Prenatal Arsenic Exposure Research Articles

Long-term health consequences of prenatal arsenic exposure: links to the genome and the epigenome

Arsenic continues to poison the water of millions of individuals around the globe. Despite the potentially devastating effects of arsenic on worldwide human health, the impacts of such exposure on vulnerable populations including pregnant women and their unborn children are understudied. Data from human populations exposed early in life highlight the increased mortality risks related to both cancer and non-cancer endpoints. The molecular underpinnings for these effects are largely unknown. Here we highlight the current studies linking prenatal arsenic exposure and health effects, particularly those that examined associations between arsenic exposure and altered genomic and epigenetic signaling. Current needs in the field to increase our understanding of the molecular basis for adult disease are mentioned.

Prenatal arsenic exposure and the epigenome: altered microRNAs associated with innate and adaptive immune signaling in newborn cord blood.

The Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort in Gómez Palacio, Mexico was recently established to better understand the impacts of prenatal exposure to inorganic arsenic (iAs). In this study, we examined a subset (n = 40) of newborn cord blood samples for microRNA (miRNA) expression changes associated with in utero arsenic exposure. Levels of iAs in maternal drinking water (DW-iAs) and maternal urine were assessed. Levels of DW-iAs ranged from below detectable values to 236 µg/L (mean = 51.7 µg/L). Total arsenic in maternal urine (U-tAs) was defined as the sum of iAs and its monomethylated and dimethylated metabolites (MMAs and DMAs, respectively) and ranged from 6.2 to 319.7 µg/L (mean = 64.5 µg/L). Genome-wide miRNA expression analysis of cord blood revealed 12 miRNAs with increasing expression associated with U-tAs. Transcriptional targets of the miRNAs were computationally predicted and subsequently assessed using transcriptional profiling. Pathway analysis demonstrated that the U-tAs-associated miRNAs are involved in signaling pathways related to known health outcomes of iAs exposure including cancer and diabetes mellitus. Immune response-related mRNAs were also identified with decreased expression levels associated with U-tAs, and predicted to be mediated in part by the arsenic-responsive miRNAs. Results of this study highlight miRNAs as novel responders to prenatal arsenic exposure that may contribute to associated immune response perturbations.

The relationship between prenatal lead, cadmium, and arsenic exposure and their neurological effects at three years old in Taiwan

Lead, cadmium, and arsenic are well-known neurotoxins in children, with particular impact on neuro-development and intellectual performance. Fetus exposure to neurontoxins may have adverse developmental outcome. The aim of this study was to investigate the relationships between neurological effects and lead, cadmium, and arsenic concentration in meconium. In this study, we recruited mother-infant pairs between August 2008 and December 2009, and a second follow-up study of these children was completed after 3 years. We collected meconium after delivery as biomarkers for examine lead, cadmium, and arsenic exposure. The Bayley Scales of Infant and Toddler Development (Bayley-III) for evaluating the cognitive, language, and motor development of 3 years old children are calculated and validated. There were total 53 mother-child pairs in this study. The mean of lead, cadmium, and arsenic concentration in meconium was 253±180 ng/g, 60.7±14.8, and 52.0±13.6 ng/g, respectively. There were no significant negative correlation between lead, cadmium, or arsenic levels and the cognitive, language or motor development of Bayley-III scores. The score of expressive of language were higher in father s of higher levels of education and in mothers who consumed traditional Chinese herbs before pregnancy. The score of motor development were higher in fathers and mothers of higher levels of education, and girls. In conclusion, the results of the present study suggest that prenatal exposure lead, cadmium, and arsenic were not associated with early neurological development.

Delayed Temporal Increase of Hepatic Hsp70 in ApoE Knockout Mice After Prenatal Arsenic Exposure

