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Background Little is known about the relationship of healthy diets, which are widely recommended to prevent diseases in general populations, with the risk of hypertensive disorders of pregnancy (HDP), particular among non‐Western populations with different dietary habits. We aimed to investigate the association between periconceptional diet quality and the risk of HDP among pregnant Japanese women. Methods and Results Dietary intake over 1 year before the first trimester of pregnancy was assessed using a validated, self‐administered food frequency questionnaire among 81 113 pregnant Japanese women who participated in a prospective cohort of the Japan Environment and Children's Study. Overall diet quality was assessed by the Balanced Diet Score (BDS) based on adherence to the country‐specific dietary guidelines and the Dietary Approaches to Stop Hypertension (DASH) score. Cases of HDP were identified by medical record transcription. The association between diet quality and HDP risk was examined using Bayesian logistic regression models with monotonic effects. We identified 2383 (2.9%) cases of HDP. A higher BDS was associated with a lower risk of HDP. When comparing the highest with the lowest quintile of the BDS, the adjusted odds ratio (aOR) of HDP was 0.83 (95% credible interval [CrI], 0.73–0.94). The DASH score and HDP risk were inversely associated in a monotonic dose–response manner (aOR per 1‐quintile increase in the DASH score, 0.92 [95% CrI, 0.89–0.95]). Conclusions A high‐quality diet, which is recommended for disease prevention in general populations, before conception may also reduce the risk of HDP among pregnant Japanese women.

Abstract Per‐ and poly‐fluoroalkyl substances (PFAS), which are long‐lasting environmental contaminants that are released into the environment during the e‐waste disassembly process, pose a threat to human health. Human milk is a complex and dynamic mixture of endogenous and exogenous substances, including steroid hormones and PFAS. Therefore, in this study, we aimed to investigate the association between PFAS and steroid hormones in human milk from women living close to an e‐waste disassembly area. In 2021, we collected milk samples from 150 mothers within 4 weeks of delivery and analyzed them via liquid chromatography‐tandem mass spectrometry to determine the levels of 21 perfluorinated compounds and five steroid hormones (estrone, estriol, testosterone, progesterone, and androstenedione [A‐dione]). We also performed multiple linear regression analysis to clarify the association between maternal PFAS exposure and steroid hormone concentrations. Our results indicated that PFOA and PFOS were positively associated with estrone (β, 0.23; 95% CI, 0.08–0.39) and A‐dione (β, 0.186; 95% CI, 0.016–0.357) concentrations in human milk, respectively. Further, the average estimated daily intake of PFOA and PFOS were 36.5 ng/kg bw/day (range, 0.52–291.7 ng/kg bw/day) and 5.21 ng/kg bw/day (range, 0.26–32.3 ng/kg bw/day), respectively. Of concern, the PFAS intake of breastfeeding infants in the study area was higher than the recommended threshold. These findings suggested that prenatal exposure to PFAS from the e‐waste disassembly process can influence steroid hormones levels in human milk. Increased efforts to mitigate mother and infant exposure to environmental pollutants are also required.

Background: High low-density lipoprotein cholesterol levels (LDL-C) during pregnancy have been associated with adverse pregnancy and offspring outcomes. While previous studies have suggested a potential link between organophosphate pesticide (OPP) exposure and higher LDL-C in the general population and agricultural workers, the relationship in pregnant women and the effect of body mass index on this relationship remain unclear. We examined the association between the urinary concentrations of OPP metabolites (dialkylphosphates) and blood lipid levels in pregnant women. Methods: We used data from the Japan Environment and Children’s Study, which included 5,169 pregnant women with urinary dialkylphosphate data. We examined the association between urinary concentrations of six dialkylphosphates (DEP, DETP, DEDTP, DMP, DMTP, DMDTP) and blood lipid levels (LDL-C, total cholesterol, high-density lipoprotein cholesterol, and triglycerides) during the first trimester using multiple linear regression under a Bayesian paradigm. We examined the association between high LDL-C, defined as ≥90th percentile of LDL-C, and urinary dialkylphosphate concentrations, using multiple logistic regression under a Bayesian paradigm. These analyses were repeated in underweight, normal-weight, and overweight participants. Results: DEP, DMP, and DMTP were detected in >50 % of the participants. Multiple linear regression analyses did not show associations between LDL-C and these dialkylphosphates. Stratified analyses showed a positive association between DEP and LDL-C in overweight women (beta coefficient = 2.13, 95 % credible interval = 0.86–3.38, probability of direction (PD) = 100 %); however, the association was not significant (percentage in region of practical equivalence (% in ROPE) = 84.0). Higher DEP was significantly associated with high LDL-C (odds ratio = 1.32, 95 % credible interval = 1.13–1.55, PD = 100 %, % in ROPE = 0.2). Conclusions: Among overweight pregnant women in the first trimester, higher urinary DEP concentrations were associated with high LDL-C. The effects of OPP on blood lipid profiles merit further investigation.

Background: Dioxin is an environmental pollutant as well as an endocrine disruptor in humans. Our longitudinal study wants to clarify the relationship between dioxin exposure and endocrine disorders in children living in the Vietnamese dioxin hotspot. Method: Seventeen congeners of polychlorinated dibenzo-p-dioxins/polychlorinated dibenzo-furans (PCDDs/PCDFs) in maternal breast milk and seven serum steroid hormones in children of 43 and 46 mothers and their 9-year-old children from the non-exposure and the hotspot areas were measured, respectively. The steroid metabolic enzyme ratios were calculated based on the hormone level ratio. Results: Most dioxin/furan congeners and toxic equivalents (TEQs) levels were significantly higher in the hotspot than in the non-exposure area, except for 2,4,7,8-TeCDF. The height and weight of girls from the hotspot area were substantially lower and inversely correlated with dioxin congener levels/total TEQs level dioxin. The dihydrotestosterone (DHT) levels in the hotspot were markedly lower than those in non-exposed in both genders. The cortisol concentrations were significantly higher in the hotspot than those from the non-exposure area only in the girls. The DHT/testosterone ratios that exhibited the 5α- or 5β-reductase activity declined by 50% in the hotspot area for both genders. The DHT levels showed strong inverse correlations with almost the PCDDs/PCDFs congeners and total TEQs dioxin in breast milk. Conclusions: This finding suggests that dioxin exposure in maternal breast milk might impact children’s endocrine system until 9 years old, especially on the DHT biosynthesis.

Abstract Background Numerous studies suggest that sex steroids might play a role in sex disparity observed in allergic diseases in adults. However, whether sex hormones influence allergic diseases in children remains unclear. The aim of the present study was to examine the association of sex steroid hormones with allergic disease in Japanese children. Methods The present cross-sectional study included 145 6-year-old children participating in a pilot birth cohort study in the Japan Environment and Children’s Study. Data on allergic diseases were obtained from questionnaires, and serum levels of sex steroid hormones and allergen-specific IgE were measured. Logistic regression was performed to evaluate the association of sex hormones with allergic diseases. Results After adjusted sex, amount of body fat at 6 years, parental history of allergic disease, and exposure to tobacco smoke, serum dehydroepiandrosterone sulfate level was significantly associated with reduced odds of any allergic disease (adjusted odds ratio, 0.58; 95% confidence interval, 0.36–0.93; P = 0.024) and serum follicle-stimulating hormone level was significantly associated with increased odds of any allergic disease (adjusted odds ratio, 2.04; 95% confidence interval, 1.01–4.11, P = 0.046). Dehydroepiandrosterone sulfate level showed a significant association with number of allergic diseases. Conclusions The current study findings suggest that sex hormones may play an important role in the development of allergic diseases in prepubertal children.

