers during the early gestational stage (mean 11.4 weeks), and from infants between 7 and 43 days of age. The data of 333 mother child pairs with OCP and thyroid hormone measurements were included in the final analyses. Multivariate regression models showed a negative association between maternal FT4 and levels of o,p'-dichlorodiphenyldichloroethylene (DDE), o,p'-dichlorodiphenyltrichloroethane (DDT), and dieldrin. The WQS analysis showed that o,p'-DDT (48.6%), cis-heptachlorepoxide (22.8%), dieldrin (15.4%) were the primary contributors to the significant multiple exposure effect of OCPs on maternal FT4. For infants, we found a positive association between FT4 and cis-nonachlor and mirex. The most contributory compounds in the multiple exposure effect were trans-nonachlor (27.1%) and cis-nonachlor (13.8%), while several compounds contributed to the WQS via small weights (0.4-9.1%). These results indicate that OCPs, even at very low levels, may influence maternal and child thyroid hormone levels, which could modulate child development.

Effects of prenatal sex hormones on behavioral sexual dimorphism.

BACKGROUND: We investigated the association between the hormone environment during the prenatal period using cord blood, and gender-role play behavior in school-aged children. METHODS: A total of 879 school-aged children (433 boys and 446 girls) in a prospective birth cohort study in Hokkaido were enrolled to analyze the relationship between cord blood level of the sex hormones estradiol (E), testosterone (T), progesterone (P), and dehydroepiandrosterone (DHEA), and the Pre-School Activities Inventory (PSAI) score. The PSAI evaluated sex-typical characteristics, the type of preferred toys and play activities. The PSAI consists of 12 masculine and 12 feminine items, and the composite scores were calculated by subtracting the feminine score from the masculine score. Higher scores indicated male-typical behavior. RESULTS: Composite and masculine PSAI scores were significantly higher in boys. Meanwhile, the feminine score was significantly lower in boys. Although T and P were significantly higher in boys, E/T was significantly higher in girls. In a multivariate regression model, including covariates of social factors, there was no correlation between any of the hormones and PSAI score in boys. In girls, only P and E/T were positively correlated with the feminine score. CONCLUSIONS: Prenatal sex hormone exposure may influence the dimorphic brain development and behavior in school-aged girls. Furthermore, the cord blood hormone levels may not fully reflect the hormone environment during the prenatal period.

Prevalence and Risk of Birth Defects Observed in a Prospective Cohort Study: The Hokkaido Study on Environment and Children's Health.

BACKGROUND: Prevalence rates of all anomalies classified as birth defects, including those identified before the 22nd gestational week, are limited in published reports, including those from the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR). In our birth cohort study, we collected the data for all birth defects after 12 weeks of gestation. METHODS: Subjects in this study comprised 19,244 pregnant women who visited one of 37 associated hospitals in the Hokkaido Prefecture from 2003 through 2012, and completed follow-up. All birth defects after 12 weeks of gestation, including 55 marker anomalies associated with environmental chemical exposures, were recorded. We examined parental risk factors for birth defects and the association between birth defects and risk of growth retardation. RESULTS: Prevalence of all birth defects was 18.9/1,000 births. The proportion of patients with birth defects delivered between 12 and 21 weeks of gestation was approximately one-tenth of all patients with birth defects. Among those with congenital malformation of the nerve system, 39% were delivered before 22 weeks of gestation. All patients with anencephaly and encephalocele were delivered before 22 weeks of gestation. We observed different patterns of parental risk factors between birth defect cases included in ISBDSR and cases not included. Cases included in ISBDSR were associated with an increased risk of preterm birth. Cases not included in ISBDSR were associated with an increased risk of being small for gestational age at term. CONCLUSIONS: Data from our study complemented the data from ICBDSR. We recommend that birth defects not included in ICBDSR also be analyzed to elucidate the etiology of birth defects.

Sex-specific differences in effect of prenatal exposure to dioxin-like compounds on neurodevelopment in Japanese children: Sapporo cohort study.