Prenatal arsenic exposure accelerates atherosclerosis in ApoE(-/-) mice by unknown mechanism. Arsenic is a hepatotoxicant, and liver disease increases atherosclerosis risk. Prenatal arsenic exposure may predispose to liver disease by priming for susceptibility to other environmental insults. Earlier microarray analyses showed prenatal arsenic exposure increased Hsc70 (HspA8) and Hsp70 (HspA1a) mRNAs in livers of 10-week-old mice. We determined effects of prenatal arsenic exposure on hepatic Hsp70 and Hsc70 expression by Western blot and on DNA methylation by methyl acceptance assay during prenatal and postnatal development. Pregnant ApoE(-/-) mice were given drinking water containing 85 mg/l NaAsO(2) (49 ppm arsenic) from gestation day (GD) 8 to 18. Hsp70 and Hsc70 expression and DNA methylation were determined in GD18 fetuses and 3-, 10-, and 24-week-old mice. Hsc70 expression was unchanged at all ages. Hsp70 induction was observed at 3 and 10 weeks, but was unchanged in GD18 fetuses and 24-week livers of mice. Global DNA methylation increased with age; arsenic had no effects. Bisulfite sequencing of DNA from livers of 10-week-old mice showed Hsp70 promoter region methylation was unchanged, but methylation was increased within the transcribed region. Hsf1 and Nrf2 nuclear translocation were investigated as potential mechanisms of Hsp70 induction and found unaltered. Putative binding sites were identified in HSP70 for in utero arsenic exposure-suppressed microRNAs suggesting a possible mechanism. Thus, prenatal arsenic exposure causes delayed temporal hepatic Hsp70 induction, suggesting a transient state of stress in livers which can predispose the mice to developing liver disease.

In Utero Arsenic Exposure Is Associated With Impaired Thymic Function in Newborns Possibly Via Oxidative Stress and Apoptosis

Prenatal arsenic exposure is associated with increased infant morbidity and reduced thymus size, indicating arsenic-related developmental immunotoxicity. We aimed to evaluate effects of prenatal arsenic exposure on thymic function at birth and related mechanisms of action. In a Bangladeshi cohort, arsenic was measured in urine (U-As, gestational week (GW) 8 and 30) and blood (B-As, GW14) in 130 women. Child thymic index was measured by sonography at birth and thymic function by signal-joint T-cell receptor-rearrangement excision circles (sjTRECs) in cord blood mononuclear cells (CBMC). In a subsample (n = 44), sjTRECs content in isolated CD4(+) and CD8(+) T cells, expression of oxidative-stress defense and apoptosis-related genes in CBMC, arsenic concentrations (urine, placenta, and cord blood), and oxidative stress markers in placenta and cord blood were measured. In multivariable-adjusted regression, ln U-As (GW8) was inversely associated with ln sjTRECs in CBMC (B = -0.25; 95% confidence interval [CI] -0.48 to -0.01). Using multivariable-adjusted spline regression, ln U-As (GW30) and ln B-As (GW14) were inversely associated with ln sjTRECs in CBMC (B = -0.53; 95% CI -0.93 to -0.13 and B = -1.27; 95% CI -1.89 to -0.66, respectively) below spline knots at U-As 150 µg/l and B-As 6 µg/kg. Similar inverse associations were observed in separated CD4(+) and CD8(+) T cells. Arsenic was positively associated with 8-hydroxy-2'-deoxyguanosine in cord blood (B = 0.097; 95% CI 0.05 to 0.13), which was inversely associated with sjTRECs in CD4(+) and CD8(+) T cells. In conclusion, prenatal arsenic exposure was associated with reduced thymic function, possibly via induction of oxidative stress and apoptosis, suggesting subsequent immunosuppression in childhood.

Prenatal Arsenic Exposure Alters Gene Expression in the Adult Liver to a Proinflammatory State Contributing to Accelerated Atherosclerosis

The mechanisms by which environmental toxicants alter developmental processes predisposing individuals to adult onset chronic disease are not well-understood. Transplacental arsenic exposure promotes atherogenesis in apolipoprotein E-knockout (ApoE−/−) mice. Because the liver plays a central role in atherosclerosis, diabetes and metabolic syndrome, we hypothesized that accelerated atherosclerosis may be linked to altered hepatic development. This hypothesis was tested in ApoE−/− mice exposed to 49 ppm arsenic in utero from gestational day (GD) 8 to term. GD18 hepatic arsenic was 1.2 µg/g in dams and 350 ng/g in fetuses. The hepatic transcriptome was evaluated by microarray analysis to assess mRNA and microRNA abundance in control and exposed pups at postnatal day (PND) 1 and PND70. Arsenic exposure altered postnatal developmental trajectory of mRNA and microRNA profiles. We identified an arsenic exposure related 51-gene signature at PND1 and PND70 with several hubs of interaction (Hspa8, IgM and Hnf4a). Gene ontology (GO) annotation analyses indicated that pathways for gluconeogenesis and glycolysis were suppressed in exposed pups at PND1, and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced by PND70. Promoter analysis of differentially-expressed transcripts identified enriched transcription factor binding sites and clustering to common regulatory sites. SREBP1 binding sites were identified in about 16% of PND70 differentially-expressed genes. Western blot analysis confirmed changes in the liver at PND70 that included increases of heat shock protein 70 (Hspa8) and active SREBP1. Plasma AST and ALT levels were increased at PND70. These results suggest that transplacental arsenic exposure alters developmental programming in fetal liver, leading to an enduring stress and proinflammatory response postnatally that may contribute to early onset of atherosclerosis. Genes containing SREBP1 binding sites also suggest pathways for diabetes mellitus and rheumatoid arthritis, both diseases that contribute to increased cardiovascular disease in humans.

