Miyuki Iwai-Shimada

Impacts of prenatal exposures to polychlorinated biphenyls, methylmercury, and lead on intellectual ability of 42-month-old children in Japan.

BACKGROUND The age-specific impacts of perinatal exposures to polychlorinated biphenyls (PCB), methylmercury (MeHg), and lead on child neurodevelopment remain controversial. Since we have already reported the prenatal effects of these chemicals on neurodevelopment in 3-day-old and 30-month-old children of a birth cohort, the following effects were analyzed in the 42-month-old children in the same cohort. METHODS The Kaufman Assessment Battery for Children (K-ABC), comprised of four scales, was used to assess their intelligence and achievement. The relationships between the chemicals and K-ABC scores were analyzed using multivariate analyses. RESULTS The median values of chemicals in cord blood of 387 children were 46.5 (5th and 95th percentiles, 16.7-115.7)ng/g-lipid for total PCB, 10.1 (4.3-22.2)ng/g for total mercury (THg), and 1.0 (0.5-1.8) μg/dL for lead. Of the highly chlorinated PCB homologs, 9 CBs was negatively correlated with the sequential and mental processing score of the K-ABC (p<0.05). There were no significant correlations between any K-ABC score and either THg or lead. The negative effect of 9 CBs remained even after adjusting for THg, lead, and other confounders. The K-ABC scores were significantly lower in the boys than in the girls, and the standardized β of 9 CBs for the sequential and mental processing scores in multiple regression analysis was statistically significant in boys. CONCLUSIONS These findings suggest that intellectual ability in the developmental stage may be impaired by prenatal exposures to highly chlorinated PCB homologs, especially in Japanese boys.

Prenatal exposures to environmental chemicals and birth order as risk factors for child behavior problems

OBJECTIVES To assess whether polychlorinated biphenyls (PCBs), methylmercury, lead, or parental child-rearing attitudes was most crucial for maladaptive behavior problems, we examined Japanese 30-month-old children followed up from pregnancy. METHODS The Child Behavior Checklist (CBCL) was used to assess the behavior problems in 306 children. The associations of cord-blood total PCBs (ΣPCB), total mercury (THg), and lead with each CBCL subscale were examined by multivariate analyses. RESULTS The median values in cord blood of the 306 children were 48.3 (5 and 95 percentiles, 18.6-116.3) ng/g-lipid for ΣPCB, 10.2 (4.1-24.5)ng/g for THg, and 1.0 (0.5-1.7)μg/dl for lead. The internalizing score of the CBCL was significantly correlated with ΣPCB (r=0.113) in the children, though no significant correlation was seen between any CBCL score and either THg or lead. The significant correlation disappeared when conducting multiple regression analysis with possible confounders; at that time, the birth order, home environment, and maternal intelligence quotient were significantly related to the internalizing score. Three CBCL scores and ΣPCB levels were significantly higher in the first-born children than in the second-born or following children, and the partial correlation coefficient with the adjustment for all confounders except birth order was significant between the internalizing score and ΣPCB in the latter children (r=0.175). CONCLUSIONS Internalizing behavior appears to be affected by prenatal exposure to PCBs at low levels. Under lower-level exposures, however, behavior problems may be more strongly associated with parental child-rearing attitudes involved in birth order, than with such hazardous chemicals.

Methylmercury in the breast milk of Japanese mothers and lactational exposure of their infants.

The human fetus is known to be exposed to methylmercury (MeHg), but little is known about the risk of infant exposure via breast milk. To evaluate the lactational exposure to MeHg via breast milk in Japanese infants, the levels of total mercury (THg) and MeHg were determined in breast milk and maternal blood using samples from a birth cohort study at the Tohoku Study of Child Development. Maternal blood and breast milk were collected one day postpartum and one month after delivery, respectively. The median THg (and MeHg) concentrations in maternal RBCs, plasma and breast milk were 17.8 ng g(-1) (17.8 ng g(-1)), 1.51 ng g(-1) (1.33 ng g(-1)) and 0.81 ng g(-1) (0.45 ng g(-1)), respectively (n=27). The median percentage of MeHg in THg was 54% in breast milk. Breast milk contained substantial amounts of MeHg, which was strongly associated with the internal accumulation of MeHg and the lipid content of the milk (r=0.684). The range of lipid contents in milk varied widely from 0.50 to 6.60 g/100 g of milk, with a median of 3.60 g/100 g. The median (range) weekly average intake of MeHg via breast milk was estimated to be 0.63 μg kg(-1) (0.08-1.68 μg kg(-1)) BW/week. Because the MeHg and lipid contents in milk substantially fluctuate, an investigation of the variations of MeHg and lipid content in breast milk may be required for a more precise risk assessment.

