Prenatal Arsenic Exposure Research Articles

Evidence of epigenetic age acceleration among adults with prenatal and early life arsenic exposure in Northern Chile

Evidence of epigenetic age acceleration among adults with prenatal and early life arsenic exposure in Northern Chile

Docosahexaenoic Acid Effect on Prenatal Exposure to Arsenic and Atopic Dermatitis in Mexican Preschoolers.

Childhood atopic dermatitis (AD) is a chronic and recurrent health problem that involves multiple factors, particularly immunological and environmental. We evaluated the impact of docosahexaenoic acid (DHA) supplementation on prenatal arsenic exposure on the risk of atopic dermatitis in preschool children as part of the POSGRAD (Prenatal Omega-3 fatty acid Supplements, GRowth, And Development) clinical trial study in the city of Morelos, Mexico. Our study population included 300 healthy mother-child pairs. Of these, 146 were in the placebo group and 154 in the supplement group. Information on family history, health, and other variables was obtained through standardized questionnaires used during follow-up. Prenatal exposure to arsenic concentrations, which appear in maternal urine, was measured by inductively coupled plasma optical emission spectrometry. To assess the effect of prenatal arsenic exposure on AD risk, we ran a generalized estimating equation model for longitudinal data, adjusting for potential confounders, and testing for interaction by omega-3 fatty acid supplementation during pregnancy. The mean and SD (standard deviation) of arsenic concentration during pregnancy was 0.06mg/L, SD (0.04mg/L). We found a marginally significant association between prenatal arsenic exposure and AD (OR = 1.12, 95% CI: 0.99, 1.26); however, DHA supplementation during pregnancy modified the effect of arsenic on AD risk (p < 0.05). The results of this study strengthen the evidence that arsenic exposure during pregnancy increases the risk of atopic dermatitis early in life. However, supplementation with omega-e fatty acids during pregnancy could modify this association.

The impact of prenatal and early-life arsenic exposure on epigenetic age acceleration among adults in Northern Chile.

Exposure to arsenic affects millions of people globally. Changes in the epigenome may be involved in pathways linking arsenic to health or serve as biomarkers of exposure. This study investigated associations between prenatal and early-life arsenic exposure and epigenetic age acceleration (EAA) in adults, a biomarker of morbidity and mortality. DNA methylation was measured in peripheral blood mononuclear cells (PBMCs) and buccal cells from 40 adults (median age = 49 years) in Chile with and without high prenatal and early-life arsenic exposure. EAA was calculated using the Horvath, Hannum, PhenoAge, skin and blood, GrimAge, and DNA methylation telomere length clocks. We evaluated associations between arsenic exposure and EAA using robust linear models. Participants classified as with and without arsenic exposure had a median drinking water arsenic concentration at birth of 555 and 2 μg/l, respectively. In PBMCs, adjusting for sex and smoking, exposure was associated with a 6-year PhenoAge acceleration [B (95% CI) = 6.01 (2.60, 9.42)]. After adjusting for cell-type composition, we found positive associations with Hannum EAA [B (95% CI) = 3.11 (0.13, 6.10)], skin and blood EAA [B (95% CI) = 1.77 (0.51, 3.03)], and extrinsic EAA [B (95% CI) = 4.90 (1.22, 8.57)]. The association with PhenoAge acceleration in buccal cells was positive but not statistically significant [B (95% CI) = 4.88 (−1.60, 11.36)]. Arsenic exposure limited to early-life stages may be associated with biological aging in adulthood. Future research may provide information on how EAA programmed in early life is related to health.

Prenatal exposure to arsenic promotes sterile inflammation through the Polycomb repressive element EZH2 and accelerates skin tumorigenesis in mouse