Influence of Prenatal Arsenic Exposure and Newborn Sex on Global Methylation of Cord Blood DNA

BackgroundAn emerging body of evidence indicates that early-life arsenic (As) exposure may influence the trajectory of health outcomes later in life. However, the mechanisms underlying these observations are unknown.ObjectiveThe objective of this study was to investigate the influence of prenatal As exposure on global methylation of cord blood DNA in a study of mother/newborn pairs in Matlab, Bangladesh.DesignMaternal and cord blood DNA were available from a convenience sample of 101 mother/newborn pairs. Measures of As exposure included maternal urinary As (uAs), maternal blood As (mbAs) and cord blood As (cbAs). Several measures of global DNA methylation were assessed, including the [3H]-methyl-incorporation assay and three Pyrosequencing assays: Alu, LINE-1 and LUMA.ResultsIn the total sample, increasing quartiles of maternal uAs were associated with an increase in covariate-adjusted means of newborn global DNA methylation as measured by the [3H]-methyl-incorporation assay (quartile 1 (Q1) and Q2 vs. Q4; p = 0.06 and 0.04, respectively). Sex-specific linear regression analyses, while not reaching significance level of 0.05, indicated that the associations between As exposures and Alu, LINE-1 and LUMA were positive among male newborns (N = 58) but negative among female newborns (N = 43); tests for sex differences were borderline significant for the association of cbAs and mbAs with Alu (p = 0.05 and 0.09, respectively) and for the association between maternal uAs and LINE-1 (p = 0.07). Sex-specific correlations between maternal urinary creatinine and newborn methyl-incorporation, Alu and LINE-1 were also evident (p<0.05).ConclusionsThese results suggest that prenatal As exposure is associated with global DNA methylation in cord blood DNA, possibly in a sex-specific manner. Arsenic-induced epigenetic modifications in utero may potentially influence disease outcomes later in life. Additional studies are needed to confirm these findings and to examine the persistence of DNA methylation marks over time.

Prenatal arsenic exposure is associated with impaired thymic function in newborns

Prenatal arsenic exposure is associated with impaired thymic function in newborns

Prenatal Arsenic Exposure and DNA Methylation in Maternal and Umbilical Cord Blood Leukocytes

Background: Arsenic is an epigenetic toxicant and could influence fetal developmental programming.Objectives: We evaluated the association between arsenic exposure and DNA methylation in maternal and umbilical cord leukocytes.Methods: Drinking-water and urine samples were collected when women were at ≤ 28 weeks gestation; the samples were analyzed for arsenic using inductively coupled plasma mass spectrometry. DNA methylation at CpG sites in p16 (n = 7) and p53 (n = 4), and in LINE-1 and Alu repetitive elements (3 CpG sites in each), was quantified using pyrosequencing in 113 pairs of maternal and umbilical blood samples. We used general linear models to evaluate the relationship between DNA methylation and tertiles of arsenic exposure.Results: Mean (± SD) drinking-water arsenic concentration was 14.8 ± 36.2 μg/L (range: < 1–230 μg/L). Methylation in LINE-1 increased by 1.36% [95% confidence interval (CI): 0.52, 2.21%] and 1.08% (95% CI: 0.07, 2.10%) in umbilical cord and maternal leukocytes, respectively, in association with the highest versus lowest tertile of total urinary arsenic per gram creatinine. Arsenic exposure was also associated with higher methylation of some of the tested CpG sites in the promoter region of p16 in umbilical cord and maternal leukocytes. No associations were observed for Alu or p53 methylation.Conclusions: Exposure to higher levels of arsenic was positively associated with DNA methylation in LINE-1 repeated elements, and to a lesser degree at CpG sites within the promoter region of the tumor suppressor gene p16. Associations were observed in both maternal and fetal leukocytes. Future research is needed to confirm these results and determine if these small increases in methylation are associated with any health effects.