BACKGROUND: Consistent reports are not available on the effects of dioxin-like polychlorinated biphenyls (PCBs) and polychlorinated dibenzo-p-dioxins (PCDD)/ polychlorinated dibenzofurans (PCDF) (dioxin-like compounds [DLCs]) on child neurodevelopment. Further, the effect of background-level exposure to individual DLC isomers is not known. OBJECTIVES: We carried out the Sapporo cohort study to evaluate the effect of prenatal exposure to each DLC isomer on child neurodevelopment at 6 and 18 months of age, and assessed sex-specific differences in these effects. METHODS: The levels of all and each individual DLC isomers were estimated in maternal peripheral blood. Neurodevelopment was evaluated using the Bayley Scales of Infant Development-2nd Edition for 6-month-old infants (n = 190) and 18-month-old children (n = 121). RESULTS: In male children, levels of 10 DLC isomers were significantly negatively associated with the Psychomotor Developmental Index (PDI) at 6 months of age after adjustment for potential confounding variables. However, at 18 months of age, these associations were absent. In female children, the level of only one DLC isomer was significantly negatively associated with PDI at 6 months of age. However, in contrast to the male children, the levels of six DLC isomers in 18-month-old female children were significantly positively associated with the Mental Developmental Index. CONCLUSIONS: These findings indicate that adverse neurodevelopmental effects of prenatal background-level exposure to DLCs may be stronger in male children.

Predictors of folate status among pregnant Japanese women: the Hokkaido Study on Environment and Children's Health, 2002-2012.

The International Clearinghouse for Birth Defects, Surveillance and Research reports a rise in the prevalence rate of spina bifida in Japan. We determined first-trimester folate status of Hokkaido women and identified potential predictors. Participants were 15 266 pregnant women of the Hokkaido Study on Environment and Children's Health Cohort. Data were extracted from self-reported questionnaires and biochemical assay results. Demographic determinants of low folate status were younger maternal age (adjusted OR (AOR) 1·48; 95 % CI 1·32, 1·66), lower educational level (AOR 1·27; 95 % CI 1·17, 1·39) and lower annual income (AOR 1·11; 95 % CI 1·01, 1·22). Plasma cotinine concentrations of 1·19-65·21 nmol/l increased the risk of low folate status (AOR 1·20; 95 % CI 1·10, 1·31) and concentrations >65·21 nmol/l further increased the risk (AOR 1·91; 95 % CI 1·70, 2·14). The most favourable predictor was use of folic acid (FA) supplements (AOR 0·19; 95 % CI 0·17, 0·22). Certain socio-demographic factors influence folate status among pregnant Japanese women. Modifiable negative and positive predictors were active and passive tobacco smoking and use of FA supplements. Avoiding both active and passive tobacco smoking and using FA supplements could improve the folate status of Japanese women.

Association of maternal whole blood fatty acid status during the prenatal period with term birth dimensions: a cross-sectional study.

OBJECTIVE: To investigate selected fatty acid (FA) profiles in maternal whole blood during normal pregnancy and to evaluate their associations with term birth dimensions. METHODS: We characterized nine major maternal blood FAs representing four FA families during the second and third trimester of pregnancy, and explored their associations with birth weight, length, and chest or head circumferences by multivariate regression models, using data from 318 mother-newborn pairs of the Hokkaido Study. RESULTS: The absolute and/or relative contents of maternal blood docosahexaenoic acid and arachidonic acid were lowest at 35-41 gestational weeks during pregnancy, as was the essential FA status index. Different from palmitic and stearic acids, palmitoleic and oleic acid contents were higher at 35-41 gestational weeks than those at 23-31 gestational weeks. Three FA components were identified through principal component analysis, and were used in association analysis. Component 3, which was positively and significantly loaded by eicosapentaenoic acid (EPA), was associated with chest circumference [ß=0.281, 95% confidence interval (CI): 0.006, 0.556] at 35-41 gestational weeks (P=0.046). No significant associations were observed for Component 1 and 2 loaded by FAs except EPA. CONCLUSION: Maternal blood EPA content may have an important influence on infant chest circumference.

Prenatal maternal blood triglyceride and fatty acid levels in relation to exposure to di(2-ethylhexyl)phthalate: a cross-sectional study.