Humans are exposed to various bisphenols, alkylphenols and nitrophenols through dietary intake, food packaging and container materials, indoor and outdoor air/dust. This study aimed to evaluate exposure of Japanese pregnant women to environmental phenols by measuring target compounds in urine samples. From a cohort of the Japan Environment and Children’s Study, 4577 pregnant women were selected. Bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF), bisphenol AF (BPAF), para-nitrophenol (PNP), 3-methyl-4-nitrophenol (PNMC), branched 4-nonylphenol (4-NP), linear 4-nonylphenol and 4-tert-octylphenol (4-t-OP) were analysed using a high-performance liquid chromatograph coupled to a triple-quadrupole mass spectrometer. The urinary metabolite data were combined with a questionnaire to examine the determinants of phenol exposure by machine learning. The estimated daily intake (EDI) and hazard quotient (HQ) of BPA were calculated. PNP (68.2%) and BPA (71.5%) had the highest detection frequencies, with median concentrations of 0.76 and 0.46 μg/g creatinine, respectively. PNMC, BPS, BPF and 4-NP were determined in 24.9%, 11.9%, 1.3% and 0.4% of samples, respectively, whereas BPAF (0.02%) and 4-t-OP (0.02%) were only determined in a few samples. The PNP concentrations measured in this study were comparable with those reported in previous studies, whereas the BPA concentrations were lower than those reported previously worldwide. The EDI of BPA was 0.014 μg/kg body weight/day. Compared with the tolerable daily intake set by the German Federal Institute for Risk Assessment, the median (95th percentile) HQ was 0.044 (0.2). This indicates that the observed levels of BPA exposure pose a negligible health risk to Japanese pregnant women. Determinants of bisphenol and nitrophenol exposure could not be identified by analysing the questionnaire solely, suggesting that biological measurement is necessary to assess exposure of pregnant women to bisphenols and nitrophenols. This is the first study to report environmental phenol exposure of Japanese pregnant women on a nationwide scale.

Background: The developing brains are sensitive to methylmercury (MeHg). However, the exposure to MeHg in baby foods and toddler meals remains unknown. This study aimed to determine MeHg intake from baby food or toddler meals, and to investigate the relationship with child hair total mercury (THg). Methods: A total of 3 days of 24-hour dietary diet and hair samples were collected from 260 consenting children aged 0–5 years. We measured the concentrations of THg and MeHg in the diet and THg in the hair. Results: The results of measuring THg were below both the method detection and method quantification limits or either of both in powdered milk (93.8%), 5–6 months (53.3%), and 7–8 months (39.5%). The median daily THg intake was 20.3 (95% confidence interval 0.72–232.5) ng/kgbw. MeHg was not detected in 213 samples with dietary THg concentrations below 1 ng/g. The MeHg concentration with THg concentrations of 1 ng/g or higher was 1.70 (0.87–6.21) ng/g, and MeHg percentage in THg was 90.0%. To estimate MeHg intake, we multiplied the THg concentration by 90.0%, resulting in an estimated MeHg intake of 18.3 (0.65–209.2) ng/kgbw/day. The THg in children’s hair was 1.05 (0.31–3.96) ppm, and a weak positive correlation was observed between hair THg and dietary MeHg (r = 0.170). Conclusions: This study highlights the accurate estimation of MeHg intake in children using a duplicate method. Japanese children consume fish, the MeHg intakes exceeded the reference dose and/or provisional tolerable weekly intake in several children. Further discussion based on epidemiological data is required.

Abstract Electronic waste that has not been properly treated can lead to environmental contamination including of heavy metals, which can pose risks to human health. Infants, a sensitive group, are highly susceptible to heavy metals exposure. The aim of this study was to investigate the association between prenatal heavy metal exposure and infant birth outcomes in an e‐waste recycling area in China. We analyzed cadmium (Cd), chromium (Cr), manganese (Mn), lead (Pb), copper (Cu), and arsenic (As) concentrations in 102 human milk samples collected 4 weeks after delivery. The results showed that 34.3% of participants for Cr, which exceeds the World Health Organization (WHO) guidelines, as well as the mean exposure of Cr exceeded the WHO guidelines. We collected data on the birth weight (BW) and length of infants and analyzed the association between metal concentration in human milk and birth outcomes using multivariable linear regression. We observed a significant negative association between the Cd concentration in maternal milk and BW in female infants (β = −162.72, 95% CI = −303.16, −22.25). In contrast, heavy metals did not associate with birth outcomes in male infants. In this study, we found that 34.3% of participants in an e‐waste recycling area had a Cr concentration that exceeded WHO guidelines, and there was a significant negative association between prenatal exposure to the Cd and infant BW in females. These results suggest that prenatal exposure to heavy metals in e‐waste recycling areas may lead to adverse birth outcomes, especially for female infants.

Background: Recent studies have reported the effect of neonicotinoid (NEO) exposures on development in human. However, information about the risk of childhood development delays due to NEO exposures is limited. Objectives: The study aimed to examine the association between NEO exposure and child development up to 4 years of age using data of the Japan Environment and Children’s Study. Methods: The study employed urinary NEO and metabolite concentrations in the first and second or third trimesters; the Japanese translation of the Ages and Stages Questionnaire (third edition; J-ASQ-3) scores on developmental delay in five domains, namely communication, gross motor skills, fine motor skills, problem solving, and personal-social characteristics from 6 months to 4 years of age; and self-reported questionnaire data. The associations between urinary NEO concentrations and J-ASQ-3 results were analysed using the treed distributed lag mixture model. A total of 8538 participants were included in statistical analyses. Results: The determination rates of urinary acetamiprid-N-desmethyl (dm-ACE), clothianidin (CLO), dinotefuran (DIN) and thiamethoxam (THX) were greater than 50%. Median urinary dm-ACE, CLO, DIN and THX concentrations were 0.34, 0.14, 0.22 and 0.05 ng/ml, respectively, in samples collected during gestational weeks

Abstract Compared with the relatively well-investigated effects of childhood exposure to lead on neurocognitive deficits, those of prenatal exposure remain relatively inconclusive. We aimed to investigate the association between prenatal blood lead levels and neurodevelopmental delay during the first three years of life. From a prospective cohort of the Japan Environment and Children’s Study, we analyzed a total of 80,759 children. The exposure factors were prenatal lead concentrations measured from maternal whole blood in the second/third trimesters and umbilical cord blood at birth. Neurodevelopment was assessed at 6, 12, 18, 24, 30, and 36 months old using a screening tool, the Ages and Stages Questionnaires, third edition (ASQ). The outcome measures were any suspected neurodevelopmental delay (sNDD) identified via the ASQ during the first (sNDD-1Y), second (sNDD-2Y), and third (sNDD-3Y) years of life. sNDD-1Y, 2Y, and 3Y were identified in 18.0%, 16.2%, and 17.2% of children, respectively. The geometric means of blood lead concentration in this study were much lower (0.62 μg/dL in maternal blood and 0.50 μg/dL in cord blood) than previously investigated levels. Multivariable regression models revealed that there were no associations between maternal blood lead and sNDD-1Y and 2Y and between cord blood lead and sNDD-1Y, 2Y, and 3Y. Although a higher maternal blood lead was associated with a reduced risk of sNDD-3Y (adjusted relative risk: 0.84, 95% confidence interval 0.75–0.94, per 1 increase in common logarithm of lead concentration), there were no dose–response relationships in the analysis using quintiles of lead concentrations. Using a large-scale data set, the present study demonstrated no convincing evidence for an inverse association between levels of prenatal blood lead and neurodevelopment in early childhood. Longitudinal measurements of prenatal and postnatal lead levels are needed to understand the relationship between lead exposure and neurocognitive development.