Arsenic and Infectious Disease: A Potential Factor in Morbidity among Bangladeshi Children

Vol. 119, No. 5 NewsOpen AccessArsenic and Infectious Disease: A Potential Factor in Morbidity among Bangladeshi Children Angela Spivey Angela Spivey Search for more papers by this author Published:1 May 2011https://doi.org/10.1289/ehp.119-a218aCited by:6AboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Lower respiratory tract infection (LRTI) and diarrhea are two of the most common causes of morbidity and mortality in children under 5 years old, especially in low-income countries. A new prospective cohort study of the link between these types of infections and arsenic exposure revealed a dose-dependent increase in LRTI and diarrhea in relation to maternal arsenic exposure [EHP119(5):719–724; Rahman et al.].Earlier studies linked prenatal arsenic exposure to increased risk of infant mortality, and infectious disease has been suggested as a potential underlying cause in these deaths. No epidemiologic studies have been conducted to support that explanation, but there is evidence from a few animal and human studies that arsenic may cause immunosuppression.The current study included 1,552 live-born infants of women enrolled during 2002–2004 in Matlab, Bangladesh. Arsenic exposure was assessed by measuring inorganic arsenic in maternal urine samples collected at gestational weeks 8 and 30. After birth, information on symptoms of LRTI and diarrhea in infants was collected at monthly home visits in which mothers recalled symptoms that had occurred over the previous 7 days.The estimated relative risk of LRTI and severe LRTI increased by 69% and 54%, respectively, in the participants whose mothers had urinary arsenic concentrations in the highest quintile (262–977 μg/L), compared with offspring of mothers whose exposure was in the lowest quintile (less than 39 μg/L). The relative risk of diarrhea increased 20% for the highest-exposure group compared with the lowest-exposure group.The authors observed that relative risks of LRTI and diarrhea increased irrespective of sociodemographic factors or nutritional status of the women. However, further evaluation is needed in a larger sample to evaluate possible effect modification, because the risks appeared more pronounced in low social strata.Strengths of the study include the large sample size, the objective measure of arsenic exposure, and the followup of infants for one full year, which the authors say would reduce any influence of seasons on infection rates. Potential limitations include lack of measurements of infant exposure to arsenic, a lack of information about other potentially toxic substances in water and food, and reliance on mothers’ reports of disease symptoms and signs. Given the millions of people worldwide who drink well water with elevated arsenic concentrations, the study results could have serious public health implications and, taken together with previous studies showing health effects from this exposure, emphasize the need to reduce arsenic exposure via drinking water.More than 50 million people in Bangladesh are believed to be chronically exposed to drinking water with arsenic concentrations exceeding the WHO standard of 10 μg/L.FiguresReferencesRelatedDetailsCited by Zheng K, Zeng Z, Tian Q, Huang J, Zhong Q and Huo X (2023) Epidemiological evidence for the effect of environmental heavy metal exposure on the immune system in children, Science of The Total Environment, 10.1016/j.scitotenv.2023.161691, (161691), Online publication date: 1-Jan-2023. Taylor S, Terkildsen M, McQuilty R, Lee D, Wing-Simpson A and Gray R (2022) Non-essential heavy metals and protective effects of selenium against mercury toxicity in endangered Australian sea lion (Neophoca cinerea) pups with hookworm disease, Environment International, 10.1016/j.envint.2022.107521, 169, (107521), Online publication date: 1-Nov-2022. Chatterjee S, Chetia M, Voronina A and Gupta D (2017) Prospects of Combating Arsenic: Physico-chemical Aspects Arsenic Contamination in the Environment, 10.1007/978-3-319-54356-7_5, (103-121), . Chatterjee S, Datta S and Gupta D (2017) Studies on Arsenic and Human Health Arsenic Contamination in the Environment, 10.1007/978-3-319-54356-7_3, (37-66), . Choudhury S, Gupta P, Ghosh S, Mukherjee S, Chakraborty P, Chatterji U and Chattopadhyay S (2016) Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses, Toxicology, 10.1016/j.tox.2016.06.005, 357-358, (85-96), Online publication date: 1-May-2016. Naujokas M, Anderson B, Ahsan H, Aposhian H, Graziano J, Thompson C and Suk W (2013) The Broad Scope of Health Effects from Chronic Arsenic Exposure: Update on a Worldwide Public Health Problem, Environmental Health Perspectives, 121:3, (295-302), Online publication date: 1-Mar-2013. Vol. 119, No. 5 May 2011Metrics About Article Metrics Publication History Originally published1 May 2011Published in print1 May 2011 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. 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Arsenic Exposure in Pregnancy Increases the Risk of Lower Respiratory Tract Infection and Diarrhea during Infancy in Bangladesh

