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Abstract 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.

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.

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: 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.

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

Abstract 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.

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 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.

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.

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.

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.

Less information is available on the metabolism of organic arsenicals compared to inorganic arsenic in mammals. In the present study, we investigated tissue distribution, metabolism and excretion in rats of organoarsenicals, dimethylarsinic acid (DMAV), arsenobetaine (AB), arsenocholine (AC) and trimethylarsine oxide (TMAOV). Among these animals, arsenic concentrations in red blood cells (RBCs) and spleen increased remarkably only in the DMAV group. Hepatic arsenic concentration increased significantly only in the AC group. Approximately 17%, 72% and 60% of the dose was excreted in urine in two days in the DMAV, AB and AC groups, respectively; virtually the entire dose was excreted in urine in one day in the TMAOV group. On the other hand, approximately 18%, 0.2%, 0.5% and 0.1% of the dose was excreted in feces in two days in the DMAV, AB, AC and TMAOV groups, respectively. A large amount of arsenic was accumulated in RBCs in the form of protein-bound dimethylarsinous acid (DMAIII), and dimethylmonothioarsinic acid (DMMTAV), a reportedly toxic thio-arsenical, was found in urine and fecal extract in the DMAV group. These results suggest that intake of DMAV is a potential health hazard, given that the metabolites of DMAV, such as DMAIII and DMMTAV, are known to be highly toxic.

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 (≥28 wk). 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. [ABSTRACT FROM AUTHOR]

Diphenylarsinic acid (DPAA) was a major compound found in the arsenic poisoning incident that occurred in Kamisu, Ibaraki, Japan in 2003. People exposed to DPAA via contaminated well water suffered from several neurological disorders, including cerebellar symptoms. We previously reported that DPAA induces cellular activation in cultured rat cerebellar astrocytes, dose-dependent promotion of cell growth (low DPAA), cell death (high DPAA), and increased phosphorylation of mitogen-activated protein (MAP) kinases (p38MAPK, SAPK/JNK, and ERK1/2). Moreover, DPAA induces up-regulation of oxidative stress-counteracting proteins, activation of CREB phosphorylation, increased protein expression of c-Jun and c-Fos, and aberrant secretion of brain-active cytokines (MCP-1, adrenomedullin, FGF2, CXCL1, and IL-6). Here, we explored the role of MAP kinases in DPAA-induced activation of astrocytes using specific MAP kinase signaling inhibitors [SB203580 (p38MAPK), SP600125 (SAPK/JNK), SCH772984 (ERK1/2), and U0126 (MEK1/2, a kinase for ERK1/2)]. DPAA-induced activation of MAP kinases had little contribution to DPAA-induced cell growth and death. On the other hand, a power relationship among MAP kinases was also observed, in which p38MAPK suppressed DPAA-induced SAPK/JNK and ERK1/2 activation, whereas ERK1/2 and MEK1/2 facilitated p38MAPK and SAPK/JNK activation. In addition, SAPK/JNK had minimal effects on the activation of other MAP kinases. DPAA-induced activation of transcription factors and secretion of brain-active cytokines were submissively but intricately dominated by MAP kinases. Collectively, our results indicate that DPAAinduced activation of MAP kinases is neither a cell growth-promoting response nor a cytoprotective one but leads to transcriptional disruption and aberrant secretion of brain-active cytokines in cerebellar astrocytes. [ABSTRACT FROM AUTHOR]

Aim: Exposure assessment of lead (Pb) and Arsenic (As) from food, water, and house dust intake were assessed among pregnant women, their children and fetuses in Pakistan and Japan, as well as their body burden of the metals in their blood.Method: Fifty families which included a pregnant woman, a fetus and the 1-3-year-old siblings were recruited in Karachi and Khairpur in Pakistan, and Shimotsuke and Asahikawa in Japan, respectively. Their dietary exposure to Pb and As was measured in 3-day food duplicates and drinking water by ICP-MP. Pb in house dust and respirable dust was evaluated with an energy dispersive X-ray fluorescence spectrometry. Non-radioactive isotope Pb profiles of blood specimens will be compared with those of the exposure origins, such as food duplicates, respirable house dust, the soils nearby, and gasoline.Results: Judging from the data collected and analyzed so far, contribution from dietary intake is highly correlated to higher body burden of Pb among Pakistani mothers. Additional data analyses will reveal the status of Pb and As body burden in Pakistani mothers, fetuses and their siblings, and causal sources of high body burden is delineated by Pb isotope profile analysis of different sources of Pb exposure. [ABSTRACT FROM AUTHOR]

Selenium is an essential trace element found in vegetables as selenomethionine (SeMet) and methylselenocysteine (MeSeCys). In the present study, we used stable isotopes of Se to investigate differences between how SeMet and MeSeCys are metabolized, using methylseleninic acid (MSA) as a reference methylselenol source. A mixture containing 76Se-SeMet, 77Se-MeSeCys, and 82Se-MSA (each 25 μg Se/kg b.w.) was orally administered to rats, and then, speciation analyses of Se in urine and exhaled gas were conducted using HPLC-inductively coupled plasma (ICP)-MS and GC-ICP-MS, respectively. The proportions of 76Se-, 77Se-, and 82Se-selenosugar (Se-sugar) to total urinary Se metabolites originating from each tracer were very similar, while the proportion of 77Se-tirmethylselenonium (TMSe) was much less than that of76Se- and 82Se-TMSe in urine, suggesting that77Se-SeMet is less efficiently metabolized to TMSe. Similarly, there was significantly less 77Se-dimethylselenide (DMSe) originating from 77Se-SeMet than76Se- and 82Se-DMSe originating from 76Se-MeSeCys and 82Se-MSA in exhaled gas. It is generally accepted that DMSe and TMSe are metabolites of methylselenol, a putative metabolic intermediate in Se metabolism. Methylselenol is believed to be responsible for the cancer chemoprevention effects of Se. These results suggest that MeSeCys is converted to methylselenol more efficiently than is SeMet and that urinary TMSe and exhaled DMSe might be useful biomarkers for the generation of cancer chemopreventive forms of Se. [ABSTRACT FROM AUTHOR]