Prenatal and postnatal life stress could be a potent programmer of phenotype or disease state of an individual in the later life. Prenatal arsenic exposure has been shown to promote developmental defects, low birth weight, immunotoxicity and is associated with various cancers including skin cancer in adulthood. To investigate the association between prenatal arsenic exposure and adult life skin carcinogenesis, we used a two-stage cutaneous carcinogenesis model in which BALB/c mice were prenatally exposed to 0.04 mg/kg and 0.4 mg/kg arsenic (As). Exposure to arsenic was sufficient to shorten the tumor latency period and promote epidermal hyperplasia in the offspring upon challenge with dimethylbenz[a]/12-O-tetradecanoylphorbol-13-acetate (DMBA/TPA). The levels of inflammatory and tissue microenvironment remodeling factors such as IL-1α and TNF-α were persistently elevated in the skin, and their inhibition through diacerein led to a significant decrease in the tumor response, suggesting their role in tumorigenesis. While there was overexpression of multiple epigenetic regulators at tissue level, we found decreased enrichment of Polycomb repressive complex 2 (PRC2) member EZH2 and H3K27me3 mark at the upstream of the affected inflammatory genes. The higher expression of the inflammatory genes suggests the gene specific selective nature of EZH2 repression which was also associated with increased binding of the activator KDM6a (demethylase). Further, arsenic conditioned basal keratinocytes cells (BKCs) showed increased migration and proliferation along with higher expression of tumor associated cytokines. Inhibition of EZH2 in the BKCs lead to their further upregulation suggesting that BKCs might be the potential cell type for the interaction of EZH2 and inflammatory cytokines. The present study provides new evidence for the role of PRC2 group regulators in inflammatory conditioning and development of skin cancer in offspring prenatally exposed to arsenic.

Effects of prenatal exposure to arsenic on neonatal birth size in Wujiang, China

To investigate prenatal exposure to arsenic and its effect on birth size, we conducted a cross-sectional study in Wujiang City, Jiangsu, China, from June 2009 to June 2010. A total of 1722 mother-infant pairs were included in the study. A questionnaire was administered to the pregnant women and umbilical cord blood(UCB) samples were collected. Arsenic concentration in UCB was detected by inductively coupled plasma emission mass spectroscopy (ICP-MS). The birth size included birth weight, birth body length and head circumference of the newborns. The effects of arsenic exposure on birth size were assessed by multiple linear regression analysis. Arsenic concentrations in UCB ranged from 0.11 to 30.36 μg/L, the median was 1.71 μg/L. In this range of exposure, arsenic concentration was significantly negatively associated with birth weight, especially among male infants. Our results showed that prenatal exposure to arsenic level was low in Wujiang City, China. However, low prenatal arsenic exposure could have negative effects on birth weight. Our research provided evidence for the adverse effects of prenatal low-level arsenic exposure on the intrauterine growth of the fetus.

In utero arsenic exposure increases DNA damage and gene expression changes in umbilical cord mesenchymal stem cells (UC-MSCs) from newborns as well as in UC-MSC differentiated hepatocytes

Prenatal exposure to arsenic is associated with an increased risk of disease development such as liver cancer in adulthood. Increasing evidence suggests that fetal stem cells are key targets during transplacental chemical exposure. Our earlier study reported that in utero arsenic exposure caused various types of DNA damage in newborns. In this study, we further investigated the effects of prenatal arsenic exposure on mutagenic DNA damage in umbilical cord mesenchymal stem cells (MSCs) that represent fetal stem cells from the same birth cohort. DNA damage measured as 8-hydroxydeoxyguanine (8-OHdG) and 8-nitroguanine was increased in umbilical cord MSCs of newborns in relation to maternal arsenic levels in a dose-dependent manner. Levels of 8-OHdG and 8-nitroguanine were significantly (p<0.05) and positively associated with arsenic levels in cord blood and maternal toenails. In vitro studies confirmed that arsenite treatment alone (0-5µM, 24h) significantly increased the levels of 8-OHdG and 8-nitroguanine in an MSC cell line derived from umbilical cord tissue (UC-MSCs). When UC-MSCs were allowed to differentiate into hepatocytes in the presence of arsenite (0.5µM, 21 days), there were significant increases (p<0.05) in 8-OHdG and 8-nitroguanine compared to those observed in undifferentiated UC-MSCs. Moreover, in these arsenite-exposed differentiated hepatocytes, expression of inflammatory genes (CXCL6 and CXCL8) and an oxidative stress response gene (NFE2L2) was increased, while that of a DNA repair gene (OGG1) was decreased. Arsenite treatment also increased cell transformation ability of hepatocytes differentiated from UC-MSCs. These results suggest that arsenic exposure increases mutagenic DNA damage in fetal stem cells which continued when these cells differentiated to become hepatocytes which have increased cell transformation ability. This study highlights the potential risk of in utero arsenic exposure, which may lead to liver disease and cancer development later in life.