BackgroundPrevious studies have reported associations between prenatal arsenic exposure and increased risk of infant mortality. An increase in infectious diseases has been proposed as the underlying cause of these associations, but there is no epidemiologic research to support the hypothesis.ObjectiveWe evaluated the association between arsenic exposure in pregnancy and morbidity during infancy.MethodsThis prospective population-based cohort study included 1,552 live-born infants of women enrolled during 2002–2004 in Matlab, Bangladesh. Arsenic exposure was assessed by the concentrations of metabolites of inorganic arsenic in maternal urine samples collected at gestational weeks 8 and 30. Information on symptoms of lower respiratory tract infection (LRTI) and diarrhea in infants was collected by 7-day recalls at monthly home visits.ResultsIn total, 115,850 person-days of observation were contributed by the infants during a 12-month follow-up period. The estimated risk of LRTI and severe LRTI increased by 69% [adjusted relative risk (RR) = 1.69; 95% confidence interval (CI), 1.36–2.09)] and 54% (RR = 1.54; 95% CI, 1.21–1.97), respectively, for infants of mothers with urinary arsenic concentrations in the highest quintile (average of arsenic concentrations measured in early and late gestation, 262–977 μg/L) relative to those with exposure in the lowest quintile (< 39 μg/L). The corresponding figure for diarrhea was 20% (RR = 1.20; 95% CI, 1.01–1.43).ConclusionsArsenic exposure during pregnancy was associated with increased morbidity in infectious diseases during infancy. Taken together with the previous evidence of adverse effects on health, the findings strongly emphasize the need to reduce arsenic exposure via drinking water.

PP-330. Tuberculin skin test and BCG scarring after BCG vaccination in preterms

Shortening of gestation and intrauterine growth restriction (IUGR) are the two main determinants of birthweight. Low birthweight has been linked with prenatal arsenic exposure, but the causal relation between arsenic and birthweight is not well understood.We applied a quantile causal mediation analysis approach to determine the association between prenatal arsenic exposure and birthweight in relation to shortening of gestation and IUGR, and whether the susceptibility of arsenic exposure varies by infant birth sizes.In a longitudinal birth cohort in Bangladesh, we measured arsenic in drinking water (n = 1182) collected at enrollment and maternal toenails (n = 1104) collected ≤ 1-month postpartum using inductively coupled plasma mass spectrometry. Gestational age was determined using ultrasound at ≤ 16 weeks' gestation. Demographic information was collected using a structured questionnaire.Of 1184 singleton livebirths, 16.4% (n = 194) were low birthweight (< 2500 g), 21.9% (n = 259) preterm (< 37 weeks' gestation), and 9.2% (n = 109) both low birthweight and preterm. The median concentrations of arsenic in drinking water and maternal toenails were 2.2 μg/L (range: below the level of detection [LOD] − 1400) and 1.2 μg/g (range: < LOD − 46.6), respectively. Prenatal arsenic exposure was negatively associated with birthweight, where the magnitude of the association varied across birthweight percentiles. The effect of arsenic on birthweight mediated via shortening of gestation affected all infants irrespective of birth sizes (β range: 10th percentile = − 19.7 g [95% CI: − 26.7, − 13.3] to 90th percentile = − 10.9 g [95% CI: − 18.5, − 5.9] per natural log water arsenic increase), whereas the effect via pathways independent of gestational age affected only the smaller infants (β range: 10th percentile = − 28.0 g [95% CI: − 43.8, − 9.9] to 20th percentile = − 14.9 g [95% CI: − 30.3, − 1.7] per natural log water arsenic increase). Similar pattern was observed for maternal toenail arsenic.The susceptibility of prenatal arsenic exposure varied by infant birth sizes, placing smaller infants at greater risk of lower birthweight by shortening of gestation and possibly growth restriction. It is important to mitigate prenatal arsenic exposure to improve perinatal outcomes in Bangladesh.

Prenatal and early life arsenic exposure induced oxidative damage and altered activities and mRNA expressions of neurotransmitter metabolic enzymes in offspring rat brain