Summary: As 3,3′,5-triiodothyroacetic acid (TRIAC), a metabolite of thyroid hormones (THs), was previously detected in sewage effluent, we aimed to investigate exogenous TRIAC’s potential for endocrine disruption. We administered either TRIAC or 3,3′,5-triiodo-L-thyronine (LT3) to euthyroid mice and 6-propyl-2-thiouracil-induced hypothyroid mice. In hypothyroid mice, TRIAC administration suppressed the hypothalamus-pituitary-thyroid (HPT) axis and upregulated TH-responsive genes in the pituitary gland, the liver, and the heart. We observed that, unlike LT3, TRIAC administration did not upregulate cerebral TH-responsive genes. Measurement of TRIAC contents suggested that TRIAC was not efficiently trafficked into the cerebrum. By analyzing euthyroid mice, we found that cerebral TRIAC content did not increase despite TRIAC administration at higher concentrations, whereas serum levels and cerebral contents of THs were substantially decreased. Disruption by TRIAC is due to the additive effects of circulating endogenous THs being depleted via a negative feedback loop involving the HPT axis and heterogeneous distribution of TRIAC among different organs.

Background: Allergen-specific immunoglobulins have a crucial role in allergic diseases. Most wheeze episodes develop before school age, and allergic rhinitis later develops during early elementary school years. However, the clinical background and cytokine/chemokine profiles associated with changes in immunoglobulins during early school-age are poorly understood. Methods: This study used blood samples from children participating in the JECS Pilot Study. We examined nineteen kinds of aeroallergen-specific immunoglobulins (IgE, IgG1, IgG4, and IgA) levels in patients at age 6 and age 8. Fluctuations of Der f 1- and Cry j 1-specific immunoglobulins levels during the two periods were compared to assess the frequency of allergic statuses and clusters of cytokine/chemokine profiles. Results: The medians of aeroallergen-specific IgE levels did not fluctuate, and almost all IgG1 and IgG4 decreased. In IgA, four (e.g., Der f 1) increased, whereas the other four (e.g., Cry j 1) decreased. The ratio of the Der f 1-specific IgG1 level at age 8 to that at age 6 was higher in children with poor asthma control than in children with better asthma control. Moreover, the cytokine/chemokine cluster with relatively lower IL-33 and higher CXCL7/NAP2 was associated with lower Der f 1- and Cry j 1-specific IgG4 levels, but not IgE levels. Conclusions: The cluster of cytokine/chemokine profiles characterized by lower IL-33 and higher CXCL7/NAP2 was associated with the maintenance of aeroallergen-specific IgG4 levels. This result provides a basis for considering the control of aeroallergen-specific immunoglobulins.

Background: The Japan Environment and Children’s Study (JECS) is a nationwide birth cohort study investigating environmental effects on children’s health and development. A Sub-Cohort Study has begun, conducting extended exposure and outcome measurements by targeting a subgroup randomly selected from the JECS Main Study. We report the Sub-Cohort Study methodology and participants’ baseline profiles. Methods: Of 100,148 children in the JECS Main Study, children born after April 1, 2013 who met eligibility criteria ([1] all questionnaire and medical record data from children and their mothers collected from the first trimester to 6 months of age, [2] biospecimens [except umbilical cord blood] from children and their mothers collected at first to second/third trimester and delivery) were randomly selected for each Regional Centre at regular intervals. Face-to-face assessment of neuropsychiatric development, body measurement, paediatrician’s examination, blood/urine collection for clinical testing and chemical analysis, and home visits (ambient and indoor air measurement and dust collection) are conducted. Participants are followed up at 1.5 and 3 years old for home visits, and 2, 4, 6, and 8 years old for developmental/medical examination. The details of protocols after age 10 are under discussion. Results: Of 10,302 selected children, 5,017 participated. The profiles of the participating mothers, fathers and children did not substantially differ between the Main Study and Sub-Cohort Study. Conclusion: The JECS Sub-Cohort Study offers a platform for investigating associations between environmental exposure and outcomes.

Background: Reluctance of people to receive recommended vaccines is a growing concern, as distribution of vaccines is considered critical to ending the COVID-19 pandemic. There is little information regarding pregnant women’s views toward coronavirus vaccination in Japan. Therefore, we investigated the vaccination rate and reasons for vaccination and vaccine hesitancy among pregnant women in Japan. Methods: We conducted a cross-sectional study involving 1,791 pregnant women using data from the Japan “COVID-19 and Society” Internet Survey, conducted from July to August 2021, and valid response from 1,621 respondents were analyzed. We defined participants with vaccine hesitancy as those who identified with the statement “I do not want to be vaccinated” or “I want to ‘wait and see’ before getting vaccinated.” Multivariate Poisson regression analysis was used to investigate the factors contributing to vaccine hesitancy. Results: The prevalence of vaccination and vaccine hesitancy among pregnant women was 13.4% (n = 217) and 50.9% (n = 825), respectively. The main reasons for hesitancy were concerns about adverse reactions and negative effects on the fetus and breastfeeding. Vaccine hesitancy was significantly associated with the lack of trust in the government (adjusted prevalence ratio, 1.26; 95% confidence interval, 1.03–1.54). Other factors, such as age, educational attainment, and state of emergency declaration, were not associated with vaccine hesitancy. Conclusions: COVID-19 vaccination is not widespread among pregnant women in Japan, although many vaccines have been shown to be safe in pregnancy. Accurate information dissemination and boosting trust in the government may be important to address vaccine hesitancy among pregnant women.

A simultaneous, high-throughput and sensitive method for analysing nine neonicotinoid pesticides (NEOs) and four metabolites (NEOms) in urine using a liquid chromatography-tandem mass spectrometry (LC–MSMS) was developed. The method detection limit (MDL) and lowest concentration minimum reporting limit (LCMRL) of the nine NEOs were 0.0013–0.048 ng/ml and 0.0050–0.17 ng/ml, respectively. The MDL and LCMRL of the four NEOms were 0.0052–0.52 ng/ml and 0.011–1.6 ng/ml, respectively. Intermediate precision for the nine NEOs and four NEOms was 7.5–12.5% and 7.4–10.9%, respectively. Accuracy for the nine NEOs and four NEOms was 3.83–5.60% and 3.01–29.2%, respectively. The developed method was applied to analyse urine samples collected from participants of a large-scale birth cohort study, namely, the Japan Environment and Children's Study (JECS). • The NEO and NEOm concentrations in 100 µl urine samples were analysed using a highly sensitive LC–MSMS. • Automated solid phase extraction in a 96-well plate was utilised to achieve high-throughput analysis. • Intermediate precision and accuracy were less than 12.5% and 94.8–99.1%, respectively.

Background: Low birth weight (LBW), which is considered a birth weight of

Urinary biomarkers are commonly used in epidemiological studies as surrogates or indicators of exposure to chemical substances. Evaluating the reliability of a biomarker is highly important because use of an unreliable marker may lead to misclassification and attenuation bias, resulting in flawed interpretations and conclusions. Although intraclass correlation coefficient (ICC) is regarded as a typical index of test reliability, methods for determining the ICCs of urinary biomarkers have not been standardised, and different methods have been used. This study evaluated different imputation methods for left-censored data, i.e., four imputation or one substitution methods, before calculating ICCs, and at the same time mathematically assessed the impact of the left-censoring proportion on the estimated ICCs. Biomarkers of exposure to organophosphate pesticides, i.e., dialkylphosphates, were used as an example. The Gibbs sampler-based left-censored missing value imputation approach had the best performance for imputation of values below reporting limits, with lower values on Kolmogorov–Smirnov test statistics than other imputation/substitution methods, i.e., a univariate distribution fitting approach, multiple imputation by chained equation, a bootstrap expectation–maximisation algorithm approach, and a single value substitution. In all imputation methods, however, ICCs decreased as censoring rates increased. We propose a method to estimate true ICCs based on mathematical estimation.

