Health Effects Of Arsenic Longitudinal Study Research Articles

Extracellular Vesicle-Encapsulated microRNAs as Novel Biomarkers of Lung Health.

Rationale: Early detection of respiratory diseases is critical to facilitate delivery of disease-modifying interventions. Extracellular vesicle-enriched microRNAs (EV-miRNAs) may represent reliable markers of early lung injury. Objectives: Evaluate associations of plasma EV-miRNAs with lung function. Methods: The prospective NAS (Normative Aging Study) collected plasma EV-miRNA measurements from 1996-2015 and spirometry every 3-5 years through 2019. Associations of EV-miRNAs with baseline lung function were modeled using linear regression. To complement the individual miRNA approach, unsupervised machine learning was used to identify clusters of participants with distinct EV-miRNA profiles. Associations of EV-miRNA profiles with multivariate latent longitudinal lung function trajectories were modeled using log binomial regression. Biological functions of significant EV-miRNAs were explored using pathway analyses. Results were replicated in an independent sample of NAS participants and in the HEALS (Health Effects of Arsenic Longitudinal Study). Measurements and Main Results: In the main cohort of 656 participants, 51 plasma EV-miRNAs were associated with baseline lung function (false discovery rate-adjusted P value < 0.05), 28 of which were replicated in the independent NAS sample and/or in the HEALS cohort. A subset of participants with distinct EV-miRNA expression patterns had increased risk of declining lung function over time, which was replicated in the independent NAS sample. Significant EV-miRNAs were shown in pathway analyses to target biological pathways that regulate respiratory cellular immunity, the lung inflammatory response, and airway structural integrity. Conclusions: Plasma EV-miRNAs may represent a robust biomarker of subclinical lung injury and may facilitate early identification and treatment of patients at risk of developing overt lung disease.

Mixed metals exposure and cognitive function in Bangladeshi adolescents

BackgroundOver 57 million people in Bangladesh have been chronically exposed to arsenic-contaminated drinking water. They also face environmental exposure to elevated levels of cadmium (Cd), manganese (Mn), and lead (Pb), all of which have been previously observed in environmental and biological samples for this population. These metals have been linked to adverse neurocognitive outcomes in adults and children, though their effects on adolescents are not yet fully characterized. Additionally, previous studies have linked selenium (Se) to protective effects against the toxicity of these other metals. ObjectivesTo examine the associations between mixed metals exposure and cognitive function in Bangladeshi adolescents. MethodsThe Metals, Arsenic, & Nutrition in Adolescents study (MANAs) is a cross-sectional study of 572 Bangladeshi adolescents aged 14–16 years, whose parents were enrolled in the Health Effects of Arsenic Longitudinal Study (HEALS). Biosamples were collected from these adolescents for measurement of whole blood metalloid/metal levels of As, Cd, Mn, Pb, and Se. Participants also completed an abbreviated version of The Cambridge Neuropsychological Test Automated Battery (CANTAB), a cognitive function test designed to measure performance across several aspects of executive function. Linear regression was used to examine associations for each metal while controlling for the other metals. Bayesian Kernel Machine Regression (BKMR) assessed the overall mixture effect in addition to confirming the effects of individual metal components observed via linear regression. ResultsLinear regression revealed negative associations for Spatial Working Memory and both As and Mn (As B=−2.40, Mn B=−5.31, p < 0.05). We also observed negative associations between Cd and Spatial Recognition Memory (B=−2.77, p < 0.05), and Pb and Delayed Match to Sample, a measure of visual recognition and memory (B=−3.67, p < 0.05). Finally, we saw a positive association for Se and Spatial Span Length (B=0.92, p < 0.05). BKMR results were largely consistent with the regression analysis, showing meaningful associations for individual metals and CANTAB subtests, but no overall mixture effect. Via BKMR, we observed negative associations between Pb and Delayed Match to Sample, and Cd and Spatial Recognition Memory; this analysis also showed positive associations for Se and the Planning, Reaction Time, and Spatial Span subtests. BKMR posterior inclusion probability consistently reported that Se, the only component of the mixture to show a positive association with cognition, was the most important member of the mixture. ConclusionsOverall, we found Se to be positively associated with cognition, while Mn and As were linked to poorer working memory, and Cd and Pb were associated with poorer visual recognition and memory. Our observations are consistent with previous reports on the effects of these metal exposures in adults and children. Our findings also suggest agreement between linear regression and BKMR methods for analyzing metal mixture exposures. Additional studies are needed to evaluate the impact of mixed metals exposure on adverse health and poorer cognition later in life for those exposed during adolescence. Findings also suggest that metal exposure mitigation efforts aimed at adolescents might influence lifelong cognitive outcomes in regions where environmental exposure to metals is endemic.

