Sonomi Nakajima

Effects of Prenatal Exposure to Polychlorinated Biphenyls and Dioxins on Mental and Motor Development in Japanese Children at 6 Months of Age

Several studies have shown that prenatal and/or postnatal background-level exposure to environmental chemicals, such as polychlorinated biphenyls (PCBs) and dioxins, induces adverse effects on the neurodevelopment of children. However, other studies have not detected any harmful influences on neurodevelopment. Furthermore, except in western countries, no developmental tests have been carried out in relation to detailed assessment of exposure to PCBs and dioxins. In this study (the Hokkaido Study on Environment and Children’s Health), the effect of prenatal exposure to background levels of PCBs and dioxins on infant neurodevelopment in Japan/Sapporo was elucidated. The associations between the total or individual isomer level of PCBs and dioxins in 134 Japanese pregnant women’s peripheral blood and the mental or motor development of their 6-month-old infants were evaluated using the second edition of the Bayley Scales of Infant Development. The mean level of total toxicity equivalency quantity (TEQ) was 18.8 (4.0–51.2) pg/g lipid in blood of 134 mothers. After adjustment for potential confounding variables, the total TEQ value was shown not to be significantly associated with mental developmental index (MDI) or psychomotor developmental index (PDI). However, the levels of one polychlorinated dibenzo-p-dioxin (PCDD) isomer, total PCDDs, and total PCDDs/polychlorinated dibenzofurans (PCDFs) were significantly negatively associated with MDI, and the levels of two PCDD isomers and three PCDF isomers were significantly negatively associated with the PDI. In conclusion, the background-level exposure of several isomers of dioxins during the prenatal period probably affects the motor development of 6-month-old infants more than it does their mental development.

Adverse Birth Outcomes Associated with Maternal Smoking and Polymorphisms in the N-Nitrosamine-Metabolizing Enzyme Genes NQO1 and CYP2E1

Maternal smoking during pregnancy can result in both pregnancy complications and reduced size of the fetus and neonate. Among women who smoke, genetic susceptibility to tobacco smoke also is a likely causative factor in adverse pregnancy outcomes. A prospective cohort study was conducted among 460 pregnant women who delivered live singletons in Sapporo, Japan, from 2002 to 2005. Multiple linear regression models were used to estimate associations of maternal smoking and polymorphisms in two genes encoding N-nitrosamine-metabolizing enzymes-NAD(P)H: quinone oxidoreductase 1 (NQO1) and cytochrome P-450 2E1 (CYP2E1)-with birth size. Among infants born to smokers with the NQO1 homozygous wild-type allele, birth weight, birth length, and birth head circumference were significantly reduced (p < 0.01 for each factor). For the homozygous wild-type CYP2E1 allele, birth weight was lower by an estimated 195 g (standard error, 55; p < 0.001) among smokers. These genotypes did not confer adverse effects among women who had never smoked or who quit smoking during the first trimester. The adverse effects of maternal smoking on infant birth size may be modified by maternal genetic polymorphisms in N-nitrosamine-metabolizing enzymes among Japanese subjects. These results may help in directing smoking cessation interventions during pregnancy, especially among susceptible women.

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 (β=-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.

Congener-specific analysis of non-dioxin-like polychlorinated biphenyls in blood collected from 195 pregnant women in Sapporo City, Japan.