OBJECTIVES: The hypolipidemic effects of di(2-ethylhexyl)phthalate (DEHP) exposure in humans have not been investigated. And the influences of maternal prenatal DEHP exposure on birth outcomes are not well-known. We aimed to estimate prenatal DEHP exposure in maternal blood, and evaluate its relationships to maternal blood triglyceride (TG) and fatty acid (FA) levels and to birth outcomes. METHODS: We studied 318 mother-newborn pairs residing in Sapporo, Japan. Blood was taken one time during pregnancy for each mother. Maternal and infant characteristics were obtained from medical records and questionnaire survey. We measured DEHP metabolite, mono(2-ethylhexyl) phthalate (MEHP), along with TG and 9 FAs using maternal blood, and analyzed associations of MEHP level with maternal blood TG/FA levels and infant birth dimensions. RESULTS: Maternal blood TG and palmitoleic/oleic acid levels were higher, but stearic/docosahexaenoic acids and MEHP were lower during late pregnancy. Maternal blood MEHP levels inversely correlated with TG and palmitic/palmitoleic/oleic/linoleic/α-linolenic acids. After adjustment for confounders, we found that a tenfold increase in blood MEHP levels correlated with a decrease in TG of 25.1 mg/dl [95% confidence interval (CI) 4.8-45.3 mg/dl], and similar relations in palmitic (ß = -581.8; 95 % CI -906.5, -257.0), oleic (ß = -304.2; 95% CI -518.0, -90.5), linoleic (ß = -348.6; 95% CI -510.6, -186.6), and α-linolenic (ß = -6.3; 95% CI -9.5, -3.0) acids. However, we observed no correlations between maternal blood MEHP levels and infant birth weight, length, chest circumference, or head circumference. CONCLUSIONS: Ambient DEHP exposure during pregnancy inversely correlated with maternal blood TG and 4 FA levels, but not birth outcomes.

Association between maternal antenatal depression and infant development: a hospital-based prospective cohort study.

OBJECTIVE: To examine the association between antenatal depression and infant development after controlling for confounding factors. METHODS: A hospital-based prospective cohort study (Hokkaido Study on Environment and Children's Health) was conducted between July 2002 and October 2005 in Sapporo, Japan. Of 309 mothers who delivered at Sapporo Toho Hospital during the study period and who agreed with the clinical assessment of depression, 154 mother-infant pairs were eligible for analysis. Antenatal depression was assessed between the second and third trimesters using the Edinburgh Postnatal Depression Scale (EPDS), and infant development was assessed at 6 months by the Bayley Scales of Infant Development II (BSID-II). Data on potential confounders, including socioeconomic status, birth complications, postnatal depression and child care environment, were obtained from medical records and self-administered questionnaires. Univariable and multivariable analyses were conducted in which the EPDS score was entered as an independent variable and the BSID-II scores as a dependent variable, adjusting for confounders. RESULTS: Although the antenatal EPDS score tended to be related to the BSID-II score in the univariable analysis, this correlation was lost in the multivariable analysis. However, based on a series of linear regression analyses, antenatal depression was found to be significantly related to shorter gestational age (ß = -0.25, 95 % confidence interval (CI) [-1.20, -0.17]), and shorter gestational age was significantly related to a lower BSID-II (mental development) score (ß = 0.23, 95 % CI [0.00, 0.00]). CONCLUSIONS: Gestational age is an important confounder in the association between maternal antenatal depression and infant development. A delay in infant development may be related to a shorter gestational period caused by maternal depression during pregnancy.

Ten years of progress in the Hokkaido birth cohort study on environment and children's health: cohort profile--updated 2013.

