Association between maternal blood or cord blood metal concentrations and catch-up growth in children born small for gestational age: an analysis by the Japan environment and children's study.

BACKGROUND: Catch-up growth issues among children born small for gestational age (SGA) present a substantial public health challenge. Prenatal exposure to heavy metals can cause adverse effects on birth weight. However, comprehensive studies on the accurate assessment of individual blood concentrations of heavy metals and their effect on the failure to achieve catch-up growth remain unavailable. This study aimed to evaluate the effects of uterine exposure to toxic metals cadmium, lead, and mercury and essential trace metals manganese and selenium at low concentrations on the postnatal growth of children born SGA. METHODS: Data on newborn birth size and other factors were obtained from the medical record transcripts and self-administered questionnaires of participants in the Japan Environment and Children's Study. The blood concentrations of lead, cadmium, mercury, selenium, and manganese in pregnant women in their second or third trimester were determined by inductively coupled plasma mass spectrometry. These heavy metal concentrations were also assessed in pregnant women's cord blood. Furthermore, the relationship between each heavy metal and height measure/catch-up growth in SGA children aged 4 years was analyzed using linear and logistic regression methods. These models were adjusted for confounders. RESULTS: We studied 4683 mother-child pairings from 103,060 pregnancies included in the Japan Environment and Children's Study. Of these, 278 pairs were also analyzed using cord blood. At 3 and 4 years old, 10.7% and 9.0% of children who were born below the 10th percentile of body weight had height standard deviation scores (SDSs) below 2, respectively. Cord blood cadmium concentrations were associated with the inability to catch up in growth by 3 or 4 years old and the height SDS at 3 years old. In maternal blood, only manganese was positively associated with the height SDS of SGA children aged 2 years; however, it was not significantly associated with catch-up growth in these children. CONCLUSION: Cadmium exposure is associated with failed catch-up development in SGA children. These new findings could help identify children highly at risk of failing to catch up in growth, and could motivate the elimination of heavy metal (especially cadmium) pollution to improve SGA children's growth.

Study Design and Participants' Profile in the Sub-Cohort Study in the Japan Environment and Children's Study (JECS).

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.

Indoor air quality of 5,000 households and its determinants. Part A: Particulate matter (PM2.5 and PM10-2.5) concentrations in the Japan Environment and Children's Study.

Exposure to particulate matter (PM) is one of the important risk factors for morbidity and mortality. Although PM concentrations have been assessed using air quality monitoring stations or modelling, few studies have measured indoor PM in large-scale birth cohorts. The Japan Environment and Children's Study (JECS) measured indoor and outdoor air quality in approximately 5000 households when the participating children were aged 1.5 and 3 years. PM was collected using portable pumps for 7 days (total of 24 h), inside and outside each home. Prediction models for indoor PM concentrations were built using data collected at age 1.5 years and post-validated against data collected at age 3 years. Median indoor/outdoor PM2.5 and PM10-2.5 concentrations at age 1.5 years [3 years] were 12.9/12.7 [12.5/11.3] µg/m3 and 5.0/6.3 [5.1/6.1] µg/m3, respectively. Random forest regression analysis found that the major predictors of indoor PM2.5 were indoor PM10-2.5, outdoor PM2.5, indoor smoking, observable smoke and indoor/outdoor temperature. Indoor PM2.5, outdoor PM10-2.5, indoor humidity and opening room windows were important predictors of indoor PM10-2.5 concentrations. Indoor benzene, acetaldehyde, ozone and nitrogen dioxide concentrations were also found to predict indoor PM2.5 and PM10-2.5 concentrations, possibly due to the formation of secondary organic aerosols. These findings demonstrate the importance of reducing outdoor PM concentrations, avoiding indoor smoking, using air cleaner in applicable and diminishing sources of VOCs that could form secondary organic aerosols, and the resulting models can be used to predict indoor PM concentrations for the rest of the JECS cohort.

Indoor air quality of 5,000 households and its determinants. Part B: Volatile organic compounds and inorganic gaseous pollutants in the Japan Environment and Children's study.