To better understand the effect of arsenic on central nervous system by prenatal and early life exposure, the oxidative stress and neurotransmitter metabolic enzymes were determined in offspring rats' brain cortex and hippocampus. Forty-eight pregnant rats were randomly divided into four groups, each group was given free access to drinking water that contained 0, 10, 50, and 100 mg/L NaAsO(2) from gestation day 6 (GD 6) until postnatal day 42 (PND 42). Once pups were weaned, they started to drink the same arsenic (As)-containing water as the dams. The level of malondialdehyde in 100 mg/L As-exposed pup's brain on PND 0 and cortex on PND 28 and 42 were significantly higher than in the control group (p < 0.05). Reduced glutathione (GSH) levels showed a clear decreasing trend in pup's cortex and hippocampus on PND 42. Activity of acetylcholinesterase was significantly higher in 100 mg/L As-exposed pup's hippocampus than in control group on PND 28 and 42. mRNA expression of glutamate decarboxylase (GAD(65) and GAD(67)) in 100 mg/L As-exposed pup's cortex or hippocampus on PND 28 and 42 were significantly higher than in control (p < 0.05). These alterations in the neurotransmitters and reduced antioxidant defence may lead to neurobehavioral and learning and memory changes in offspring rats.

Arsenic Exposure During Pregnancy and Size at Birth: A Prospective Cohort Study in Bangladesh

The authors evaluated the association of prenatal arsenic exposure with size at birth (birth weight, birth length, head and chest circumferences). This prospective cohort study, based on 1,578 mother-infant pairs, was conducted in Matlab, Bangladesh, in 2002-2003. Arsenic exposure was assessed by analysis of arsenic in urine collected at around gestational weeks 8 and 30. The association of arsenic exposure with size at birth was assessed by linear regression analyses. In analysis over the full range of exposure (6-978 microg/L), no dose-effect association was found with birth size. However, significant negative dose effects were found with birth weight and head and chest circumferences at a low level of arsenic exposure (<100 microg/L in urine). In this range of exposure, birth weight decreased by 1.68 (standard error (SE), 0.62) g for each 1-microg/L increase of arsenic in urine. For head and chest circumferences, the corresponding reductions were 0.05 (SE, 0.03) mm and 0.14 (SE, 0.03) mm per 1 microg/L, respectively. No further negative effects were shown at higher levels of arsenic exposure. The indicated negative effect on birth size at a low level of arsenic exposure warrants further investigation.

Is Arsenic “Lactation Intolerant”?: Study Indicates Low Excretion in Breast Milk

Arsenic is known to readily cross the placenta, but few data exist on postnatal exposure to arsenic in breast milk. Results of a study conducted in Bangladesh now suggest that infants who are exclusively breastfed are protected against arsenic, despite high maternal exposures [EHP 116:963–969; Fangstrom et al.]. Numerous studies have linked arsenic exposure in adults to various diseases, including cancer, cardiovascular disease, and diabetes mellitus. Exposure in school-age children has been associated with neurodevelopmental disorders. During fetal development, the brain is particularly vulnerable to arsenic exposure, as it readily crosses the placenta, possibly altering fetal programming and leading to a higher risk of susceptibility to disease later in life. The subjects in the current study included 98 mothers and their 3-month-old infants who participated in the Maternal and Infant Nutrition Interventions of Matlab in Bangladesh, one of the most severely affected countries in terms of high prevalence of extremely elevated levels of arsenic in drinking water supplies. The investigators evaluated nutritional status and arsenic exposure as reflected by arsenic metabolites in infant urine and maternal blood, urine, and saliva samples. They also analyzed breast milk samples at 2 months postpartum for arsenic. Questionnaires completed by the mothers provided data on infant feeding practices. The median sum of arsenic metabolites in infant urine was 1.2 μg/L, with significantly lower concentrations in infants who were exclusively breastfed compared with those who received some solid food. Arsenic concentrations in breast milk were low (median 1.0 μg/kg) and mostly in the form of trivalent inorganic arsenic. The researchers observed a significant association between arsenic in infant urine and breast milk, but noted that some mothers with low breast milk arsenic had infants with high urine concentrations, possibly because the infants had been given water to drink. Median maternal blood and urine concentrations were high (5.7 and 67 μg/L, respectively), whereas median maternal saliva concentrations were low (1.3 μg/L). Among infants who were exclusively breastfed, urine levels did not exceed 19 μg/L inorganic arsenic and its metabolites, whereas infants who received infant formula prepared with local drinking water in addition to some breast milk had urine levels up to 1,100 μg/L. The authors demonstrate for the first time that arsenic in human breast milk is mostly the inorganic arsenite form. Although there was a significant relationship between arsenic concentrations in milk and in maternal blood, arsenic concentrations in breast milk were relatively low despite the mothers’ high exposures. The findings suggest that breastfeeding exclusively can protect infants from arsenic exposure during this critical development period, but the authors note that researchers have yet to determine the extent to which breastfeeding decreases the health risks associated with prenatal arsenic exposure.