The Hokkaido Study on Environment and Children's Health is an ongoing cohort study that began in 2002. The study consists of two prospective birth cohorts, the Sapporo cohort (n = 514) and the Hokkaido large-scale cohort (n = 20,940). The primary goals of this study are to first examine the potential negative effects of perinatal environmental chemical exposures on birth outcomes, including congenital malformations and growth retardation; second, to evaluate the development of allergies, infectious diseases and neurodevelopmental disorders and perform longitudinal observations of the children's physical development to clarify the causal relationship between these outcomes and environmental chemicals; third, to identify individuals genetically susceptible to environmental chemicals; finally, to identify the additive effects of various environmental factors in our daily life, such as secondhand smoke exposure or low folate intake during early pregnancy. In this paper, we introduce our recent progress in the Hokkaido study with a cohort profile updated in 2013. For the last ten years, we followed pregnant women and their offspring, measuring various environmental chemicals, i.e., PCB, OH-PCB and dioxins, PFCs (Perfluorinated Compounds), Organochlorine pesticides, Phthalates, bisphenol A and mercury. We discovered that the concentration of toxic equivalents (TEQ) of dioxin and other specific congeners of PCDF or PCDD have effects on birth weight, infants' neurodevelopment and immune function. There were significant gender differences in these effects; our results suggest that male infants have more susceptibility to those chemical exposures than female infants. Interestingly, we found maternal genetic polymorphisms in AHR, CYP1A1 or GSTs that significantly modified the dioxin concentrations in maternal blood, suggesting different dioxin accumulations in the bodies of individuals with these genotypes, which would lead to different dioxin exposure levels. These genetic susceptibility factors influenced the body size of children born from mothers that either smoked or were passively exposed to tobacco smoke. Further studies investigating the correlation between epigenetics, the effects of intrauterine exposure to environmental chemicals and developmental factors related to health and disease are warranted.

A randomized controlled trial of a Functioning Improvement Tool home-visit program and its effect on cognitive function in older persons.

OBJECTIVE: The aim was to determine whether mini mental state examination (MMSE) scores improved in older participants of a Functioning Improvement Tool (FIT) home-visit program. METHODS: Two hundred fifty-two participants aged 65 years or older living at home and receiving preventive services or a community long-term care prevention project according to the Japanese social long-term care insurance system were enrolled and randomly assigned to an intervention group (n = 128) or a control group (n = 124). Intervention group subjects received a 60-min FIT home-visit program for 3 months, which included guidance, assistance, and help in writing and teaching calculation in order to complete the FIT. Control subjects did not receive any home visits. Cognitive function was evaluated by MMSE. Analysis of covariance was used to examine the effects of the FIT adjusting for baseline MMSE scores, age, and sex. RESULTS: Fifty-three subjects were excluded because of withdrawal, hospitalization, death, relocation, or missing data of MMSE; 199 subjects (60 men, 139 women; age 78.6 ± 7.4 years) were analyzed. The baseline MMSE scores did not differ between the intervention and control groups (24.2 ± 4.3 vs. 24.1 ± 4.7, p = 0.90). After the study period, the change in the MMSE score was significantly better in the intervention group than in the control group (0.8 ± 0.3 vs. -0.1 ± 0.2, p = 0.04). Stratified analyses showed that the intervention strategy was most effective in subjects with mild cognitive decline, with baseline MMSE scores from 18 to 23 points (1.9 ± 0.5 vs. -0.1 ± 2.8, p = 0.04). CONCLUSIONS: Our FIT home-visit program improved MMSE scores in older participants with mild cognitive decline.

[A qualitative study on perceived changes and improvement in the current state of public health activities of public health nurses in Hokkaido, Japan].

OBJECTIVES: This study aimed to clarify perceived changes in the current state of public health activities by Japanese public health nurses, and further to gather their ideas and proposals for coping with changes from a public health point of view considering the community as a whole. METHODS: Three separate focus group discussions (FGD) were conducted among public health nurses who had at least five years work experience at prefectural public health centers or municipalities in Hokkaido, Japan. Dialogs were analyzed using the qualitative research method developed by Berelson. RESULTS: Changes in the current work situation that twenty four public health nurses perceived through the FGD were categorized into the following five categories, along with their opinions on how to cope with them. First, both the system and curriculum at nursing schools in Japan have recently changed and issues remain on postgraduate education for newly graduated public health nurses as well as those with more experience. Second, job content has been transformed because of public health reform, which resulted in a growing burden on public health nurses due to an increase in workload, collaboration with clerical staff, and allocation of designated tasks. Increased liaison with office staff and regional personnel was suggested as a solution for coping with the work burden. Third, psychological changes in public health nurses were emphasized, especially worry and anxiety arising from changes in their social role, motivation and community health activities. To overcome such a distressed mental state, they believed they needed to improve awareness of their capability as public health specialists, with better real communication among themselves. Finally, focus group members identified how prefectural and municipal health systems as well as the sense of community had gradually changed. Strengthening interactions both between and within systems as well as acting locally were acknowledged as means of mitigating the disadvantages of change. CONCLUSION: This study indicated that to deal with the drastically changing situation in the current community health system, postgraduate education promotion for public health nurses, a redefinition of their mission with more emphasis on self-motivation, sharing worries among colleagues, reinforcing communication with clerical staff as well as the institutions and people concerned, and a reconstruction of the relationship between municipalities and provincial public health centers may be necessary.