Abstract Background A variety of dietary supplements are commercially available. However, the efficacy and safety of dietary supplement use in children are not well established. Understanding dietary supplement use is important for developing public health policy regarding dietary supplements. This study aimed to investigate the types of dietary supplements used and characteristics of dietary supplement users among Japanese elementary school children. Method We conducted a cross-sectional web-based questionnaire study. Dietary supplement use, socio-demographics, and health-related behaviors were assessed through mother-reported questionnaire. Types of dietary supplements were identified based on ingredient using product barcodes and brand names. Multivariate logistic regression analysis was conducted to investigate the socio-demographics and health-related behaviors associated with supplement use. Results Among 4933 children, 333 (6.8%) were identified as dietary supplement users. The most common supplement was amino acids or protein (1.4%), followed by n–3 fatty acids or fish oil (1.0%), probiotics (1.0%), multivitamins (0.9%), multivitamin-minerals (0.8%), and botanicals (0.8%). Overall, any dietary supplement use was significantly associated with the highest frequency of sports participation (odds ratio [OR], 2.58; 95% confidence interval [CI], 1.65–4.02), highest household income (OR, 1.87; 95% CI, 1.13–3.10), highest maternal educational level (OR, 1.82; 95% CI, 1.31–2.52), and male sex (OR, 1.38; 95% CI, 1.09–1.75). The highest frequency of sports participation was significantly associated with higher odds of use of amino acids or protein (OR, 6.06; 95% CI, 1.78–20.6) and multivitamins (OR, 3.56; 95% CI, 1.11–11.5), compared to the lowest frequency of sports participation. Conclusion This study showed that Japanese children primarily use non-vitamin, non-mineral supplements. Non-vitamin, non-mineral supplements should thus be included in future studies aimed at monitoring dietary supplement use. We also found that dietary supplement use in children was associated with sports participation. Guidelines for dietary supplement use for children, in particular sport participants, are needed.

Background: Growth restriction in the prenatal period is a significant public health concern. Metals can negatively affect birth size, and pregnant women may be exposed to metal mixtures. Comprehensive studies analyzing the effects of combined metal exposure with accurate individual blood metal concentrations are limited. The current study investigated the associations between maternal metal exposure and birth size in a large, nationwide Japanese cohort using individual and mixed model approaches. Methods: Lead, cadmium, mercury, selenium, and manganese blood concentrations were measured in pregnant women in the Japan Environment and Children’s Study (JECS). Measurements of infant birth size—including body weight, body length, and head and chest circumference—were collected. Linear and logistic regressions were used for birth size measurements and the odds of an infant being small in size for gestational age, respectively. Associations between combined metal mixtures and measurements at birth were evaluated using quantile g-computation and Bayesian kernel machine regression (BKMR). Results: Of the 103,060 JECS pregnancies, 93,739 mother–infant pairs were analyzed. The linear regression models showed that lead, selenium, cadmium, and manganese—but not mercury—were associated with body weight. Cadmium was associated with length and chest circumference and mercury was associated with head circumference. Quantile g-computation revealed that manganese increased infant birth weight, length, head circumference, and chest circumference. Lead was the strongest negative factor for infant birth weight, length, head circumference, and chest circumference. The BKMR analysis revealed that the metals had an additive, rather than a synergistic effect. Conclusion: Metal exposure is associated with infant birth size, with lead and manganese playing a more significant role in Japan. The effects of prenatal combined metal exposure at low levels warrant public health attention.

Background: Manganese (Mn) is an essential trace metal and a neurotoxicant. Adverse effects of Mn exposure on the neurodevelopment of children have been reported. However, there is limited information on the effects of maternal exposure during pregnancy. Objectives: We aimed to investigate the association between maternal and cord blood Mn levels and neurodevelopment in children aged between 6 months and 3 years using data from a Japanese nationwide birth cohort study. Methods: We used the data of 63,767 mother–child pairs with maternal blood Mn measurements recorded during the second and third trimester and of 3,787 mother–child pairs with cord blood Mn measurements. Neurodevelopment was assessed using the Japanese version of the Ages and Stages Questionnaires, third edition (J-ASQ-3), which was completed by parents or guardians at 6 months, 1 year, 1.5 years, 2 years, 2.5 years, and 3 years of age. Results: The median maternal and cord blood Mn levels were 15.2 and 44.5 ng/g, respectively. After adjusting for covariates, both maternal and cord blood Mn levels were negatively associated with J-ASQ-3 scores. Maternal blood Mn levels were negatively associated with gross motor function scores at all ages except for that at 1.5 years (adjusted β: −0.55 to −1.23 for a two-fold increase in maternal Mn levels). The risk of developmental delay (score below the cut-off) in gross motor function increased at the same time points (adjusted odds ratio: 1.08 to 1.13). In the subgroup, cord blood Mn levels were negatively associated with gross motor function scores at 1, 2, and 2.5 years (adjusted β: −1.84 to −3.27). Discussion: Maternal blood Mn levels during pregnancy and cord blood Mn levels were negatively associated with neurodevelopment in children up to 3 years of age. Excessive maternal and fetal exposure to Mn may have adverse effects on neuromotor function in children.

Abstract Objective For several observational studies that have reported the factors related to gastroschisis, the target population in these studies was mainly residents of Europe or the US, and there is little data on the Asian population. In this study, we summarised characteristics of Japanese women who delivered infants with gastroschisis, particularly focusing on the pre-pregnancy body mass index (BMI), which was found to be inversely associated with gastroschisis in past studies, because the distribution of BMI is clearly different in Asia and the West. Results We used data from a nationwide birth cohort study which recruited pregnant women between 2011 and 2014. Among 92,796 women who delivered singleton live births, the frequency of underweight (pre-pregnancy BMI

Air pollution has been associated with childhood neurodevelopment. However, the role of indoor air pollution, especially volatile organic compounds (VOCs), on childhood neurodevelopment has been poorly explored to date. We investigated the association between indoor air pollutants and childhood neurodevelopment in 5,017 randomly selected children from the Japan Environment and Children’s Study. When the participants reached 1.5 and 3 years of age, they were followed up with home visits and neurodevelopmental tests using the Ages and Stages Questionnaire (ASQ). At both ages, we collected indoor air samples for 1 week and measured 13 indoor air pollutants: particulate matter with an aerodynamic diameter of ≤2.5 μm, ozone, nitrogen dioxide, sulfur dioxide, and nine VOCs. The associations between air pollutants and ASQ scores were estimated using linear mixed effects models and weighted quantile sum regressions (WQS) at each age separately. Stratified analysis by sex was conducted. Exposure to m,p-xylene at the age of 3 was associated with lower communication, fine motor, and overall ASQ scores (coefficients: −0.18 [99% confidence intervals (CI): −0.35, −0.02], −0.23 [99 %CI: −0.43, −0.03], and − 0.72 [99 %CI: −1.41, −0.04] per 1 µg/m3 increase, respectively). Exposure to o-xylene at the age of 3 was associated with lower communication, gross motor, fine motor, and overall ASQ scores (coefficients: −0.48 [99 %CI: −0.90, −0.07], −0.45 [99 %CI: −0.78, −0.13], −0.65 [99 %CI: −1.14, −0.16], and −2.15 [99 %CI: −3.83, −0.47] per 1 µg/m3 increase, respectively). The WQS index was associated with lower gross motor ASQ scores at the age of 3 (coefficient: −0.27 [95 %CI: −0.51, −0.03] for one-unit WQS index increases), which was attributed to benzene (33.96%), toluene (26.02%), o-xylene (13.62%), and ethylbenzene (9.83%). Stratified analysis showed similar results. Although further investigations are required, our results suggest an association of neurodevelopmental delays with indoor low-level exposure to m,p-xylene and o-xylene in early life.