Prenatal arsenic exposure, arsenic methylation efficiency, and neuropsychological development among preschool children in a Spanish birth cohort

BackgroundPrenatal arsenic (As) exposure could negatively affect child neuropsychological development, but the current evidence is inconclusive. ObjectivesTo explore the relationship between prenatal urinary total As (TAs) concentrations, the As species and the methylation efficiency, and child neuropsychological development in a Spanish birth cohort. We also studied the effect modification produced by sex and several nutrients and elements. Materials and methodsStudy subjects were 807 mother–child pairs participating in the INMA (Childhood and Environment) Project. Urinary TAs and its metabolites, monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), inorganic As (iAs) and arsenobetaine were measured in the first trimester of pregnancy. Methylation efficiency was determined through the percentages of the metabolites and using principal component analysis. Children's neuropsychological development was assessed at the age of 4–5 years using the McCarthy Scales of Children's Abilities (MSCA). Multivariable linear regression models were built to assess the association between TAs, the As species and the maternal methylation efficiency, and the neuropsychological scores. We explored effect modification by sex, iron status, maternal nutrients status (serum manganese and selenium, and urinary zinc), and maternal vitamins intake (folate, and vitamins B12 and B6). ResultsThe geometric mean (95%CI) of ∑As (sum of DMA, MMA and iAs) was 7.78 (7.41, 8.17) μg/g creatinine. MMA concentrations were inversely associated with the scores for the general, verbal, quantitative, memory, executive function and working memory scales (i.e. β [CI95%] = −1.37 [-2.33, −0.41] for the general scale). An inverse association between %MMA and the memory scores was found. Children whose mothers had lower manganese, zinc and ferritin concentrations obtained lower scores on several MSCA scales with decreasing As methylation efficiency. DiscussionAn inverse association was observed between MMA concentrations and children's neuropsychological development. Maternal levels of manganese, zinc and ferritin affected the association between As methylation efficiency and MSCA scores.

Increased arsenic levels in both environmental measurements and biomonitoring results are associated with elevated risk of spina bifida

BACKGROUND AND AIM: Arsenic is associated with multiple adverse reproductive outcomes, and previous studies suggested higher risk of neural tube defects among mothers exposed to higher concentration of well water arsenic in Bangladesh. We further examine the association using water arsenic as proxy for external exposure and toenail as biomarkers for internal dose. METHODS: Parental toenail and water arsenic concentrations were examined in a case-control study in National Institute of Neurosciences & Hospital, Dhaka, Bangladesh. The associations between log-transformed and percentile arsenic concentrations and physician-diagnosed spina bifida were evaluated with logistic regression and cluster analysis, adjusted for maternal age, maternal BMI, parity, educational level, folic acid use and second-hand smoke exposure during pregnancy and weighted by self-reported dietary patterns. RESULTS:Median concentration for water, maternal and paternal arsenic are 2.0 ppb, 0.4 and 0.5 microgram per gram toenail among 280 included child-parent trios (156 with spina bifida) with complete exposure data. We observed associations between highest quartile maternal arsenic levels, higher than 10 ppb arsenic in water and spina bifida risk for their children after weighted for diet (Adjusted OR for water arsenic=1.49, 95% CI=1.00-2.06; adjusted OR for maternal arsenic=1.57, 95% CI=1.10-2.24), and higher composite exposure in both hierarchical clustering and k-means clustering were also associated with increased risk after weighting. Effect heterogeneity was observed between different folic acid supplement conditions, in which dose-response was attenuated for both water and paternal concentrations. CONCLUSIONS:Prenatal inorganic arsenic exposure was associated with elevated risk of spina bifida in Bangladesh, and joint parental exposure is associated with a higher risk. Investigations and interventions to mitigate arsenic exposure during for pregnant women are warranted. KEYWORDS: Heavy metals, birth outcomes, children's environmental health

Association between prenatal metal exposure and respiratory symptoms in childhood