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.

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.

Effects of low-level prenatal exposure to dioxins on cognitive development in Japanese children at 42months.

BACKGROUND: Prenatal exposure to polychlorinated dibenzo-p-dioxins (PCDDs) or polychlorinated dibenzofurans (PCDFs) and dioxin-like polychlorinated biphenyls (dioxin-like compounds [DLCs]) through environmental chemicals may affect the neurodevelopment of children. In our previous study, an inverse association was observed between prenatal DLCs and neurodevelopment of infants aged 6months in both sexes. However, studies are yet to determine how long these adverse effects last. OBJECTIVE: To examine whether the effects of DLCs on cognitive development remains at 42months. METHODS: In this prospective cohort study conducted in Sapporo, Japan, pregnant mothers' blood was analyzed for the congener level of DLCs. The Kaufman Assessment of Battery for Children (K-ABC) was used to test their children's cognitive development at 42months. A total of 141 mother-child pairs were included in the final analysis. The multiple linear regression analysis was used to examine the association between the K-ABC scores and DLC levels in the maternal blood. RESULTS: Seven isomers (1,2,3,6,7,8-HxCDD, 2,3,4,7,8-PeCDF, 33'44'55'-HxCB(#169), 2344'5- PenCB(#114), 233'44'5-HexCB(#156), 233'44'5'-HexCB(#157), 23'44'55'-HexCB(#167), total PCDF, and TEQ-PCDD, PCDF, PCDD/DFs levels were positively associated with the achievement score (AS) of K-ABC. However, total non-ortho PCBs were negatively associated with the Mental Processing Composite Score (MPCS) of K-ABC in males. In females, increased TEQ-dl PCB and TEQ-PCDD/F/dl-PCB were also associated with increasing AS score. CONCLUSIONS: This study suggests that the negative effects of prenatal DLC exposure on children's cognitive development at 6months were not observed in children aged 42months. Regarding the sex-specific effects, AS and DLCs were positively correlated in females, whereas those of MPCS and DLCs were significantly negative in males.

Effects of prenatal perfluoroalkyl acid exposure on cord blood IGF2/H19 methylation and ponderal index: The Hokkaido Study.

Prenatal exposure to perfluoroalkyl acids (PFAAs) influences fetal growth and long-term health. However, whether PFAAs affect offspring DNA methylation patterns to influence health outcomes is yet to be evaluated. Here, we assessed effect of prenatal PFAA exposure on cord blood insulin-like growth factor 2 (IGF2), H19, and long interspersed element 1 (LINE1) methylation and its associations with birth size. Mother-child pairs (N=177) from the Hokkaido Study on Environment and Children's Health were included in the study. Perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) levels in maternal serum were measured by liquid chromatography-tandem mass spectrometry. IGF2, H19, and LINE1 methylation in cord blood DNA was determined by pyrosequencing. After full adjustment in multiple linear regression models, IGF2 methylation showed a significant negative association with log-unit increase in PFOA (partial regression coefficient=-0.73; 95% confidence interval: -1.44 to -0.02). Mediation analysis suggested that reduced IGF2 methylation explained ~21% of the observed association between PFOA exposure and reduced ponderal index of the infant at birth. These results indicated that the effects of prenatal PFOA exposure could be mediated through DNA methylation. Further study will be required to determine the potential for long-term adverse health effects of reduced IGF2 methylation induced by PFOA exposure.

Prenatal exposure to perfluorinated chemicals and neurodevelopment in early infancy: The Hokkaido Study.