Volatile organic compounds (VOCs) are major indoor air pollutants. Quantification of indoor concentrations of VOCs and identification of factors associated with these concentrations can help manage indoor air quality. This study measured the concentrations of VOCs and inorganic gaseous pollutants in around 5000 households in Japan and utilised a random forest model to estimate these concentrations and identify important determinants. The homes of 5017 randomly selected participants in the Japan Environment and Children's Study (JECS) were visited twice, when the children were aged 1.5 and 3 years. Twelve VOCs and inorganic gaseous pollutants were measured during 7 days by passive samplers. Various factors in these households, including household appliances, building characteristics, cooking styles, use of consumer products, renovation, pets, personal behaviours and ventilation were recorded. A random forest model with recursive feature elimination was utilised to identify factors predictive of VOCs and inorganic gaseous pollutants. Toluene, formaldehyde and acetaldehyde were the dominant indoor VOCs. The 95th percentiles of indoor p-dichlorobenzene concentrations at 1.5 and 3 years were 67 µg/m3 and 71 µg/m3, respectively. Random forest models with coefficients of determination ranging from 0.34 to 0.76 outperformed the traditional linear regression models. Factors associated with indoor VOC and inorganic gaseous pollutant concentrations included their outdoor concentrations, indoor and outdoor temperature and relative humidity, month of the year, hours windows were open, kerosene heater use and times of operation and building age. The results provided basic descriptions of indoor VOCs and inorganic gaseous pollutants in Japan and identified several determinants of these concentrations. These determinants should be considered to maintain indoor air quality. These results can be used in epidemiological assessments of the effects of VOCs and inorganic gaseous pollutants on health in children.

Maternal intake of one-carbon metabolism-related B vitamins and anorectal malformations in the Japan Environment and Children's Study.

The occurrence of anorectal malformations (ARM) is thought to be reduced with sufficient folate intake. However, there is no apparent evidence. We focused on enzyme cofactors for one-carbon metabolism, including folate (vitamin B9), vitamin B6 and vitamin B12, and explored the association between maternal combined intake of these B vitamins and the risk of ARM. Using baseline data from a Japanese nationwide birth cohort study between 2011 and 2014, we analysed data of 89 235 women (mean age at delivery = 31·2 years) who delivered singleton live births without chromosomal anomalies. Information on dietary intake was obtained via a FFQ focused on early pregnancy and used to estimate B vitamin intake. We also collected information on the frequency of folic acid supplement use. ARM occurrence was ascertained from medical records. We identified forty-three cases of ARM diagnosed up to the first month after birth (4·8 per 10 000 live births). In terms of individual intake of the respective B vitamins, high vitamin B6 intake was non-significantly associated with reduced odds of ARM. Compared with women in the low combined B vitamin intake group, the OR of having an infant with ARM was 0·4 (95 % CI 0·2, 1·0) in the high intake group (folate ≥400 µg/d, and upper half of vitamin B6 and/or vitamin B12). In conclusion, our cohort analysis suggested an inverse association between the combined intake of one-carbon metabolism-related B vitamins in early pregnancy and ARM occurrence.

Genome-Scale CRISPR/Cas9 Screening Reveals Squalene Epoxidase as a Susceptibility Factor for Cytotoxicity of Malformin†A1.

Malformin A1 (MA1) is a fungus-produced cyclic pentapeptide. MA1 exhibits teratogenicity to plants, fibrinolysis-enhancing activity, and cytotoxicity to mammalian cells. To clarify the cytotoxic mechanism of MA1, we screened for the genes involved in the cytotoxicity of MA1 in monocytoid U937 cells by using a CRISPR/Cas9-based genome-wide knockout library. Screening was performed by positive selection for cells that were resistant to MA1 treatment, and single guide RNAs (sgRNAs) integrated into MA1-resistant cells were analyzed by high-throughput sequencing. As a result of the evaluation of sgRNAs that were enriched in MA1-resistant cells, SQLE, which encodes squalene epoxidase, was identified as a candidate gene. SQLE-depleted U937 cells were viable in the presence of MA1, and squalene epoxidase inhibitor conferred MA1 resistance to wild-type cells. These results indicate that squalene epoxidase is implicated in the cytotoxicity of MA1. This finding represents a new insight into applications of MA1 for treating ischemic diseases.

Maternal dietary intake of vitamin A during pregnancy was inversely associated with congenital diaphragmatic hernia: the Japan Environment and Children's Study.