Background: Prenatal cadmium exposure has been associated with adverse neurodevelopmental outcomes. However, previous findings are contradictory, and little is known about the potential modifiers of the cadmium-related neurodevelopmental risk. We investigated the associations between prenatal cadmium exposure and neurodevelopment in 2-year-old children and examined the influence of mother/child characteristics. Methods: We recruited 3545 mother–child pairs from the Japan Environment and Children’s Study. We collected maternal blood during mid/late pregnancy and cord blood at delivery, and measured cadmium concentrations using inductively coupled plasma mass spectrometry. Neurodevelopment was assessed using the Kyoto Scale of Psychological Development (KSPD), which includes cognitive-adaptive (C-A), language-social (L-S), postural-motor (P-M) and developmental quotient (DQ) domains. Associations between cadmium and KSPD scores were tested using multivariable models after controlling for confounders. Results: Median levels (interquartile ranges) of cadmium in maternal and cord blood were 0.70 (0.52–0.95) and 0.04 (0.03–0.06) μg/L, respectively. Maternal blood cadmium concentrations were inversely associated with P-M scores in boys (β = −1.4, 95% confidence interval (CI): −2.7, −0.038), DQ in children of mothers who smoked during pregnancy (β = −2.9, 95% CI: −5.7, −0.12), P-M (β = −5.4, 95% CI: −10, −0.67), C-A (β = −6.1, 95% CI: −11, −1.8), L-S (β = −9.0, 95% CI: −13, −4.8) and DQ scores (β = −6.4, 95% CI: −9.6, −3.1) in children born to mothers with gestational diabetes. Cord blood cadmium concentrations were negatively associated with L-S scores (β = −6.0., 95% CI: −11, −0.91) in children born to mothers with gestational diabetes. Conclusions: Prenatal cadmium exposure was negatively associated with neurodevelopment in boys, in children whose mothers smoked, and in children born to mothers with gestational diabetes. Further studies in other populations are needed to confirm our findings.

Background: The aims of the present report were to estimate the prevalence of congenital anomalies (CAs) among infants in Japan using data from the Japan Environment and Children’s Study (JECS) and to evaluate the validity of CA classification within JECS. Methods: Data on CAs were collected at delivery and at age 1 month from the medical records of 101,825 infants at 15 regional centers. The analyses focused on 61 CAs, selected on the basis of reported associations with environmental exposure. Prevalence per 10,000 pregnancies (including miscarriages, stillbirths, and live births) was stratified according to four reporting patterns (at delivery, at age 1 month, at either, and at both). To evaluate the accuracy of observed CA prevalence, the medical records of 179 cases from a single JECS regional center underwent independent, retrospective re-evaluation. Results: The prevalence of major CAs in four reporting patterns (at delivery, at age 1 month, at either, and at both) was 2.4, 2.6, 3.5, and 1.4 for myelomeningocele/spina bifida; 4.3, 4.2, 5.3, and 3.2 for cleft palate; 18.1, 17.4, 19.5, and 15.1 for cleft lip with or without cleft palate; 73.4, 100.3, 120.8, and 52.8 for congenital heart disease; and 10.5, 14.1, 15.0, and 9.6 for Down’s syndrome, respectively. In the subsample re-evaluation, CA diagnoses were confirmed for 92.7%, 93.3%, 90.5%, and 97.8% of cases in the four reporting patterns (at delivery, at age 1 month, at either, and at both), respectively. Conclusions: The present report generated reliable data concerning the prevalence of major CAs in JECS.

Background: In the context of climate change, extreme temperature events are known to be associated with increased mortality risk. However, data about the mortality risk related to temperature variability (TV) accounting for both intra- and inter-day variations in temperature are limited. Objectives: The present study aims to quantify the associations between TV and cause-specific mortality in Japan, evaluate whether the effects of TV are modified by prefecture-level characteristics and examine the temporal trend in mortality risk of TV. Methods: Data on daily all-cause and 11 cause-specific mortality and meteorological variables in 47 Japanese prefectures from 1972 to 2015 were collected. TV was defined as the standard deviation of daily minimum and maximum temperatures during exposure days. A quasi-Poisson regression model combined with a distributed lag non-linear model was firstly applied to assess the prefecture-specific mortality effects of TV, adjusting for potential confounders. The pooled effects of TV at the national level were then obtained via a meta-analysis through the restricted maximum-likelihood estimation. Potential effect modification by prefecture characteristics was firstly examined using a meta-regression analysis, and the joint modification of season and humidity was then evaluated after including product terms in two-stage analyses. Finally, the temporal trend in TV effects was evaluated by a random-effect meta regression model after obtaining the prefecture-year-specific effects. Results: TV had significant adverse effects on all-cause and cause-specific mortality. The effects of TV were more detrimental to those with asthma and senility. In general, the estimates of mortality risk increased with longer exposure days. A 1 °C increase in TV at 0–7 days of exposure was associated with a 0.9% (95% confidence intervals: 0.82%–0.98%) increase in all-cause mortality. All-cause mortality risk of TV showed a decreasing trend during our study period. TV effects were larger in densely populated prefectures and on warm and humid days. Conclusions: TV-related death is a significant issue in Japan that requires effective interventions. Keywords: Climate change, Temperature variability, Cause-specific mortality, Japan

Abstract Background The effects of prenatal exposure to toxic elements on birth outcomes and child development have been an area of concern. This study aimed to assess the profile of prenatal exposure to toxic elements, arsenic (As), bismuth (Bi), cadmium (Cd), mercury (total mercury (THg), methylmercury (MHg), inorganic mercury (IHg)), lead (Pb), antimony (Sb) and tin (Sn), and essential trace elements, copper (Cu), selenium (Se) and zinc (Zn), using the maternal blood, cord blood and placenta in the Tohoku Study of Child Development of Japan (N = 594–650). Methods Inductively coupled plasma mass spectrometry was used to determine the concentrations of these elements (except mercury). Levels of THg and MeHg were measured using cold vapour atomic absorption spectrophotometry and a gas chromatograph-electron capture detector, respectively. Results Median concentrations (25th–75th) of As, Cd, Pb, Sb, Sn and THg in the maternal blood were 4.06 (2.68–6.81), 1.18 (0.74–1.79), 10.8 (8.65–13.5), 0.2 (0.06–0.40) and 0.2 (0.1–0.38) ng mL−1 and 5.42 (3.89–7.59) ng g−1, respectively. Median concentrations (25th–75th) of As, Cd, Pb, Sb, Sn and THg in the cord blood were 3.68 (2.58–5.25), 0.53 (0.10–1.25), 9.89 (8.02–12.5), 0.39 (0.06–0.92) and 0.2 (0.2–0.38) ng mL−1 and 9.96 (7.05–13.8) ng g−1, respectively. Conclusions THg and Sb levels in the cord blood were twofold higher than those in the maternal blood. Cord blood to maternal blood ratios for As, Cd and Sb widely varied between individuals. To understand the effects of prenatal exposure, further research regarding the variations of placental transfer of elements is necessary.