Perfluorinated chemicals (PFCs) are ubiquitous and persistent pollutants widely detected in blood samples of animals and humans across the globe. Although animal studies have shown the potential neurotoxicity of PFCs, there are few epidemiological studies regarding neurological effects of PFCs in humans, and those studies have had inconclusive results. In this study, we conducted a hospital-based prospective birth cohort study between 2002 and 2005 (n=514) to examine the associations between prenatal perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) exposures and the neurodevelopment of infants at 6 (n=173) and 18 (n=133) months of age. Using the second edition of the Bayley Scales of Infant Development (BSID II), the Mental and Psychomotor Developmental Indices (MDI and PDI, respectively) were assessed. PFOS and PFOA were measured in maternal serum samples by liquid chromatography-tandem mass spectrometry. After controlling for confounders, prenatal PFOA concentrations were associated with the MDI of female (but not male) infants at 6 months of age (ß=-0.296; 95% confidence interval (CI): -11.96, -0.682). Furthermore, females born to mothers with prenatal concentrations of PFOA in the fourth quartile had MDI scores -5.05 (95% CI: -10.66 to 0.55) lower than females born to mothers with concentrations of PFOA in the first quartile (p for trend=0.045). However, PFOA concentrations were not significantly associated with neurodevelopmental indices at 18 months of age. In addition, we did not observe any significant association between PFOS concentrations and neurodevelopmental outcomes in early infancy. In conclusion, our results suggest that prenatal PFOA exposure may affect female mental scales of neurodevelopment at 6 months of age. Further studies with larger sample sizes and longer observation periods are required to clarify sex difference of the neurodevelopmental effects.

Effects of prenatal phthalate exposure on thyroid hormone levels, mental and psychomotor development of infants: The Hokkaido Study on Environment and Children's Health.

Di (2-ethylhexyl) phthalate (DEHP) is commonly used phthalates and concerns of adverse effects of prenatal DEHP exposure on neonatal thyroid hormone (TH) and neurodevelopment are increasing. However, there is no report regarding association between prenatal DEHP exposure and infant neurodevelopment including TH levels in Japanese population. Thus the aim of present study was to evaluate the associations between prenatal DEHP exposure and mental and psychomotor development of infants 6 and 18months along with investigating influence on neonatal free thyroxine (FT4) and thyroid stimulating hormone (TSH) levels in the prospective birth cohort study. Maternal blood samples collected between 23 and 41weeks of gestation was analyzed for mono (2-ethylhexyl) phthalate (MEHP), metabolite of DEHP levels. Neonatal FT4 and TSH were obtained from mass screening data. Infant neurodevelopment was assessed by Bayley Scale of Infant Development second edition at 6 and 18month of age. For the final analysis, 328 participants were included. The median levels of maternal MEHP was 10.6ng/ml, neonatal TSH and FT4 was 2.20 µU/ml and 2.03ng/ml, respectively. We did not find any associations between prenatal DEHP exposure and neonatal TH levels or infant mental and psychomotor development at 6 and 18month. In this study, prenatal DEHP exposure did not show adverse effects on infant TH levels or mental and psychomotor development in early life stage. However, our previous study revealed negative effects of prenatal DEHP exposure on sex hormone levels, continuous investigation on neurodevelopment in later life in association with prenatal DEHP exposure is necessary.

The Relationship between the Second-to-Fourth Digit Ratio and Behavioral Sexual Dimorphism in School-Aged Children.

Sexually dimorphic brain development and behavior are known to be influenced by sex hormones exposure in prenatal periods. On the other hand, second-to forth digit ratio (2D/4D) has been used as an indirect method to investigate the putative effects of prenatal exposure to androgen. In the present study, we herein investigated the relationship between gender-role play behavior and the second-to-fourth digit ratio (2D/4D), which has been used as an indirect method to investigate the putative effects of prenatal exposure to androgens, in school-aged children. Among 4981 children who became 8 years old by November 2014 and were contactable for this survey by The Hokkaido Study of Environment and Children's Health, 1631 (32.7%), who had data for 2D/4D and Pre-school Activities Inventory (PSAI) as well as data for the survey at baseline, were available for analysis. Parents sent reports of PSAI on the sex-typical characteristics, preferred toys, and play activities of children, and black and white photocopies of the left and right hand palms via mail. PSAI consisted of 12 masculine items and 12 feminine items, and a composite score was created by subtracting the feminine score from the masculine score, with higher scores representing masculine-typical behavior. While composite scores in PSAI were significantly higher in boys than in girls, 2D/4D was significantly lower in boys than in girls. Although the presence or absence of brothers or sisters affected the composite, masculine, and feminine scored of PSAI, a multivariate regression model revealed that 2D/4D negatively correlated with the composite scores of PSAI in boys, whereas no correlation was found in girls. Although 2D/4D negatively correlated with the masculine score in boys and girls, no correlation was observed between 2D/4D and the feminine score. In conclusion, although social factors, such as the existence of brother or sisters, affect dimorphic brain development and behavior in childhood, the present study revealed that the prenatal hormonal environment was an important factor influencing masculine-typical dimorphic brain development and behavior in school-aged children.