BACKGROUND AND AIM: Arsenic, manganese, and lead have been cross-sectionally associated with adverse respiratory outcomes in childhood but there is limited data on their combined effects starting in utero. Our aim was to examine associations between prenatal lead, arsenic, and manganese exposure and respiratory symptoms in childhood. METHODS: We assessed 637 mother-child dyads enrolled in the Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) birth cohort in Mexico City. Blood manganese (BMn), arsenic (BAs), and lead (BPb) were measured in mothers at 2nd trimester. Ever wheeze, current wheeze and asthma diagnosis was based on the caregiver’s answers (yes/no) from the International Study of Asthma and Allergies in Childhood (ISAAC) survey applied at 4-5 and 6-7 years old. Covariates included maternal education, maternal asthma status, maternal age at enrollment, child’s sex, and prenatal environmental tobacco smoke exposure. A logistic mixed model regression was generated to simultaneously assess the association between prenatal metals and ever wheeze, current wheeze, and asthma diagnosis longitudinally across both the 4-5 and 6-7 year study visits. RESULTS:The mean ± standard deviation for log-transformed BMn, BPb, and BAs at 2nd trimester were 0.14 µg/dL ± 0.15, 0.48 µg/dL ± 0.27, and -1.11 µg/dL ± 0.19, respectively. In the adjusted model, BPb (Odds Ratio (OR): 1.95, 95% CI: 1.04-3.66) and BAs (OR: 3.44, 95% CI: 1.05-11.34) at 2nd trimester were associated with increased odds of ever wheeze and current wheeze, respectively. BMn at 2nd trimester (OR: 0.05, 95% CI: 0.01-0.27) was negatively associated with current wheeze. CONCLUSIONS:Prenatal exposure to arsenic and lead was associated with higher odds of ever and current wheeze while manganese was negatively associated with odds of current wheeze in childhood. These findings underscore the need to consider prenatal metal exposure, including low levels of exposure, in the study of respiratory diseases. KEYWORDS: Respiratory outcomes, Heavy metals, Allergies, Asthma, Children's environmental health

Prenatal exposure to arsenic and lung function in children from the New Hampshire Birth Cohort Study

Prenatal arsenic exposure is associated with an increased risk of lung cancer along with multiple non-carcinogenic outcomes, including respiratory diseases in arsenic-contaminated areas. Limited epidemiologic data exist on whether in utero arsenic exposure influences lung development and subsequent respiratory health. We investigated the association between gestational arsenic exposure and childhood lung function in the New Hampshire Birth Cohort Study. Urinary arsenic speciation including inorganic arsenic (iAs), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA) and arsenobetaine was measured in maternal urine samples collected during pregnancy and spirometry was performed in offspring at a median age of 7.4 years. Forced vital capacity (FVC), forced expiratory volume in the first second of exhalation (FEV1), and forced expiratory flow between 25% and 75% of FVC (FEF25-75) standardized z-scores were assessed in linear models as dependent variables with the log2-transformed summation of urinary arsenic species (ΣAs = iAs + MMA + DMA) corrected for specific gravity as an independent variable and with adjustment for maternal smoking status, children’s age, sex and height. Among the 358 children in the study, a doubling of ΣAs was associated with a −0.08 (ß) decrease in FVC z-scores (95% confidence interval (CI) from −0.14 to −0.01) and −0.10 (ß) (95% CI from −0.18 to −0.02) decrease in FEV1 z-scores. The inverse association appeared stronger among those mothers with lower secondary methylation index (urinary DMA/MMA), especially among girls. No association was observed for FEF25-75 z-scores. Our results suggest that gestation arsenic exposure at levels relevant to the general US population during the vulnerable period of lung formation may adversely affect lung function in childhood.

A cohort study of the association between prenatal arsenic exposure and age at menarche in a rural area, Bangladesh