Background: It is necessary to determine whether there are adverse health effects of prenatal exposure to long-term, low levels of mercury and selenium. However, there are limited that reports on the association between mercury levels by selenium levels and birth size. Therefore, we examined whether maternal mercury levels during pregnancy had any effect on infant birth size, and size, and whether selenium levels influenced this relationship. Objectives: To examine the association between mercury and selenium levels during pregnancy with infant birth size. Methods: The Japan Environment and Children's Study is a prospective birth cohort conducted between 2011 and 2014. Total mercury levels and total selenium levels in maternal blood during the second and third trimesters were measured using Inductively Coupled Plasma-Mass Spectrometry. Birth weight and small-for-gestational-age were confirmed by medical records. Small-for-gestational-age was defined as birth weight below the 10th percentile according to standard percentile for gender, parity, and gestational age. Multiple linear and logistic regression analyses were used to examine the association between maternal mercury exposure and birth weight or small-for-gestational-age adjusted for confounders (including maternal age and body mass index pregnancy). Results: Overall, 15,444 pregnant women were included in this study. Median (inter-quartile range) of blood mercury and selenium levels were 3.66 (2.59–5.18) ng/g and 170.0 (158.0–183.0) ng/g, respectively. Compared to infants of mothers with the highest blood selenium level, those of mothers with the lowest blood selenium level had neither a significant birth weight increase (9 g, 95% confidence interval: −6, 25) nor a significant odds ratio for small-for-gestational-age (0.903, 95% confidence interval: 0.748, 1.089). Compared to infants of mothers with the lowest blood mercury level, those of mothers with the highest blood mercury level had neither a significant birth weight reduction (−12 g, 95% confidence interval: −27, 4) nor a significant odds ratio for small-for-gestational-age (0.951, 95% confidence interval: 0.786, 1.150). Compared to infants of mothers with the lowest quartile of maternal blood mercury level, all infants of mothers with the highest quartile of maternal blood mercury level had a reduced birth head circumference of 0.073 cm (95% confidence interval: −0.134, −0.011). Conclusions: There was no association between maternal blood mercury levels and small-for-gestational-age and birth weight among 15,444 pregnant women. In a Japanese population, which has a relatively higher blood mercury level than reported in Western population, reduced birth size was not found to be associated with blood mercury levels, with the exception of birth head circumference. Keywords: Mercury, Selenium, Pregnancy, Birth weight, Small-for-gestational-age, The Japan Environment and Children's Study

Abstract Background Low-dose exposure to organophosphate (OP) insecticides during pregnancy may adversely affect neurodevelopment in children. To evaluate the OP exposure levels, single urine sampling is commonly adopted to measure the levels of dialkylphosphates (DAPs), common OP metabolites. However, the inter-day variations of urinary DAP concentrations within subjects are supposed to be large due to the short biological half-lives of the metabolites, and it is thus considered difficult to accurately assess OP exposure during pregnancy with single sampling. This study aimed to assess intra-individual variations of DAP concentrations and the reproducibility of the exposure dose categorization of OPs according to DAP concentration ranges in pregnant women in Japan. Methods Urine samples were collected from 62 non-smoking pregnant women (12–22 weeks of gestation) living in Aichi Prefecture, Japan. First morning void (FMV) and spot urine samples taken between lunch and dinner on the same day were collected on five different days during 2 weeks. The concentrations of DAP and creatinine in urine samples were measured using an ultra performance liquid chromatography with tandem mass spectrometry. Creatinine-adjusted and unadjusted concentrations were used for the intraclass correlation coefficient (ICC) calculations and surrogate category analyses. Results For all DAP metabolites, the creatinine-adjusted single ICCs exceeded 0.4, indicating moderate reliability. Overall, ICCs of spot urine samples taken in the afternoon were better than those taken as FMV. Surrogate category analyses showed that participants were categorized accurately into four exposure dose groups according to the quartile points. Conclusion This study indicated that a single urine sample taken in the afternoon may be useful in assessing OP exposure as long as the exposure is categorized into quartiles when conducting epidemiological studies in early to mid-pregnant women in Japan.

Abstract Background Over the past few decades, the Japanese Ministry of the Environment has been biomonitoring dioxins in the general Japanese population and, in response to public concerns, has taken measures to reduce dioxin exposure. The objectives of this study were to assess the current dioxin dietary intake and corresponding body burden in the Japanese and compare Japanese dioxin data from 2011 to 2016 and 2002–2010 surveys. We also examined the relationship between blood dioxins and health parameters/clinical biomarkers. Methods From 2011 to 2016, cross-sectional dioxin surveys were conducted on 490 Japanese (242 males and 248 females, aged 49.9 ± 7.6 years) from 15 Japanese prefectures. Blood (n = 490) and food samples (n = 90) were measured for 29 dioxin congeners including polychlorinated dibenzo-para-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and coplanar polychlorinated biphenyls (Co-PCBs) using gas chromatography coupled with high-resolution mass spectrometry. Using the 2006 World Health Organization toxic equivalence factors, the toxic equivalents (TEQs) were calculated. Clinical biomarkers and anthropometric parameters were also measured and information on lifestyle behaviours collected. Data imputations were applied to account for blood dioxins below the detection limit. Results The median (95% confidence interval or CI) blood levels and dioxin dietary intake was respectively 9.4 (8.8–9.9) pg TEQ/g lipid and 0.3 (0.2–0.4) pg TEQ/kg body weight/day. The median blood dioxin level in the 2011–2016 survey was found to have decreased by 41.3% compared to the 2002–2010 surveys. Participants who were older were found to be more likely to have higher dioxin levels. Blood dioxins were also significantly associated with body mass index, triglycerides, docosahexaenoic acid, eicosapentaenoic acid, and dihomo-gamma-linoleic acid levels in blood. Furthermore, associations between blood dioxin and dietary dioxin intake were evident in the unadjusted models. However, after adjusting for confounders, blood dioxins were not found to be associated with dietary dioxin intake. Conclusions Blood dioxin levels declined over the past decade. This study showed that the measures and actions undertaken in Japan have possibly contributed to these reductions in the body burden of dioxins in the Japanese population.

Clinical guidelines including those set by the US Institute of Medicine, have based optimal gestational weight gain (GWG) on maternal pre-pregnancy body mass index (BMI), but have not considered the role of environmental toxicants such as heavy metals that can disrupt these processes. This study designed to determine optimal GWG ranges in women grouped according to BMI, and to assess whether blood concentrations of heavy metals alter the relationships between GWG and outcomes. A total of 103,060 participants in the Japan Environment and Children’s Study recruited between 2011 and 2014 were followed until their children reached 3 years of age. Outcomes included 1 min Apgar score 5.21 ng/g and overweight women with Hg 3.67–5.21 ng/g, Pb > 7.31 ng/g and Cd > 0.66 ng/g had null effects. Heavy metals can modify the associations between GWG and outcomes, particularly for underweight and overweight women. Because of the complex interactions of environmental toxicants with pre-pregnancy BMI, GWG and adverse outcomes, GWG guidelines should be interpreted cautiously. Environmental toxicants may influence the determination of a clinical guideline.

Developmental exposure to environmental chemicals with estrogen-like activity is suspected to permanently impair women’s health. In this study, a mouse model was used to evaluate whether tris(2,6-dimethylphenyl) phosphate (TDMPP), a chemical with a putative estrogen-like action, impairs sexual differentiation of the brain. Either TDMPP and 17β-estradiol (E2) as positive controls or sesame oil as a negative control were administered subcutaneously to dams from gestational day (GD) 14 to parturition, and to pups from postnatal day (PND) 0 to 9. Precocious puberty, irregular estrous cycles, and a lowered lordosis response were found in the TDMPP- and E2-treated groups. A certain amount of TDMPP and its metabolites in the perinatal brain and the masculinization of sexual dimorphic nuclei in the hypothalamus of female mice after treatment were also detected. The experimental evidence demonstrates that TDMPP directly enters the fetal and neonatal brain, thereby inducing changes of sex-related brain structures and impairing female reproductive functions. Keywords: Environmental chemicals, Tris(2,6-dimethylphenyl) phosphate, Sexual differentiation, Estrogen-like activity

For infants in the first months of life, breast milk is a complete source of nutrition; however, it can also contain elements that are harmful to the infant. It is therefore critical for infant health to characterize breast milk. The aim of this study was to determine the intra- and inter-day variation of elements in breast milk, for which there is currently limited information, as a pilot study for a larger study. Firstly, we developed a simple and robust analytical method for the determination of multiple elements in breast milk. It was accurate (accuracy ranged from 98% to 107%) for measurement of 26 elements in breast milk by quadrupole inductively coupled plasma-mass spectrometry. Intra- and inter-day variation of elements, protein, and fat in breast milk was determined by analyzing breast milk collected from 11 women at 12 sampling points over three days and calculating intraclass correlation coefficients. Intraclass correlation coefficients showed that while some elements were consistent across time points (e.g., Sr, Ca, and Cu), others showed very high variability (e.g., As, Cd, and Ni). Correlation analyses between elements in breast milk showed strong relationships between those including Fe and Mo, Ca and Sr, and Cd and Fe.