Effects of in utero exposure to polychlorinated biphenyls, methylmercury, and polyunsaturated fatty acids on birth size.

The adverse effects of in utero exposure to polychlorinated biphenyls (PCBs) or methylmercury (MeHg), and the beneficial effects of nutrients from maternal fish intake might have opposing influences on fetal growth. In this study, we assessed the effects of in utero exposure to PCBs and MeHg on birth size in the Japanese population, which is known to have a high frequency of fish consumption. The concentrations of PCBs and polyunsaturated fatty acids in maternal blood, and the total mercury in hair (as a biomarker of MeHg exposure) were measured during pregnancy and at delivery. Maternal intakes of fish (subtypes: fatty and lean) and shellfishes were calculated from a food frequency questionnaire administered at delivery. Newborn anthropometric measurement data were obtained from birth records. The associations between chemical exposures and birth size were analyzed by using multiple regression analysis with adjustment for confounding factors among 367 mother-newborn pairs. The birth weight was 3073±37 g (mean±SD). The incidence of babies small for gestational age (SGA) by weight was 4.9%. The median concentrations of total PCBs and hair mercury were 108 ng/g lipid and 1.41 µg/g, respectively. There was no overall association between mercury concentrations and birth weight, birth length, chest circumference, and head circumference. We observed that the risk of SGA by weight decreased with increasing mercury concentration in regression analyses with adjustment for polyunsaturated fatty acids. Our results suggest that the beneficial effect of essential nutrition may mask the adverse effects of MeHg on birth size. The concentrations of PCBs had no association with birth size.

The Association of Prenatal Exposure to Perfluorinated Chemicals with Maternal Essential and Long-Chain Polyunsaturated Fatty Acids during Pregnancy and the Birth Weight of Their Offspring: The Hokkaido Study.

BACKGROUND: Fatty acids (FAs) are essential for fetal growth. Exposure to perfluorinated chemicals (PFCs) may disrupt FA homeostasis, but there are no epidemiological data regarding associations of PFCs and FA concentrations. OBJECTIVES: We estimated associations between perfluorooctane sulfonate (PFOS)/perfluorooctanoate (PFOA) concentrations and maternal levels of FAs and triglyceride (TG) and birth size of the offspring. METHODS: We analyzed 306 mother-child pairs in this birth cohort between 2002 and 2005 in Japan. The prenatal PFOS and PFOA levels were measured in maternal serum samples by liquid chromatography-tandem mass spectrometry. Maternal blood levels of nine FAs and TG were measured by gas chromatography-mass spectrometry and TG E-Test Wako kits, respectively. Information on infants' birth size was obtained from participant medical records. RESULTS: The median PFOS and PFOA levels were 5.6 and 1.4 ng/mL, respectively. In the fully adjusted model, including maternal age, parity, annual household income, blood sampling period, alcohol consumption, and smoking during pregnancy, PFOS but not PFOA had a negative association with the levels of palmitic, palmitoleic, oleic, linoleic, α-linolenic, and arachidonic acids (p < 0.005) and TG (p-value = 0.016). Female infants weighed 186.6 g less with mothers whose PFOS levels were in the fourth quartile compared with the first quartile (95% CI: -363.4, -9.8). We observed no significant association between maternal levels of PFOS and birth weight of male infants. CONCLUSIONS: Our data suggest an inverse association between PFOS exposure and polyunsaturated FA levels in pregnant women. We also found a negative association between maternal PFOS levels and female birth weight.