The pathogenesis of congenital diaphragmatic hernia (CDH) is largely unknown; however, vitamin A seems to play a role in diaphragmatic development. Previous case-control studies reported that maternal dietary vitamin A intake was inversely associated with the risk of CDH. To our knowledge, however, there is no prospective evidence regarding this association. Our aim was to examine whether maternal intake of vitamin A was associated with CDH occurrence. Baseline data, from the Japan nationwide birth cohort study (2011-2014) of 89 658 mothers (mean age at delivery = 31·2 years) who delivered singleton live births, were analysed. We assessed dietary habits using an FFQ focused on the first trimester and estimated the daily intake of total vitamin A (retinol activity equivalents), retinol, provitamin A carotenoids and vegetables. The occurrence of CDH was ascertained from medical records. A total of forty cases of CDH were documented. The adjusted OR of CDH occurrence for the high total vitamin A intake category (median = 468 µg/d) was 0·6 (95 % CI 0·3, 1·2) with reference to the low intake category (230 µg/d). When we restricted to mothers with a prepregnancy BMI of 18·5-24·9 kg/m2, vitamin A intake was inversely associated with the risk of their children being born with CDH (OR 0·5, 95 % CI 0·2, 1·0). Even given the limited number of cases in the study, our findings provide additional evidence to link vitamin A with CDH.

Fish consumption in early pregnancy and congenital gastrointestinal tract atresia in the Japan Environment and Children's Study.

Current evidence suggests that the aetiology of congenital gastrointestinal (GI) tract atresia is multifactorial, and not based solely on genetic factors. However, there are no established modifiable risk factors for congenital GI tract atresia. We used data from a Japanese nationwide birth cohort study launched in 2011, and examined whether fish consumption in early pregnancy was associated with congenital GI tract atresia. We analysed data of 89 495 women (mean age at delivery=31·2 years) who delivered singleton live births without chromosomal anomalies. Based on the results of the FFQ, we estimated the daily intake of fish and n-3 PUFA consumption in early pregnancy. We defined a composite outcome (oesophageal atresia, duodenal atresia, jejunoileal atresia and/or anorectal malformation) as congenital GI tract atresia. In this population, median fish intake was 31·9 g/d, and seventy-four cases of congenital GI tract atresia were identified. Fish consumption in early pregnancy was inversely associated with the composite outcome (multivariable-adjusted OR for the high v. low consumption category=0·5, 95 % CI 0·3, 1·0). For all the specific types of atresia, decreased OR were observed in the high consumption category, although not statistically significant. Reduced atresia occurrence was observed even beyond the US Food and Drug Administration's recommended consumption of no more than 340 g/week. Also, n-3 PUFA-rich fish and n-3 PUFA consumptions tended to be inversely associated with atresia. Fish consumption in early pregnancy may be a preventive factor for congenital GI tract atresia.

Oral exposure to lead for Japanese children and pregnant women, estimated using duplicate food portions and house dust analyses.

BACKGROUND: Lead is a toxic metal abundant in the environment. Consumption of food contaminated at low levels of lead, especially by small children and pregnant women, raises a health concern. METHODS: Duplicated food portions and drinking water were collected over 3 days from 88 children and 87 pregnant women in Shimotsuke, Tochigi, Japan. Participants were recruited in this study between January 2014 and October 2015. Dust was also collected from their homes. Lead concentrations were measured and consequent oral lead exposure levels were estimated for this population at high risk to environmental toxicants. Lead concentrations of peripheral and cord blood, taken from children and pregnant women, and were also analyzed. RESULTS: Lead concentrations in food, drinking water, and house dust were low in general. Oral lead exposure to lead was higher for children (Mean ± SEM; 5.21 ± 0.30 µg/kg BW/week) than in pregnant women (1.47 ± 0.13 µg/kg BW/week). Food and house dust were main sources of lead contamination, but the contribution of house dust widely varied. Means ± SEM of peripheral and cord blood lead concentrations were 0.69 ± 0.04 µg/dL and 0.54 ± 0.05 µg/dL, respectively for pregnant women and 1.30 ± 0.07 µg/dL (peripheral only) in children. We detect no correlation between smoking situations and blood lead concentration in pregnant women. CONCLUSION: We conclude that oral lead exposure levels for Japanese children and pregnant women were generally low, with higher concentrations and exposure for children than for pregnant women. More efforts are necessary to clarify the sources of lead contamination and reduce lead exposure of the population at high risk even in Japan.

Solubility changes of promyelocytic leukemia (PML) and SUMO monomers and dynamics of PML nuclear body proteins in arsenite-treated cells.