Arsenic exposure from drinking water and endothelial dysfunction in Bangladeshi adolescents

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, with ∼80% of CVD-related deaths occurring in low- and middle-income countries. Growing evidence suggests that chronic arsenic exposure may contribute to CVD through its effect on endothelial function in adults. However, few studies have examined the influence of arsenic exposure on cardiovascular health in children and adolescents. To examine arsenic's relation to preclinical markers of endothelial dysfunction, we enrolled 200 adolescent children (ages 15–19 years; median 17) of adult participants in the Health Effects of Arsenic Longitudinal Study (HEALS), in Araihazar, Bangladesh. Participants' arsenic exposure was determined by recall of lifetime well usage for drinking water. As part of HEALS, wells were color-coded to indicate arsenic level (<10 μg/L, 10–50 μg/L, >50 μg/L). Endothelial function was measured by recording fingertip arterial pulsatile volume change and reactive hyperemia index (RHI) score, an independent CVD risk factor, was calculated from these measurements. In linear regression models adjusted for participant's sex, age, education, maternal education, land ownership and body weight, individuals who reported always drinking water from wells with >50 μg/L arsenic had a 11.75% lower level of RHI (95% CI: −21.26, −1.09, p = 0.03), as compared to participants who drank exclusively from wells with ≤50 μg/L arsenic. Sex-stratified analyses suggest that these associations were stronger in female participants. As compared to individuals who drank exclusively from wells with ≤50 μg/L arsenic, the use of wells with >50 μg/L arsenic was associated with 14.36% lower RHI (95% CI: −25.69, −1.29, p = 0.03) in females, as compared to 5.35% lower RHI (95% CI: −22.28, 15.37, p = 0.58) in males for the same comparison. Our results suggest that chronic arsenic exposure may be related to endothelial dysfunction in adolescents, especially among females. Further work is needed to confirm these findings and examine whether these changes may increase risk of later adverse cardiovascular health events.

A mass-balance model to assess arsenic exposure from multiple wells in Bangladesh.

Background:Water arsenic (As) sources beyond a rural household’s primary well may be a significant source for certain individuals, including schoolchildren and men working elsewhere.Objective:To improve exposure assessment by estimating the fraction of drinking water that comes from wells other than the household’s primary well in a densely populated area.Methods:We use well-water and urinary As data collected in 2000–01 within a 25 km2 area of Araihazar upazila, Bangladesh, for 11,197 participants in the Health Effects of Arsenic Longitudinal Study (HEALS). We estimate the fraction of water that participants drink from different wells by imposing a long-term mass-balance constraint for both As and water.Results:The mass-balance model suggest that, on average, HEALS participants obtain 60–75% of their drinking water from their primary household wells and 25–40% from other wells, in addition to water from food and cellular respiration. Because of this newly quantified contribution from other wells, As in drinking water rather than rice was identified as the largest source of As exposure at baseline for HEALS participants with a primary household well containing ≤50 μg/L As.Significance:Dose-response relationships for As based on water As should take into account other wells. The mass-balance approach could be applied to study other toxicants.

Water arsenic exposure and endothelial dysfunction in Bangladeshi adolescents

BACKGROUND AND AIM: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide, with ~80% of CVD-related deaths occurring in low- and middle-income countries. Growing evidence suggests that chronic arsenic (As) exposure may contribute to CVD through its effect on endothelial dysfunction in adults. However, few studies have examined the influence of As exposure on cardiovascular health in children and adolescents. METHODS: To examine As’s relation to preclinical markers of endothelial dysfunction, we enrolled 200 adolescent children (ages 15-19 years; median: 17) of adult participants in the Health Effects of Arsenic Longitudinal Study (HEALS), in Araihazar, Bangladesh. Participant’s water As exposure was determined by recall of lifetime well usage. Wells are color coded to indicate As level (10 µg/L, 10-50 µg/L, 50 µg/L As). Endothelial function was measured by recording fingertip arterial pulsatile volume change using Endo-PAT2000 (Itamar Medical) and reactive hyperemia index (RHI) score, an independent CVD risk factor, was calculated from these measurements. RESULTS:In linear regression models adjusted for sex, age, education and weight at the time of RHI measurement, individuals who reported always using wells with ≥50 µg/L As had a lower level of RHI by 11.62% (95% CI: -20.94, -1.16, p=0.03), as compared to participants who drank exclusively from wells with 50 µg/L As. Sex-stratified analyses suggest that these associations were stronger in female participants. The use of wells with ≥50 µg/L As was associated with 14.87% lower RHI (95% CI: -25.59, -2.60, p=0.02) in females, as compared to 5.05% lower RHI (95% CI: -21.81, 15.29, p=0.60) in males for the same comparison. CONCLUSIONS:Our results suggest that chronic As exposure may be related to endothelial dyfunction and vascular reactivity in adolescents, with potential differences by sex. Further work is needed to confirm these findings and examine whether these changes may increase risk of later adverse cardiovascular health effects. KEYWORDS: Arsenic, adolescents, cardiovascular health, endothelial function, Bangladesh

Reliability of a computer-based neurobehavioral assessment test battery for Bangladeshi adolescent children