Abstract Background Atopic dermatitis is the first clinical manifestation of the atopic march, with the highest incidence in the first year of life. Those affected often go on to develop other allergic diseases including food allergy, asthma, and allergic rhinitis. Recent evidence suggests that sensitization to foods may occur through a defective skin barrier which is common in atopic dermatitis in early life. We hypothesize that therapeutic aggressive intervention to treat new onset atopic dermatitis may prevent the development of later allergen sensitization, and associated food allergy, asthma, and allergic rhinitis. Methods This study is a multi-center, pragmatic, two-parallel group, assessor-blind, superiority, individually randomized controlled trial. Atopic dermatitis infants (N = 650) 7–13 weeks old who develop an itchy rash within the previous 28 days are randomly assigned to the aggressive treatment or the conventional treatment in a 1:1 ratio. The primary outcome is oral food challenge-proven IgE-mediated hen’s egg allergy at the age of 28 weeks. Discussion This is a novel pragmatic RCT study to examine the efficacy of early aggressive treatment for atopic dermatitis to prevent later food allergy. If our hypothesis is correct, we hope that such a strategy might impact on disease prevention in countries where food allergy is common, and that our results might reduce the frequency and associated costs of all food allergies as well as hens egg food allergy. Long-term follow and other similar studies will help to determine whether such a strategy will reduce the burden of other allergic diseases such as asthma and allergic rhinitis. Trial registration UMIN-CTR: UMIN000028043

Abstract Background The Japan Environment and Children’s Study (JECS) is a nation-wide birth cohort study investigating environmental effects on children’s health and development. In this study, the exposure characteristics of the JECS participating mothers were summarized using two questionnaires administered during pregnancy. Methods Women were recruited during the early period of their pregnancy. We intended to administer the questionnaire during the first trimester (MT1) and the second/third trimester (MT2). The total number of registered pregnancies was 103,099. Results The response rates of the MT1 and MT2 questionnaires were 96.8% and 95.1%, respectively. The mean gestational ages (SDs) at the time of the MT1 and MT2 questionnaire responses were 16.4 (8.0) and 27.9 (6.5) weeks, respectively. The frequency of participants who reported “lifting something weighing more than 20 kg” during pregnancy was 5.3% for MT1 and 3.9% for MT2. The Cohen kappa scores ranged from 0.07 to 0.54 (median 0.31) about the occupational chemical use between MT1 and MT2 questionnaires. Most of the participants (80%) lived in either wooden detached houses or steel-frame collective housing. More than half of the questionnaire respondents answered that they had “mold growing somewhere in the house”. Insect repellents and insecticides were used widely in households: about 60% used “moth repellent for clothes in the closet,” whereas 32% applied “spray insecticide indoors” or “mosquito coil or an electric mosquito repellent mat.” Conclusions We summarized the exposure characteristics of the JECS participants using two maternal questionnaires during pregnancy.

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.

Endotoxins are biological components of particulate matter that cause adverse respiratory system effects. Recently, air purifiers have been widely used; however, their effects on endotoxins are not fully understood. We conducted a randomized crossover intervention study to evaluate the effects of air purifiers on indoor endotoxins and occupants’ respiratory health. Thirty-two healthy subjects were randomly assigned to two groups; each group spent four weeks using either a true or sham (filter removed) air purifier. Subsequently, the subjects spent an additional four weeks using the alternative air purifier. The indoor endotoxins in fine (PM2.5) and coarse (PM10–2.5) particulate matter were continuously collected, and pulmonary function was tested repeatedly during the study period. Household characteristics were assessed using a questionnaire. The geometric mean of the PM2.5 endotoxin concentrations was 0.13 EU/m3, which was significantly lower with true purifiers compared with sham purifiers, after adjusting for household characteristics (0.17 EU/m3). In addition, the PM2.5 endotoxin concentrations were significantly greater in reinforced concrete houses than in wooden houses. The PM10–2.5 endotoxin concentrations were significantly greater in homes with two or more household members, and in those with pets. No association was found between endotoxin concentration and respiratory health among the subjects.

Satellite-based models for estimating concentrations of particulate matter with an aerodynamic diameter less than 2.5 μm (PM2.5) have seldom been developed in islands with complex topography over the monsoon area, where the transport of PM2.5 is influenced by both the synoptic-scale winds and local-scale circulations compared with the continental regions. We validated Multi-Angle Implementation of Atmospheric Correction (MAIAC) aerosol optical depth (AOD) with ground observations in Japan and developed a 1-km-resolution national-scale model between 2011 and 2016 to estimate daily PM2.5 concentrations. A two-stage random forest model integrating MAIAC AOD with meteorological variables and land use data was applied to develop the model. The first-stage random forest model was used to impute the missing AOD values. The second-stage random forest model was then utilised to estimate ground PM2.5 concentrations. Ten-fold cross-validation was performed to evaluate the model performance. There was good consistency between MAIAC AOD and ground truth in Japan (correlation coefficient = 0.82 and 74.62% of data falling within the expected error). For model training, the model showed a training coefficient of determination (R2) of 0.98 and a root mean square error (RMSE) of 1.22 μg/m3. For the 10-fold cross-validation, the cross-validation R2 and RMSE of the model were 0.86 and 3.02 μg/m3, respectively. A subsite validation was used to validate the model at the grids overlapping with the AERONET sites, and the model performance was excellent at these sites with a validation R2 (RMSE) of 0.94 (1.78 μg/m3). Additionally, the model performance increased as increased AOD coverage. The top-ten important predictors for estimating ground PM2.5 concentrations were day of the year, temperature, AOD, relative humidity, 10-m-height zonal wind, 10-m-height meridional wind, boundary layer height, precipitation, surface pressure, and population density. MAIAC AOD showed high retrieval accuracy in Japan. The performance of the satellite-based model was excellent, which showed that PM2.5 estimates derived from the model were reliable and accurate. These estimates can be used to assess both the short-term and long-term effects of PM2.5 on health outcomes in epidemiological studies.

Abstract There is worldwide concern about the effects of environmental factors on children’s health and development. The Miami Declaration was signed at the G8 Environment Ministers Meeting in 1997 to promote children’s environmental health research. The following ministerial meetings continued to emphasize the need to foster children’s research. In response to such a worldwide movement, the Ministry of the Environment, Japan (MOE), launched a nationwide birth cohort study with 100,000 pairs of mothers and children, namely, the Japan Environment and Children’s Study (JECS), in 2010. Other countries have also started or planned large-scale studies focusing on children’s environmental health issues. The MOE initiated dialogue among those countries and groups to discuss and share the various processes, protocols, knowledge, and techniques for future harmonization and data pooling among such studies. The MOE formed the JECS International Liaison Committee in 2011, which plays a primary role in promoting the international collaboration between JECS and the other children’s environmental health research projects and partnership with other countries. This review article aims to present activities that JECS has developed. As one of the committee’s activities, a workshop and four international symposia were held between 2011 and 2015 in Japan. In these conferences, international researchers and government officials, including those from the World Health Organization, have made presentations on their own birth cohort studies and health policies. In 2015, the MOE hosted the International Advisory Board meeting and received constructive comments and recommendations from the board. JECS is a founding member of the Environment and Child Health International Birth Cohort Group, and has discussed harmonization of exposure and outcome measurements with member parties, which will make it possible to compare and further combine data from different studies, considering the diversity in the measurements of variables between the studies. JECS is expected to contribute to the international environmental health research community and policy-making. More international collaboration would enhance our understanding of the possible environmental causes of diseases and disabilities.