Promyelocytic leukemia (PML) and a suite of other proteins form nuclear bodies (NBs) where SUMOylation of PML and tumor suppression events occur in response to arsenite (As3+) treatment. Soluble PML is rapidly modified to the insoluble form in response to As3+, yet the relationship between the solubility change and nuclear localization of PML and PML-nuclear body (PML-NB) proteins remained elusive. We have investigated differences in the solubility change of well-known PML-NB proteins such as death-associated protein 6 (DAXX), SUMO, and PML in genetically engineered HEK293, and Jurkat and HL60 cells. The solubility of PML and SUMO2/3 monomers in RIPA solution decreased in 2 h in response to As3+. Live image analysis of GFP-PML revealed that extranuclear PML was insoluble in RIPA irrespective of the As3+-treatment and PML in PML-NBs, which was soluble in the untreated cells, was converted to insoluble forms by As3+. The solubility of DAXX was not changed by As3+, even though PML and DAXX co-localized completely in the subcellular compartments. Murine double mutant 2 (MDM2), which is known to interacts with intranuclear PML, did not affect the As3+-induced solubility change of PML. These results indicate that As3+ selectively reorganizes PML and SUMO2/3 monomers into insoluble forms in PML-NBs, and then PML SUMOylation proceeds.

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.

Questionnaire results on exposure characteristics of pregnant women participating in the Japan Environment and Children Study (JECS).

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.

Solubility shift and SUMOylaltion of promyelocytic leukemia (PML) protein in response to arsenic(III) and fate of the SUMOylated PML.

Promyelocytic leukemia (PML), which is a tumor suppressor protein that nevertheless plays an important role in the maintenance of leukemia initiating cells, is known to be biochemically modified by As(3+). We recently developed a simple method to evaluate the modification of PML by As(3+) resulting in a change in solubility and the covalent binding of small ubiquitin-like modifier (SUMO). Here we semi-quantitatively investigated the SUMOylation of PML using HEK293 cells which were stably transfected with PML-VI (HEK-PML). Western blot analyses indicated that PML became insoluble in cold RadioImmunoPrecipitation Assay (RIPA) lysis buffer and was SUMOylated by both SUMO2/3 and SUMO1 by As(3+). Surprisingly SUMO1 monomers were completely utilized for the SUMOylation of PML. Antimony (Sb(3+)) but not bismuth (Bi(3+)), Cu(2+), or Cd(2+) biochemically modified PML similarly. SUMOylated PML decreased after removal of As(3+) from the culture medium. However, unSUMOylated PML was still recovered in the RIPA-insoluble fraction, suggesting that SUMOylation is not requisite for changing the RIPA-soluble PML into the RIPA-insoluble form. Immunofluorescence staining of As(3+)-exposed cells indicated that SUMO2/3 was co-localized with PML in the nuclear bodies. However, some PML protein was present in peri-nuclear regions without SUMO2/3. Functional Really Interesting New Gene (RING)-deleted mutant PML neither formed PML nuclear bodies nor was biochemically modified by As(3+). Conjugation with intracellular glutathione may explain the accessibility of As(3+) and Sb(3+) to PML in the nuclear region evading chelation and entrapping by cytoplasmic proteins such as metallothioneins.

The effect of a methyl-deficient diet on the global DNA methylation and the DNA methylation regulatory pathways.

Methyl-deficient diets are known to induce various liver disorders, in which DNA methylation changes are implicated. Recent studies have clarified the existence of the active DNA demethylation pathways that start with oxidization of 5-methylcytosine (5meC) to 5-hydroxymethylcytosine by ten-eleven translocation (Tet) enzymes, followed by the action of base-excision-repair pathways. Here, we investigated the effects of a methionine-choline-deficient (MCD) diet on the hepatic DNA methylation of mice by precisely quantifying 5meC using a liquid chromatography-electrospray ionization-mass spectrometry and by investigating the regulatory pathways, including DNA demethylation. Although feeding the MCD diet for 1 week induced hepatic steatosis and lower level of the methyl donor S-adenosylmethionine, it did not cause a significant reduction in the 5meC content. On the other hand, the MCD diet significantly upregulated the gene expression of the Tet enzymes, Tet2 and Tet3, and the base-excision-repair enzymes, thymine DNA glycosylase and apurinic/apyrimidinic-endonuclease 1. At the same time, the gene expression of DNA methyltransferase 1 and a, was also significantly increased by the MCD diet. These results suggest that the DNA methylation level is precisely regulated even when dietary methyl donors are restricted. Methyl-deficient diets are well known to induce oxidative stress and the oxidative-stress-induced DNA damage, 8-hydroxy-2'-deoxyguanosine (8OHdG), is reported to inhibit DNA methylation. In this study, we also clarified that the increase in 8OHdG number per DNA by the MCD diet is approximately 10 000 times smaller than the reduction in 5meC number, suggesting the contribution of 8OHdG formation to DNA methylation would not be significant.