Baseline Profile of Participants in the Japan Environment and Children’s Study (JECS)

Background The Japan Environment and Children’s Study (JECS), known as Ecochil-Chosa in Japan, is a nationwide birth cohort study investigating the environmental factors that might affect children’s health and development. We report the baseline profiles of the participating mothers, fathers, and their children. Methods Fifteen Regional Centres located throughout Japan were responsible for recruiting women in early pregnancy living in their respective recruitment areas. Self-administered questionnaires and medical records were used to obtain such information as demographic factors, lifestyle, socioeconomic status, environmental exposure, medical history, and delivery information. In the period up to delivery, we collected bio-specimens, including blood, urine, hair, and umbilical cord blood. Fathers were also recruited, when accessible, and asked to fill in a questionnaire and to provide blood samples. Results The total number of pregnancies resulting in delivery was 100,778, of which 51,402 (51.0%) involved program participation by male partners. Discounting pregnancies by the same woman, the study included 95,248 unique mothers and 49,189 unique fathers. The 100,778 pregnancies involved a total of 101,779 fetuses and resulted in 100,148 live births. The coverage of children in 2013 (the number of live births registered in JECS divided by the number of all live births within the study areas) was approximately 45%. Nevertheless, the data on the characteristics of the mothers and children we studied showed marked similarity to those obtained from Japan’s 2013 Vital Statistics Survey. Conclusions Between 2011 and 2014, we established one of the largest birth cohorts in the world.

Psychomotor Ability in Children Prenatally Exposed to Methylmercury: The 18-Month Follow-Up of Tohoku Study of Child Development

Fish contain nutrients essential to the developing fetal brain, but they are contaminated with methylmercury. The Tohoku Study of Child Development, now underway in the Sanriku coastal area of Miyagi prefecture, Japan, follows mother-child pairs to examine the risks and benefits of fish consumption during pregnancy, especially the effects of prenatal exposures to methylmercury, selenium, and docosahexaenoic acid (DHA) on child neurodevelopment. Children aged 18 months were administered the Bayley Scales of Infant Development second edition (BSID-II) and Kyoto Scale of Psychological Development (KSPD) in 2004-2008. Complete data of cord-blood total mercury (THg), cord-plasma selenium, maternal-plasma DHA, the above test scores, and confounders for 566 mother-child pairs were available. The median cord-blood THg level was 15.7 (range, 2.7-96.1) ng/g. Since the BSID-II and KSPD scores were significantly lower in the 285 boys than in the 281 girls, analyses were conducted separately. The Psychomotor Development Index (PDI) of BSID-II was significantly correlated with cord-blood THg only in the boys, and significance of the association remained unchanged after adjusting for possible confounders; i.e., a 10-fold increase in cord-blood THg was associated with a 8.3-point decrease in the score of the PDI. Other significant correlations of THg were not seen in the boys or girls. Selenium and DHA showed no significant correlations with the BSID-II or KSPD scores in either sex. In conclusion, intrauterine methylmercury exposure may affect psychomotor development, and boys appear to be more vulnerable to the exposure than girls.

Methylmercury induces the expression of TNF-α selectively in the brain of mice.

Methylmercury selectively damages the central nervous system (CNS). The tumor necrosis factor (TNF) superfamily includes representative cytokines that participate in the inflammatory response as well as cell survival, and apoptosis. In this study, we found that administration of methylmercury selectively induced TNF-α expression in the brain of mice. Although the accumulated mercury concentration in the liver and kidneys was greater than in the brain, TNF-α expression was induced to a greater extent in brain. Thus, it is possible that there may exist a selective mechanism by which methylmercury induces TNF-α expression in the brain. We also found that TNF-α expression was induced by methylmercury in C17.2 cells (mouse neural stem cells) and NF-κB may participate as a transcription factor in that induction. Further, we showed that the addition of TNF-α antagonist (WP9QY) reduced the toxicity of methylmercury to C17.2 cells. In contrast, the addition of recombinant TNF-α to the culture medium decreased the cell viability. We suggest that TNF-α may play a part in the selective damage of the CNS by methylmercury. Furthermore, our results indicate that the higher TNF-α expression induced by methylmercury maybe the cause of cell death, as TNF-α binds to its receptor after being released extracellularly.