Prenatal exposure to methylmercury (MeHg) affects child development after birth. However, many epidemiological studies have evaluated total mercury levels without analyzing speciation. Biomonitoring of MeHg and inorganic mercury (IHg) is essential to reveal each exposure level. In this study, we compared a high-throughput analysis for mercury speciation in blood using liquid chromatography-inductively coupled plasma-mass spectrometry (LC-ICP-MS) and liquid chromatography-cold vapor atomic fluorescence spectrometry (LC-CVAFS). The validated LC-ICP-MS method was applied to 101 maternal blood and 366 cord blood samples in the pilot study of the Japan Environment and Children’s Study (JECS). The accuracy of the LC-CVAFS method ranged 90–115% determined by reference material analysis. To evaluate the reliability of 366 cord blood samples, fifty cord blood samples were randomly selected and analyzed using LC-CVAFS. The median (5th–95th percentile) concentrations of MeHg and IHg were 5.4 (1.9–15) and 0.33 (0.12–0.86) ng/mL, respectively, in maternal blood, and 6.3 (2.5–15) and 0.21 (0.08–0.49) ng/mL, respectively, in cord blood. Inter-laboratory comparison showed a relatively good agreement between LC-ICP-MS and LC-CVAFS. The median cord blood:maternal blood ratios of MeHg and IHg were 1.3 and 0.5, respectively. By analyzing speciation, we could focus on the health effects of each chemical form.

An amendment to this paper has been published and can be accessed via the original article.

Kawasaki disease (KD) is common among pediatric patients and is associated with an increased risk of later cardiovascular complications, though the precise pathophysiology of KD remains unknown. Per- and polyfluoroalkyl substances (PFAS) have gathered notoriety as the causal pathogens of numerous diseases as well as for their immunosuppressive effects. The present epidemiological study aims to assess whether PFAS may affect KD risk. We evaluated research participants included in the ongoing prospective nationwide birth cohort of the Japan Environment and Children’s Study (JECS). Among the over 100,000 pregnant women enrolled in the JECS study, 28 types of PFAS were measured in pregnancy in a subset of participants (N = 25,040). The JECS followed their children born between 2011 and 2014 (n total infants = 25,256; n Kawasaki disease infants = 271), up to age four. Among the 28 types of PFAS, those which were detected in >60 % of participants at levels above the method reporting limit (MRL) were eligible for analyses. Multivariable logistic regressions were implemented on the seven eligible PFAS, adjusting for multiple comparison effects. Finally, we conducted Weighted Quantile Sum (WQS) and Bayesian kernel machine regression (BKMR) to assess the effects of the PFAS mixture on KD. Therefore, we ran the BKMR model using kernel mechanical regression equations to examine PFAS exposure and the outcomes of KD. Upon analysis, the adjusted multivariable regression results did not reach statistical significance for the seven eligible substances on KD, while odds ratios were all under 1.0. WQS regression was used to estimate the mixture effect of the seven eligible PFAS, revealing a negative correlation with KD incidence; similarly, BKMR implied an inverse association between the PFAS mixture effect and KD incidence. In conclusion, PFAS exposure was not associated with increased KD incidence.

Background: Both poor maternal nutrition and toxic heavy metal exposure influence foetal growth and development. However, whether consumption of a variety of healthy foods modifies the association between prenatal heavy metal exposure and foetal growth is unknown. Objective: We examined whether long-term maternal diet quality in periconception modifies the associations between maternal circulating concentrations of heavy metals and foetal growth. Design: Data of 72,317 Japanese women who delivered singleton infants was extracted from the Japan Environment and Children’s Study. Maternal diet over a 1-year before the first trimester of pregnancy was assessed using a validated food frequency questionnaire, and overall diet quality was determined using the balanced diet score based on the Japanese Food Guide Spinning Top. Maternal whole-blood concentrations of mercury (Hg), lead (Pb) and cadmium (Cd) were measured during the second/third trimester of pregnancy. Bayesian inference of multiple linear regression analysis was performed to evaluate the relationships between maternal diet quality and the blood concentrations of heavy metals; Bayesian logistic regression was used to analyse the risk of low birth weight (LBW;

OBJECTIVES:No previous study has used repeated measures data to examine the associations of dog/cat ownership with wheezing and asthma prevalence among children. This prospective study used repeated measurers analysis to determine whether dog/cat ownership in childhood is an independent risk factor for wheezing and asthma, after adjustment for gestational, socio-economical, and demographical confounders confounders, in Japan. METHODS:We conducted a multicenter pilot study of the Japan Environment and Children's Study (JECS) during 2009-2010. Among 440 newborn infants enrolled, 410 (52.8% males) were evaluated for dog/cat ownership in the home and history of wheezing and asthma in five follow-up questionnaire surveys (until age 6 years). Dog/cat ownership during follow-up period was categorized into four groups: 7.6% were long-term dog/cat owners, 5.9% were toddler-age owners, 5.9% were preschool-age owners, and 80.7% were never owners. RESULTS:The prevalence of wheezing during follow-up period increased from 20.8% to 35.4% and the prevalence of asthma increased from 1.3% to 16.3%. A fitted logistic generalized estimating equation models including important confounders showed no significant associations of the interaction between dog and/or cat ownership and follow-up time with the risks of wheezing and asthma. However, the risks of wheezing and asthma were slightly lower for long-term and toddler-age dog/cat owners than for preschool-age and never owners. CONCLUSIONS:The present findings suggest that dog and cat ownership from toddler-age does not increase the risks of wheezing and asthma compared with never owners among Japanese children.

Neonicotinoid, a widely-used pesticide group designed to selectively bind to insect nicotinic acetylcholine receptors, were considered to be relatively safe for mammalian species. However, it has been found to activate vertebrate nicotinic acetylcholine receptors than ever anticipated, and could be toxic to the mammalian brain. In the present study, we evaluated the developmental neurotoxicity of acetamiprid (ACE), one of the most-widely used neonicotinoid, in C57BL/6J mice whose mothers were administered ACE via gavage at doses of either 0 mg/kg (control), 1.0 mg/kg (low-dose) or 10.0 mg/kg (high-dose) from gestational day 6 to lactation day 21. As possible endpoints, a battery of behavior tests, socio-sexual and anxiety-related behaviors, as well as testosterone level and the number of vasopressin-immunoreactive cells in the paraventricular nucleus of the hypothalamus were examined. In addition, behavioral flexibility was assessed for mice in a group-housed environment using an IntelliCage, a fully automated mouse behavioral analysis system. In adult male mice exposed to ACE at both low and high doses, significant reduction of anxiety level was found in the light-dark transition test. Males in the low-dose group also showed a significant increase in sexual and aggressive behaviors. In contrast, neither the anxiety nor the sexual behavior of females was altered. No impairments in testosterone level, the number of vasopressin-immunoreactive cells, and behavioral flexibility were detected in either sex. These results suggest the possibility that in utero and lactational ACE exposure interferes with the development of the neural circuits required for executing socio-sexual and anxiety-related behaviors in male mice specifically.