Effects of arsenic on modification of promyelocytic leukemia (PML): PML responds to low levels of arsenite.

Inorganic arsenite (iAs(3+)) is a two-edged sword. iAs(3+) is a well-known human carcinogen; nevertheless, it has been used as a therapeutic drug for acute promyelocytic leukemia (APL), which is caused by a fusion protein comprising retinoic acid receptor-α and promyelocytic leukemia (PML). PML, a nuclear transcription factor, has a RING finger domain with densely positioned cysteine residues. To examine PML-modulated cellular responses to iAs(3+), CHO-K1 and HEK293 cells were each used to establish cell lines that expressed ectopic human PML. Overexpression of PML increased susceptibility to iAs(3+) in CHO-K1 cells, but not in HEK293 cells. Exposure of PML-transfected cells to iAs(3+) caused PML to change from a soluble form to less soluble forms, and this modification of PML was observable even with just 0.1 µM iAs(3+) (7.5 ppb). Western blot and immunofluorescent microscopic analyses revealed that the biochemical changes of PML were caused at least in part by conjugation with small ubiquitin-like modifier proteins (SUMOylation). A luciferase reporter gene was used to investigate whether modification of PML was caused by oxidative stress or activation of antioxidant response element (ARE) in CHO-K1 cells. Modification of PML protein occurred faster than activation of the ARE in response to iAs(3+), suggesting that PML was not modified as a consequence of oxidative stress-induced ARE activation.

Prenatal exposure to selenium, mercury, and manganese during pregnancy and allergic diseases in early childhood: The Japan Environment and Children's study.

BACKGROUND: Prenatal exposure to metallic elements may adversely affect early childhood health. However, more evidence is needed as population-based cohort studies are currently limited. OBJECTIVES: We aimed to examine the associations between prenatal metallic (mercury, selenium, and manganese) exposure and the risk of allergic diseases in early childhood until three years of age. METHODS: The data from 94,794 mother-infant pairs, who participated in the Japan Environment and Children's study, were used in this study. Prenatal metallic element exposure was measured in maternal blood collected during mid-pregnancy. The incidence of atopic dermatitis, food allergies, asthma, and allergic rhinitis during the first three years of life was prospectively investigated using self-reports of physician-diagnosed allergies. A multivariable modified Poisson regression model was used to estimate the cumulative incidence ratio and their 95% confidence intervals of allergic diseases associated with prenatal exposure to mercury, selenium, and manganese. We further evaluated the interaction between mercury and selenium exposures in this association. RESULTS: We confirmed 26,238 cases of childhood allergic diseases: atopic dermatitis, food allergies, asthma, and allergic rhinitis in 9,715 (10.3%), 10,897 (11.5%), and 9,857 (10.4%), 4,630 (4.9%), respectively. No association was found between prenatal mercury or manganese exposure and the risk of allergic diseases. Prenatal selenium exposure was inversely associated with atopic dermatitis, food allergies, allergic rhinitis, and any allergic diseases, but not with asthma. These inverse associations were more pronounced for lower mercury exposures than for higher exposures. CONCLUSIONS: Our findings suggest that prenatal exposure to selenium may be beneficial for reducing the risk of atopic dermatitis, food allergies, allergic rhinitis, and any allergic diseases in early childhood, especially with lower prenatal mercury exposure.

Association between prenatal cadmium exposure and child development: The Japan Environment and Children's study.