BackgroundMillions of individuals worldwide, particularly in Bangladesh, are exposed to arsenic, mainly through drinking water from tube wells. Arsenic is a reproductive toxicant, but there is limited knowledge of whether it influences pubertal development. ObjectivesWe evaluated the association between prenatal arsenic exposure and age at menarche. MethodsThis prospective study was based on data from two studies conducted in Matlab, Bangladesh—the Maternal and Infant Nutrition Interventions in Matlab (MINIMat) trial and the Health Consequences of Arsenic in Matlab (AsMat) study. We included 809 MINIMat girls who participated in assessing age at menarche from July 2016 to June 2017 and had prenatal arsenic exposure data through the AsMat study via measurements in tube well water used by the mothers during pregnancy. The exposure was categorized into <10, 10–49, 50–99, 100–199, and ≥200 µg/L. We used Kaplan-Meier and Cox proportional hazards analyses with adjustment for potential confounders to evaluate the association between arsenic exposure and age at menarche. The results were presented by adjusted hazards ratio (aHR) with a 95% confidence interval (CI). ResultsThe median arsenic concentration in tube well water consumed by pregnant women was 80 µg/L (interquartile range 2–262 µg/L), and 55% drank water with concentrations above Bangladesh’s acceptable value of 50 µg/L. The median age at menarche was 13.0 years. The unadjusted analysis revealed 3.2 months delay in menarche for girls exposed to arsenic concentrations ≥200 µg/L compared with the girl exposed to arsenic concentrations <10 µg/L. Girls exposed to the same higher arsenic concentrations were 23% (aHR 0.77, 95% CI: 0.63–0.95) less likely to have reached menarche than girls exposed to low arsenic concentrations. ConclusionsIncreased levels of prenatal arsenic exposure were associated with older age at menarche. This delay may indicate endocrine disruptions that could potentially result in adverse health consequences in later life. This finding, along with other severe adverse health reinforces the need for arsenic mitigation at the population level.

Transgenerational male reproductive effect of prenatal arsenic exposure: abnormal spermatogenesis with Igf2/H19 epigenetic alteration in CD1 mouse

ABSTRACT Developmental exposure to environmental toxicants can induce transgenerational reproductive disease phenotypes through epigenetic mechanisms. We treated pregnant CD-1 (F0) mice with drinking water containing sodium arsenite (85 ppm) from days 8 to 18 of gestation. Male offspring were bred with untreated female mice until the F3 generation was produced. Our results revealed that F0 transient exposure to arsenic can cause decreased sperm quality and histological abnormalities in the F1 and F3. The overall methylation status of Igf2 DMR2 and H19 DMR was significantly lower in the arsenic-exposed group than that of the control group in both F1 and F3. The relative mRNA expression levels of Igf2 and H19 in arsenic-exposed males were significantly increased in both F1 and F3. This study indicates that ancestral exposure to arsenic may result in transgenerational inheritance of an impaired spermatogenesis phenotyping involving both epigenetic alterations and the abnormal expression of Igf2 and H19.

Impact of prenatal arsenic exposure on the testes and epididymides of prepubertal rats

Arsenic is a pollutant widely found in the environment due to natural and anthropogenic sources. Exposure to arsenic forms in drinking water has been related with male reproductive dysfunctions in humans and experimental animals at adult age. However, the impact of this pollutant on postnatal reproductive development of male offspring exposed in utero to arsenic is still unknown. Therefore, this study aimed to investigate the effects of prenatal arsenic exposure on the postnatal development of the testes and epididymides of rats, during prepuberty. For this purpose, pregnant female Wistar rats were provided drinking water containing 0 or 10 mg/L sodium arsenite (AsNaO2) from gestational day 1 (GD 1) until GD 21 and the male offspring was evaluated in different periods of prepuberty. Our results showed that prenatal arsenic exposure affected the initial sexual development of male pups, reducing their body weight and relative anogenital distance at postnatal day 1. At different periods of prepuberty, male pups from arsenic exposed dams showed a reduction of body and reproductive organs weights, testosterone levels and testis morphometric parameters. Moreover, these pups presented changes in the expression of SOD1, SOD2, CAT and GSTK1 genes and in the activity of superoxide dismutase, catalase and glutathione s-transferase in the testes and epididymides during prepuberty. Taken together, our results show that prenatal arsenic exposure provoked reproductive disorders in prepubertal male rats, probably due to reproductive reprograming and oxidative stress induced by this pollutant.

Single-cell RNA-seq Analysis Reveals That Prenatal Arsenic Exposure Results in Long-term, Adverse Effects on Immune Gene Expression in Response to Influenza A Infection.