Prenatal arsenic exposure altered liver gene expression associated with accelerated atherosclerosis

Offspring of ApoE‐knockout mice exposed to arsenic in drinking water while pregnant exhibit accelerated and exacerbated atherosclerosis. Microarray analyses of liver mRNAs and microRNAs were performed to investigate the potential role of altered liver development in arsenic induced atherosclerosis. Liver RNAs from newborn and 10 week old mice were analyzed. Principal component analysis indicated that developmental trajectory was altered by arsenic exposure. A 51 gene signature of mRNAs altered by arsenic exposure at both ages was obtained. Nodes of interaction identified by Pathway Architect within this gene set include HSPA8, IgM and HNF4A. DAVID analysis of the overlap of arsenic exposure‐altered mRNAs and putative targets of altered microRNAs suggested that gluconeogeneis and glycolysis pathways were suppressed in newborn mice and pathways for protein export, ribosome, antigen processing and presentation, and complement and coagulation cascades were induced in 10 week old mice. These results support the hypthesis that in utero arsenic exposure induces changes in liver development that may alter liver inflammatory responses contributing to athero accelerated atherosclerosis. (Supported by PHS grants R01ES011314 &amp; P30ES014443, UofL Center for Genetics and Molecular Medicine pilot grant, UofL Collaborative Planning and Development Grant and Intramural Research Program of NIA/NIH)

Health Effects of Early Life Exposure to Arsenic

Inorganic arsenic is a potent human carcinogen and general toxicant. More than one hundred million people are exposed to elevated concentrations, mainly via drinking water, but also via industrial emissions. Arsenic is metabolized via methylation and reduction reactions, methylarsonic acid and dimethylarsinic acid being the main metabolites excreted in urine. Both inorganic arsenic and its methylated metabolites easily pass the placenta and both experimental and human studies have shown increased risk of impaired foetal growth and increased foetal loss. Recent studies indicate that prenatal arsenic exposure also increases the risk of adverse effects during early childhood. There is a growing body of evidence that the intrauterine or early childhood exposure to arsenic also induces changes that will become apparent much later in life. One epidemiological study indicated that exposure to arsenic in drinking water during early childhood or in utero was associated with an increased mortality in young adults from both malignant and non-malignant lung disease. Furthermore, a series of experimental animal studies provide strong support for late effects of arsenic, including various forms of cancer, following intrauterine arsenic exposure. The involved modes of action include epigenetic effects, mainly via DNA hypomethylation, endocrine effects (most classes of steroid hormones), immune suppression, neurotoxicity, and interaction with enzymes critical for foetal development and programming.

Activation of Inflammation/NF-κB Signaling in Infants Born to Arsenic-Exposed Mothers

The long-term health outcome of prenatal exposure to arsenic has been associated with increased mortality in human populations. In this study, the extent to which maternal arsenic exposure impacts gene expression in the newborn was addressed. We monitored gene expression profiles in a population of newborns whose mothers experienced varying levels of arsenic exposure during pregnancy. Through the application of machine learning–based two-class prediction algorithms, we identified expression signatures from babies born to arsenic-unexposed and -exposed mothers that were highly predictive of prenatal arsenic exposure in a subsequent test population. Furthermore, 11 transcripts were identified that captured the maximal predictive capacity to classify prenatal arsenic exposure. Network analysis of the arsenic-modulated transcripts identified the activation of extensive molecular networks that are indicative of stress, inflammation, metal exposure, and apoptosis in the newborn. Exposure to arsenic is an important health hazard both in the United States and around the world, and is associated with increased risk for several types of cancer and other chronic diseases. These studies clearly demonstrate the robust impact of a mother's arsenic consumption on fetal gene expression as evidenced by transcript levels in newborn cord blood.