Cadmium is a heavy metal that can be found in soil, air, food, and water. Cadmium has toxic effects on the kidneys, bones, and respiratory system. Prenatal exposure to cadmium has been found to affect the mental development of children, but inconsistent results have been found in different studies. Therefore, it is unknown that prenatal cadmium exposure associated with child development after birth. To elucidate whether cadmium affect the child development or not, we analyzed nation-wide cohort study data, the Japan Environment and Children's Study. Prenatal cadmium concentrations in blood from mothers in the second or third trimester were determined by inductively coupled plasma mass spectrometry. Child development was evaluated using "Ages and Stages" questionnaires. The association between cadmium and child development were investigated by performing logistic regression analyses, multinomial logistic regression analyses and generalized linear mixed model using the child development parameters as dependent variables and the cadmium concentrations in maternal blood as the independent variable. There were significant associations between the cadmium concentration and child development at 6 months, 1 year, and 1.5 years after birth. However, the effect had disappeared at 2 years after birth or later. The number of developmental delays was positively associated with the cadmium concentration after adjusting individual difference. The results indicate that prenatal exposure affects child development, but the effect decreases with age.

Intra- and Inter-Day Element Variability in Human Breast Milk: Pilot Study.

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.

Baseline Complete Blood Count and Chemistry Panel Profile from the Japan Environment and Children's Study (JECS).

BACKGROUND: The Japan Environment and Children's Study (JECS) is a nationwide birth cohort study of environmental factors affecting children's health and development. We summarize the complete blood count and chemistry panel statistical data from pregnant women enrolled in JECS. METHODS: Statistical data of up to 58,056 mother's sample in their first (gestational age ≤ 13 weeks) and second trimester (22-27 weeks) were calculated. RESULTS: Mean (SD) values in the first trimester were: white blood cell count, 7866 (1906)/µL; red blood cell count, 417 (33) 104/µL; hemoglobin, 12.4 (1.0) g/dL; hematocrit, 37.1 (2.6)%; mean corpuscular volume, 89.2 (4.7) fL; mean corpuscular hemoglobin, 29.8 (1.9) pg; mean corpuscular hemoglobin concentration, 33.3 (0.9)%; platelet count, 24.8 (5.2) 104/µL; HbA1c, 5.26 (0.26)%; total cholesterol, 181 (28) mg/dL; low density lipoprotein cholesterol, 95 (23) mg/dL; high density lipoprotein cholesterol, 73 (13) mg/dL; free cholesterol, 41 (7) mg/dL; triglycerides, 109 (47) mg/dL; total protein, 6.9 (0.4) g/dL; and albumin, 4.1 (0.2) g/dL. Mean values (SD) in the second trimester were: total cholesterol, 246 (38) mg/dL; free cholesterol, 61 (9) mg/dL; triglycerides, 183 (70) mg/dL; total protein, 6.5 (0.4) g/dL; and albumin, 3.6 (0.2) g/dL. CONCLUSIONS: These data will be useful for future JECS studies.

Maternal Metals Exposure and Infant Weight Trajectory: The Japan Environment and Children's Study (JECS).

BACKGROUND: To our knowledge, the association of maternal exposure to metallic elements with weight trajectory pattern from the neonatal period has not been investigated. OBJECTIVES: The goals of this study were to identify infant growth trajectories in weight in the first 3 y of life and to determine the associations of maternal blood levels of lead, cadmium, mercury, selenium, and manganese with growth trajectory. METHODS: This longitudinal study, part of the Japan Environment and Children Study, enrolled 103,099 pregnant women at 15 Regional Centres across Japan between 2011 and 2014. Lead, cadmium, mercury, selenium, and manganese levels were measured in blood samples collected in the second (14-27 wk gestational age) or third trimester (≥28wk). Growth trajectory of 99,014 children was followed until age 3 y. Raw weight values were transformed to age- and sex-specific weight standard deviation (SD) scores, and latent-class group-based trajectory models were estimated to determine weight trajectories. Associations between maternal metallic element levels and weight trajectory were examined using multinomial logistic regression models after confounder adjustment. RESULTS: We identified 5 trajectory patterns based on weight SD score: 4.74% of infants were classified in Group I, very small to small; 31.26% in Group II, moderately small; 21.91% in Group III, moderately small to moderately large; 28.06% in Group IV, moderately large to normal; and 14.03% in Group V, moderately large to large. On multinomial logistic regression, higher maternal lead and selenium levels tended to be associated with increased odds ratios (ORs) of poor weight SD score trajectories (Groups I and II), in comparison with Group III. Higher levels of mercury were associated with decreased ORs, whereas higher levels of manganese were associated with increased ORs of "moderately large" trajectories (Groups IV and V). DISCUSSION: Maternal lead, mercury, selenium, and manganese blood levels affect infant growth trajectory pattern in the first 3 y of life. https://doi.org/10.1289/EHP10321.