We conducted a congener-specific analysis of non-dioxin-like polychlorinated biphenyls (non-dioxin-like PCBs) in blood collected between July 2002 and July 2004 from 195 pregnant women living in Sapporo City of Hokkaido Prefecture, Japan. The present study is one of the few studies in which full congener concentrations of non-dioxin-like PCBs have been measured in the blood of pregnant women. Of the 195 pregnant women, 101 were primipara (mean: 28.8 years, median: 28.0 years) and 94 were multipara (mean: 32.3 years, median: 33.0 years). Among the 197 non-dioxin-like PCB congeners, 58 congeners were identified in the blood of pregnant women. The arithmetic mean total concentrations of 58 non-dioxin-like PCB congeners in the blood of primiparous and multiparous mothers in Sapporo City were 42.2-329.3 (mean: 114.5, median: 98.6) and 31.5-258.0 (mean: 100.3, median: 91.4)ngg(-1)lipid, respectively. The results show that the contamination of non-dioxin-like PCBs in the blood of women has decreased compared to past levels in other domestic areas, in which the subject age was similar to that in this study. The results of the present study indicate that current levels of non-dioxin-like PCBs in the blood of Japanese women and can be used as baseline data for future temporal trends. The sums of the ratios of the concentrations of hexaCBs and heptaCBs to the total concentrations of 58 non-dioxin-like PCB congeners in the blood of primiparous and multiparous mothers were 78.5% and 77.7%, respectively. The hexaCBs ratios in the blood of primiparous and multiparous mothers were 45.4% and 44.7%, respectively. HexaCB-153 among hexaCBs congeners, the most abundant congener in the blood of primiparous and multiparous mothers, contributed approximately 22.0% and 21.8% to the total concentrations of 58 non-dioxin-like PCBs congeners that were measured in the blood, respectively. Among the non-dioxin-like PCB congeners measured in the present study, hexaCB-138, heptaCB-170, heptaCB-180, and heptaCB-182/heptaCB-187 also showed high ratios to total concentrations of 58 non-dioxin-like PCB congeners detected in the blood of primiparous and multiparous mothers. With regard to the relationship between the total concentrations of 58 non-dioxin-like PCB congeners in maternal blood and the number of deliveries or the age of primiparous and multifarious mothers, the total levels of these PCB congeners tended to decreases with increases in the number of deliveries and significantly increased with increasing maternal age in both groups. Furthermore, significant correlations were observed between the total concentrations of these PCB congeners in blood and the age of primiparae and multiparae. The concentrations of hexaCB-153 in the blood of primiparous and multiparous mothers showed a close correlation to the total concentrations of these PCBs, suggesting that hexaCB-153 could be an indicator of total concentrations of non-dioxin-like PCB congeners in the blood of pregnant women.

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.

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. HighlightsAdverse developmental effects of prenatal exposure to DLCs may be stronger in male.A significant negative association to development of DLCs was absent at 18 m of age.Some of DLCs were positively associated with MDI at 18 m of age in female.

Association of maternal serum concentration of hydroxylated polychlorinated biphenyls with maternal and neonatal thyroid hormones: The Hokkaido birth cohort study

Background: Evidence on the toxicity of hydroxylated metabolites of polychlorinated biphenyls (OH‐PCBs) for thyroid hormones (TH) is limited, and the underlying mechanism remains unknown. Objectives: We aimed to investigate the effects of environmental prenatal exposure to OH‐PCBs and maternal and neonatal TH levels, taking the maternal‐fetal TH transfer into account. Methods: In this prospective birth cohort (the “Hokkaido study”) we included 222 mother‐neonate pairs. We measured five OH‐PCB isomers in maternal serum samples either during pregnancy or within 5 days of delivery. Thyroid stimulating hormone (TSH) and free thyroxine (FT4) levels were obtained from maternal blood samples at an early gestational stage (median; 11.1 weeks) and from heel prick samples of neonates between 4 and 7 days after birth. Multiple linear regression analysis and structural equation modeling (SEM) were performed to investigate the associations between maternal OH‐PCB and maternal and neonatal TH levels. Results: Median concentration of ∑OH‐PCBs was 25.37 pg/g wet weight. The predominant isomer was 4‐OH‐CB187, followed by 4‐OH‐CB146+3‐OH‐CB153. In the fully adjusted linear regression analysis, maternal ∑OH‐PCBs was positively associated with maternal FT4, and 4‐OH‐CB187 was positively associated with both maternal and neonatal FT4 levels. Maternal OH‐PCBs showed no significant association with TSH among mothers and neonates. Path analysis indicated the indirect pathway from 4‐OH‐CB187 exposure to increased neonatal FT4, via maternal THs and neonatal TSH. Conclusions: These findings suggest that maternal exposure to OH‐PCBs during pregnancy may increase both maternal and neonatal FT4 levels. Neonatal FT4 is presumed to be increased by prenatal 4‐OH‐CB187 indirectly, and this process may be mediated by maternal THs and neonatal TSH. HighlightsWe examined the effect of OH‐PCBs on maternal and neonatal thyroid hormones (THs).Maternal OH‐PCB exposure were positively associated with both maternal and neonatal FT4.Maternal OH‐PCB exposure were not associated with maternal or neonatal TSH.Path analysis suggests the indirect effect of OH‐PCB exposure on neonatal FT4 via maternal THs and neonatal TSH.

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.