Transplacental arsenic carcinogenesis in mice

Our work has focused on the carcinogenic effects of in utero arsenic exposure in mice. Our data show that a short period of maternal exposure to inorganic arsenic in the drinking water is an effective, multi-tissue carcinogen in the adult offspring. These studies have been reproduced in three temporally separate studies using two different mouse strains. In these studies pregnant mice were treated with drinking water containing sodium arsenite at up to 85 ppm arsenic from days 8 to 18 of gestation, and the offspring were observed for up to 2 years. The doses used in all these studies were well tolerated by both the dam and offspring. In C3H mice, two separate studies show male offspring exposed to arsenic in utero developed liver carcinoma and adrenal cortical adenoma in a dose-related fashion during adulthood. Prenatally exposed female C3H offspring show dose-related increases in ovarian tumors and lung carcinoma and in proliferative lesions (tumors plus preneoplastic hyperplasia) of the uterus and oviduct. In addition, prenatal arsenic plus postnatal exposure to the tumor promoter, 12- O-tetradecanoyl phorbol-13-acetate (TPA) in C3H mice produces excess lung tumors in both sexes and liver tumors in females. Male CD1 mice treated with arsenic in utero develop tumors of the liver and adrenal and renal hyperplasia while females develop tumors of urogenital system, ovary, uterus and adrenal and hyperplasia of the oviduct. Additional postnatal treatment with diethylstilbestrol or tamoxifen after prenatal arsenic in CD1 mice induces urinary bladder transitional cell proliferative lesions, including carcinoma and papilloma, and enhances the carcinogenic response in the liver of both sexes. Overall this model has provided convincing evidence that arsenic is a transplacental carcinogen in mice with the ability to target tissues of potential human relevance, such as the urinary bladder, lung and liver. Transplacental carcinogenesis clearly occurs with other agents in humans and investigating a potential transplacental component of the human carcinogenic response to arsenic should be a research priority.

A Liquid Path to Lung Disease: EarlyArsenicExposureand EffectsinYoung Adults

Vol. 114, No. 8 EnvironewsOpen AccessA Liquid Path to Lung Disease: EarlyArsenicExposureand EffectsinYoung Adultsis accompanied byIncreased Mortality from Lung Cancer and Bronchiectasis in Young Adults after Exposure to Arsenic in Utero and in Early Childhood Tanya Tillett Tanya Tillett Search for more papers by this author Published:1 August 2006https://doi.org/10.1289/ehp.114-a486aAboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Increased rates of cancer and mortality have been documented in areas of the world where drinking water contains high concentrations of naturally occurring arsenic. A new study by a group of Californian and Chilean researchers now provides strong evidence of a link in humans between prenatal and early childhood arsenic exposure and significantly higher rates of lung disease in young adulthood [EHP 114:1293–1296; Smith et al.].Both malignant and nonmalignant lung disease are known to develop with exposure to arsenic in drinking water. Recent evidence from a project in India by the same research group showed decreased lung function similar to that of smokers in adults exposed to the semimetallic carcinogen.The current study took advantage of a unique opportunity to study the long-term health effects of a discrete prenatal and early childhood exposure. From 1958 to 1970, the water supply for the neighboring Chilean cities of Antofagasta and Mejillones was supplemented with water from rivers with arsenic concentrations near 1,000 μg/L, 100 times the current acceptable standard for arsenic concentration in the United States. With the 1971 activation of an arsenic removal plant, however, levels plummeted to about 90 μg/L and have continued to drop ever since.The research team studied mortality data obtained from Chile’s Ministry of Health for the years 1989 through 2000 for all 13 regions of the country. They divided the population into two groups: individuals born between 1958 and 1970 (who likely would have had prenatal arsenic exposure if their mothers lived in Antofagasta or Mejillones) and those born between 1950 and 1957 (who likely would have had childhood but not prenatal exposure if they lived in either of the two cities). The researchers also divided overall deaths for Chile into two groups: residents of Antofagasta and Mejillones, and residents of all other regions. They used the International Classification of Diseases, Ninth Revision, to code causes of death, including lung cancer and bronchiectasis, a form of chronic respiratory disease.The investigators’ findings show a distinct connection between prenatal and early childhood exposure to arsenic and lung disease–related mortality before age 50. Lung cancer death rates for those exposed to arsenic in early childhood were 7 times higher than those for the rest of the Chilean population, and bronchiectasis death rates were 12 times higher. In cases where exposure occurred both prenatally and in early childhood, lung cancer death rates were 6 times higher and bronchiectasis death rates were 46 times higher than those for the rest of the population.The authors believe these results describe the highest increase in death rates for arsenic-related lung cancer and bronchiectasis ever documented among young adults, and add that this study is one of the first to provide evidence of human adult disease resulting from prenatal and early childhood exposure to any environmental toxicant. They conclude that an increase in young adult mortality should be of concern to public health officials, and should influence future decisions regarding sources of drinking water.A big gulp of newsThe link between early arsenic exposure and later lung disease is the first such association to be confirmed in humans.FiguresReferencesRelatedDetailsRelated articlesIncreased Mortality from Lung Cancer and Bronchiectasis in Young Adults after Exposure to Arsenic in Utero and in Early Childhood27 March 2006Environmental Health Perspectives Vol. 114, No. 8 August 2006Metrics About Article Metrics Publication History Originally published1 August 2006Published in print1 August 2006 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.