Total mercury levels in hair of children aged 7 years before and after the Great East Japan Earthquake

The Great East Japan Earthquake on March 11, 2011 caused severe damage to the Sanriku coastal area, where we have been conducting a birth cohort study. The disaster occurred in the middle of 7-year-old examination. The mother-child pairs who participated in our study were compulsorily divided into two groups: the examination was finished for 157 children before the disaster, and for 335 after the disaster. We examined whether the disaster affected total mercury (THg) levels of the cohort, as well as a relationship between the THg levels at birth and at present. Although there was no significant difference between the predisaster and postdisaster groups for THg levels in cord blood (16.3 and 16.1ngg-1, respectively) or maternal hair at parturition (2.57 and 2.55μgg-1, respectively), the THg in hair of the 7-year-old children was significantly lower in the postdisaster group (1.79μgg-1) than in the predisaster group (2.51μgg-1). The difference remained significant after adjusting for the prenatal exposure level of THg. In the 492 mother-child pairs, the cord-blood THg was significantly correlated with the THg in maternal hair at parturition (r=0.846) and in hair of the 7-year-old children (r=0.147). In conclusion, the 29% decrease in hair THg after the disaster appears to have been due to the fact that children in the affected area could not consume fish/seafood as usual, probably because of destructive damage to the fishery. Nevertheless, the THg levels at 7years of age reflected the prenatal exposure levels to some extent.

Effects of intrauterine exposures to polychlorinated biphenyls, methylmercury, and lead on birth weight in Japanese male and female newborns

BackgroundThe effects of prenatal exposures to polychlorinated biphenyls (PCBs), methylmercury, and lead on birth weight remain disputable. The aim of this study was to investigate whether these chemicals affect birth weight of Japanese newborns, with special emphasis on determining whether these effects differ between males and females.MethodsThe subjects from Tohoku Study of Child Development, which was designed to examine the developmental effects of prenatal exposures to such hazardous chemicals, were 489 mother-newborn pairs with complete data including smoking habit during pregnancy.ResultsThe mean birth weight of all newborns was 3083 (range, 2412–4240) g. The median values of biomarkers in cord blood were 46.0 (5th and 95th percentiles, 18.6–113.8) ng/g–lipid for total PCBs, 10.1 (4.3–22.4) ng/g for total mercury (THg), and 1.0 (0.6-1.7) μg/dL for lead. The birth weight was significantly heavier in the 252 male newborns than in the 237 female ones. A negative association between total PCBs and birth weight was observed in both male and female newborns, even after adjusting for possible confounders. However, a negative association of THg with birth weight was found only in the male newborns. There was no significant relationship between lead and birth weight in both groups.ConclusionBirth weight appears to be affected by prenatal PCB exposure in Japanese male and female newborns, and the effect of methylmercury exposure on male fetal growth may be stronger than that for females. This implication is that the effects on fetal growth should be assessed in males and females separately.

Chemokine CCL4 Induced in Mouse Brain Has a Protective Role against Methylmercury Toxicity

Methylmercury (MeHg) is selectively toxic to the central nervous system, but mechanisms related to its toxicity are poorly understood. In the present study, we identified the chemokine, C-C motif Chemokine Ligand 4 (CCL4), to be selectively upregulated in the brain of MeHg-administered mice. We then investigated the relationship between CCL4 expression and MeHg toxicity using in vivo and in vitro approaches. We confirmed that in C17.2 cells (a mouse neural stem cell line) and the mouse brain, induction of CCL4 expression occurs prior to cytotoxicity caused by MeHg. We also show that the addition of recombinant CCL4 to the culture medium of mouse primary neurons attenuated MeHg toxicity, while knockdown of CCL4 in C17.2 cells resulted in higher MeHg sensitivity compared with control cells. These results suggest that CCL4 is a protective factor against MeHg toxicity and that induction of CCL4 expression is not a result of cytotoxicity by MeHg but is a protective response against MeHg exposure.

Exposure Assessment in Japan Environment and Children’s Study

In this review, we present an initial plan for exposure assessment in the Japan Environment and Childrens Study (JECS) by focusing on a biomonitoring technique and discuss the challenges encountered when using the biomonitoring technique for exposure measurements. JECS registered 103,099 pregnant mothers and has been following children born to them. Various biological samples were collected from mothers during pregnancy (blood and urine), at birth (blood and hair) and at check-up one month after birth (breast milk). Samples were also collected from children at birth (cord blood) and at check-up one month after birth (hair and blood spot). Those samples will be used to assess maternal and foetal exposures to chemical substances. Measurement reliability, i.e., intraclass correlation coefficient (ICC), and attenuation bias related to low ICCs should be taken into consideration when using the biomonitoring results. Along with the biomonitoring technique, simulation models, pharmacokinetic (PK) models and exposomics techniques are under development in JECS. New analytical techniques include deciduous teeth measurements and -omics analyses. In particular, PK models and sensor technologies are one of the most important methodologies for future JECS exposure analyses. Statistical methods for examining the effects of intercorrelated multiple exposures as well as nondetection data should also be explored.