Arsenic exposure via drinking water is a serious environmental health concern. Epidemiological studies suggest a strong association between prenatal arsenic exposure and subsequent childhood respiratory infections, as well as morbidity from respiratory diseases in adulthood, long after systemic clearance of arsenic. We investigated the impact of exclusive prenatal arsenic exposure on the inflammatory immune response and respiratory health after an adult influenza A virus (IAV) lung infection. C57BL/6J mice were exposed to 100 ppb sodium arsenite in utero, and subsequently infected with IAV (H1N1) after maturation to adulthood. Assessment of lung tissue and bronchoalveolar lavage fluid at various time points post-IAV infection reveals greater lung damage and inflammation in arsenic-exposed mice versus control mice. Single-cell RNA sequencing analysis of immune cells harvested from IAV-infected lungs suggests that the enhanced inflammatory response is mediated by dysregulation of innate immune function of monocyte-derived macrophages, neutrophils, natural killer cells, and alveolar macrophages. Our results suggest that prenatal arsenic exposure results in lasting effects on the adult host innate immune response to IAV infection, long after exposure to arsenic, leading to greater immunopathology. This study provides the first direct evidence that exclusive prenatal exposure to arsenic in drinking water causes predisposition to a hyperinflammatory response to IAV infection in adult mice, which is associated with significant lung damage.

Prenatal and childhood arsenic exposure through drinking water and food and cognitive abilities at 10 years of age: A prospective cohort study

BackgroundOur studies of children in a rural Bangladeshi area, with varying concentrations of arsenic in well-water, indicated modest impact on child verbal cognitive function at 5 years of age. ObjectivesFollow-up of arsenic exposure and children’s cognitive abilities at school-age. MethodsIn a nested sub-cohort of the MINIMat supplementation trial, we assessed cognitive abilities at 10 years of age (n = 1523), using Wechsler Intelligence Scale for Children (WISC-IV). Arsenic in maternal urine and erythrocytes in early pregnancy, in child urine at 5 and 10 years, and in hair at 10 years, was measured using Inductively Coupled Plasma Mass Spectrometry. ResultsMedian urinary arsenic at 10 years was 58 µg/L (range 7.3–940 µg/L). Multivariable-adjusted regression analysis showed that, compared to the first urinary arsenic quintile at 10 years (<30 µg/L), the third and fourth quintiles (30–45 and 46–73 µg/L, respectively) had 6–7 points lower Full developmental raw scores (B: −7.23, 95% CI −11.3; −3.18, and B: −6.37, 95% CI −10.5; −2.22, respectively), corresponding to ~0.2 SD. Verbal comprehension and Perceptual reasoning seemed to be affected. Models with children’s hair arsenic concentrations showed similar results. Maternal urinary arsenic in early pregnancy, but not late pregnancy, showed inverse associations with Full developmental scores (quintiles 2–4: B: −4.52, 95% CI −8.61; −0.43, B: −5.91, 95% CI −10.0; −1.77, and B: −5.98, 95%CI −10.2; −1.77, respectively, compared to first quintile), as well as with Verbal comprehension, Perceptual reasoning, and Processing speed, especially in girls (p < 0.05 for interaction of sex with Full developmental scores and Perceptual reasoning). In models with all exposure time points included, both concurrent exposure at 10 years and early prenatal exposure remained associated with cognitive abilities. ConclusionsBoth early prenatal and childhood arsenic exposure, even at low levels (about 50 µg/L in urine), was inversely associated with cognitive abilities at school-age, although the estimates were modest.

Arsenic and birth outcomes in a predominately lower income Hispanic pregnancy cohort in Los Angeles

Prenatal arsenic exposure has been associated with reduced fetal growth and increased risk for preterm birth, but most studies have been conducted in highly exposed populations outside the U.S. or in non-Hispanic populations in the rural U.S. The objectives of the current study were to: 1) examine the impact of early pregnancy exposure to arsenic on birth weight and gestational age at birth in a predominately lower income Hispanic pregnancy cohort in urban Los Angeles and 2) compare multiple biomarkers of arsenic exposure (blood, urine, and hair) assessed in early pregnancy (mean ± SD gestational age at biospecimen collection: 14 ± 4 weeks). Total arsenic (blood, hair) was measured by ICP-MS and speciated arsenic (urine) was measured by HPLC coupled to ICP-MS. Associations between log2-transformed arsenic measures and birth outcomes were evaluated using multivariable linear regression. A doubling in hair arsenic was associated with a 72.2 g (95% CI: −144.3, −0.1, P = 0.05) lower birth weight, after adjusting for potential confounders and gestational age at birth. A similar but non-significant trend was observed for blood arsenic, but not urine arsenic. The inverse association between hair arsenic and birth weight was more pronounced among infants whose mothers gained greater amounts of weight during pregnancy (Pinteraction = 0.02). The association between urinary monomethyl arsenic and GA at birth differed by pre-pregnancy BMI (Pinteraction<0.01). This study provides evidence that even at relatively low levels of exposure, arsenic exposure (measured in hair samples collected in early pregnancy) may adversely affect fetal growth in this understudied population, particularly in combination with greater gestational weight gain. Future studies with larger sample sizes are needed to confirm these findings and to further investigate some of the inconsistencies observed for the different arsenic biomarkers evaluated.

Maternal exposure to arsenic and mercury and associated risk of adverse birth outcomes in small-scale gold mining communities in Northern Tanzania

BackgroundExposure to arsenic and mercury in artisanal and small-scale gold mining (ASGM) communities is an issue that predominantly affects low and middle-income countries. Large epidemiology studies in these communities are rare, and the impact of such exposures on reproductive outcomes are not well understood. ObjectiveTo examine associations between prenatal maternal arsenic and mercury exposure and birth outcomes in both ASGM and non-ASGM communities in Northern Tanzania. MethodsThis longitudinal prospective study included 961 women (ASGM = 788, non-ASGM = 173) of the original cohort of 1056 who were followed until a pregnancy outcome was registered. Maternal spot urine samples and dried blood spots were used to measure total arsenic (T-As) and total mercury (T-Hg) in the second trimester of pregnancy. Data on adverse birth outcomes were collected in 5 categories: spontaneous abortion, stillbirth, preterm birth, low birth weight, and visible congenital anomalies. Mann-Whitney U-tests were used to test for differences between median T-As and T-Hg by area of residence. Logistic regression models were used to estimate the odds of stillbirth and visible congenital anomalies given maternal T-As and T-Hg levels. Modified Poisson regressions were used to estimate relative risk ratios between maternal T-As and T-Hg levels and composite adverse birth outcome, spontaneous abortion, low birth weight, and preterm birth. ResultsStatistically significant differences were found in median T-As (9.6 vs. 6.3 µg/L, Mann-Whitney U-tests, Z = −3.50, p < 0.001) and median T-Hg blood concentrations (1.2 vs. 0.70 µg/L, Z = −9.88, p-value < 0.001) between women living in ASGM and non-ASGM areas respectively. In ASGM areas, the adjusted relative risk (aRR) of a composite adverse birth outcome increased with increasing T-As (aRR 1.23, 95%CI: 1.14–1.33, p < 0.0001) and T-Hg (aRR 1.17, 95%CI: 1.1–1.25, p < 0.0001) exposure. Spontaneous abortion (aRR 1.53, 95%CI: 1.28–1.83), stillbirth (adjusted odds ratio (aOR) 1.97, 95%CI: 1.45–2.66) and preterm birth (1.17, 95%CI: 1.01–1.36) were significantly associated with elevated T-As, whereas elevated T-Hg was significantly associated with stillbirth (aOR 2.49, 95%CI: 1.88–3.29) and visible congenital anomalies (aOR 2.24, 95%CI: 1.3–3.87). ConclusionOver half (54.7%) of women in ASGM areas of Northern Tanzania had adverse birth outcomes and the risk of adverse birth outcomes was significantly associated with increased prenatal exposure to arsenic and mercury.

Association between prenatal arsenic exposure, birth outcomes, and pregnancy complications: An observational study within the National Children's Study cohort

BackgroundChronic arsenic exposure has been associated with pregnancy complications and reduced fetal growth in populations where total arsenic exposure exceeds 50 μg/L. However, the potential effect on pregnancy outcomes remains unclear at lower levels of arsenic exposure, such as those most commonly observed in the United States. ObjectivesWe evaluated the associations between arsenic exposure during pregnancy with fetal growth and risk of pregnancy complications using data from mother-infant pairs participating in the National Children's Study. MethodsPrenatal arsenic exposure was measured using maternal urine collected during the third trimester. Information about pregnancy complications was abstracted from medical records. Fetal growth, including gestational age, birth weight, birth length, head circumference, and ponderal index, was ascertained through physical measurement at birth and extracted from medical records. ResultsMedians [interquartile range (IQR)] of maternal urinary total arsenic and dimethylarsinic acid (DMA) were 7.77 μg/L (7.98) and 3.44 μg/L (3.13), respectively. Each increase in IQR of prenatal total arsenic level was associated with greater birth length (+0.28 cm; 95% CI: 0.14, 0.42), greater head circumference (+0.12 cm; 95% CI: 0.04, 0.21), and lower ponderal index (−0.37 kg/m3; 95% CI: −0.58, −0.17). Similar results were obtained for levels of prenatal DMA. Tests for multiplicative interaction indicate that prenatal urinary DMA was negatively associated with gestational age among female infants (−0.44 week decrease in gestational age estimated for each IQR increase in DMA; 95% CI: −0.84, −0.05), while no association was observed among male infants (pinteraction = 0.02). No significant associations were detected between arsenic and birth weight or pregnancy complications. ConclusionsHigher prenatal arsenic exposure was associated with longer birth length, greater head circumference, and lower ponderal index. Associations between arsenic and gestational age may be modified by infant sex.

Prenatal arsenic exposure interferes in postnatal immunocompetence despite an absence of ongoing arsenic exposure

Arsenic (As) readily crosses the placenta and exposure of the fetus may cause adverse consequences later in life, including immunomodulation. In the current study, the question was asked how the immune repertoire might respond in postnatal life when there is no further As exposure. Here, pregnant mice (Balb/c [H-2d]) were exposed to arsenic trioxide (As2O3) through their drinking water from time of conception until parturition. Their offspring, 4-week-old mice who had not been exposed again to As, were used for functional analyses of innate, humoral and cellular immunity. Compared to cells from non-As-exposed dam offspring, isolated peritoneal macro-phages (Mϕ) displayed no differences in T-cell stimulating ability. Levels of circulating IgG2a but not IgG1 were decreased in As-exposed dam offspring as compared to control offspring counterparts. Mixed-leukocyte reactions (MLR) indicated that CD4+ T-cells from the prenatal As-exposed mice were significantly less responsive to allogenic stimulation as evidenced by decreases in interferon (IFN)-γ and IL-2 production and in expression of CD44 and CD69 (but not CD25) activation markers. Interestingly, the Mϕ from the prenatal As-exposed mice were capable of stimulating normal allogenic T-cells, indicating that T-cells from these mice were refractory to allogenic signals. There was also a significant decrease in absolute numbers of splenic CD4+ and CD8+ T-cells due to prenatal As exposure (as compared to control). Lastly, the impaired immune function of the prenatal As-exposed mice was correlated with a very strong susceptibility to Escherichia coli infection. Taken together, the data from this study clearly show that in utero As exposure may continue to perpetuate a dampening effect on the immune repertoire of offspring, even into the early stages of postnatal life.

Domain- and sex-specific effects of prenatal exposure to low levels of arsenic on children’s development at 6 months of age: Findings from the Ma’anshan birth cohort study in China

The relationship between prenatal arsenic exposure at low levels and poor development in children, especially in regard to neurodevelopment, has aroused several concerns, but the conclusions have been inconsistent. It still remains unclear whether such adverse effect is associated with a specific profile of the developing brain in early life. To investigate the association between arsenic exposure in utero and children’s development and behaviour, we performed a large prospective birth cohort study including 2315 mother-infant pairs in Anhui Province, China. The Ages and Stages Questionnaire of China (ASQ-C) was used to assess the status of children’s development and behaviour at 6 months postpartum, and the levels of arsenic were determined in umbilical cord serum samples. Odds ratios for suspected developmental delay (SDD) in each domain of the ASQ-C clusters were estimated using logistic regression models. Compared with low arsenic levels group, medium and high arsenic levels were significantly associated with the increased risks of SDD in the personal-social domain among infants aged 6 months after adjustment for all potential confounders (OR = 1.33, 95% CI (1.01, 1.75) and OR = 1.47, 95% CI (1.08, 2.00), respectively). Sex stratification analysis demonstrated that this association was stronger in females. The sensitivity analyses also showed that high cord serum arsenic levels were associated with a 1.80-fold (95% CIs (1.12, 2.90)) higher risk of a more severe developmental delay in the personal-social domain among six-month-old females. Our results suggest that low-level arsenic exposure in utero could have an adverse domain-specific effect on children’s development at 6 months of age, particularly among females. Further studies are warranted to support the findings and explore the mechanism of these domain-and sex-specific associations.