In developing countries, there is a need for low-cost neurobehavioral (NB) test batteries for vulnerable populations, particularly for children exposed to environmental neurotoxicants. The objective of the current study was to assess the feasibility and test-retest reliability of the Behavioral Assessment and Research System (BARS) in children from a rural community in Bangladesh. Fifty healthy adolescents living in the Health Effects of Arsenic Longitudinal Study (HEALS) area in Araihazar, Bangladesh completed all six tests from the BARS in two test sessions scheduled two weeks apart. The BARS tests evaluated NB functions such as motor coordination, attention, memory, and information processing speed. The reliability assessment, evaluated by test-retest correlations demonstrated moderate to strong correlations (i.e., correlation coefficients ranged from 0.43 to 0.85), which were statistically significant (p < 0.05). Paired t-tests for comparing the test and retest outcomes indicated significant improvement in NB performance, highlighting learning and practice effects. NB performance improved with increasing age in most cases. Adolescent boys performed better than the girls in Finger Tapping, Digit Span, and Simple Reaction Time, whereas the girls performed better in Continuous Performance and Symbol Digit tests. The reliability scores (Pearson’s correlations 0.43−0.85) were consistent with other children studies in different cultural settings. The effects of age and sex on NB tests were also consistent with findings reported in other countries. Overall, the findings of the study support the feasibility of using this computer-based test system to assess vulnerability of brain health due to environmental exposures among rural Bangladeshi children.

Rare, Protein-Altering Variants in AS3MT and Arsenic Metabolism Efficiency: A Multi-Population Association Study.

Background:Common genetic variation in the arsenic methyltransferase (AS3MT) gene region is known to be associated with arsenic metabolism efficiency (AME), measured as the percentage of dimethylarsinic acid (DMA%) in the urine. Rare, protein-altering variants in AS3MT could have even larger effects on AME, but their contribution to AME has not been investigated.Objectives:We estimated the impact of rare, protein-coding variation in AS3MT on AME using a multi-population approach to facilitate the discovery of population-specific and shared causal rare variants.Methods:We generated targeted DNA sequencing data for the coding regions of AS3MT for three arsenic-exposed cohorts with existing data on arsenic species measured in urine: Health Effects of Arsenic Longitudinal Study (HEALS, ), Strong Heart Study (SHS, ), and New Hampshire Skin Cancer Study (NHSCS, ). We assessed the collective effects of rare (allele frequency ), protein-altering AS3MT variants on DMA%, using multiple approaches, including a test of the association between rare allele carrier status (yes/no) and DMA% using linear regression (adjusted for common variants in 10q24.32 region, age, sex, and population structure).Results:We identified 23 carriers of rare-protein-altering AS3MT variant across all cohorts (13 in HEALS and 5 in both SHS and NHSCS), including 6 carriers of predicted loss-of-function variants. DMA% was 6–10% lower in carriers compared with noncarriers in HEALS [ (95% CI: , )], SHS [ (95% CI: , )], and NHSCS [ (95% CI: , )]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ (95% CI: , )].Discussion:Rare, protein-altering variants in AS3MT were associated with lower mean DMA%, an indicator of reduced AME. Although a small percentage of the population (0.5–0.7%) carry these variants, they are associated with a 6–10% decrease in DMA% that is consistent across multiple ancestral and environmental backgrounds. https://doi.org/10.1289/EHP8152

Early life and adolescent arsenic exposure from drinking water and blood pressure in adolescence

OPS 24: Drinking water contamination and children’s health, Room 411, Floor 4, August 27, 2019, 10:30 AM - 12:00 PM Background: Inorganic arsenic (As) exposure from drinking water has been related to cardiovascular disease and increased blood pressure (BP) in adults. However, evidence of the association between inorganic As exposure, especially early-life exposure, and BP in adolescence is limited. Methods: We conducted a cross-sectional study of 726 adolescents aged 14–17 (mean 14.75) years whose mothers were participants in the Bangladesh Health Effects of Arsenic Longitudinal Study (HEALS). Adolescents’ BP was measured at the time of their recruitment between December 2012 and December 2016. We considered maternal urinary As (UAs) which was repeatedly measured during childhood as proxy measures of early childhood (< 5 years old, T1) and childhood (5-12 years old, T2) exposure and current UAs from the adolescents at the time of the recruitment (14-17 years of age, T3). Results: Every doubling of UAs at T3 and maternal UAs at T1 was positively associated with a difference of 0.7-mmHg (95% confidence interval [CI]: 0.1, 1.3) and a 0.7-mmHg (95% CI: 0.05, 1.4) in SBP, respectively. These associations were stronger in adolescents with a BMI above the median (17.7 kg/m2) than those with a BMI below the median (P for interaction = 0.03 and 0.03, respectively). There was no significant association between any of the exposure measures and DBP. Mixture analyses using Bayesian Kernel Machine Regression identified UAs at T3 as a significant contributor to SBP and DBP independent of other concurrent blood levels of cadmium, lead, manganese, and selenium. Conclusions: Our findings suggest an association of current exposure and early childhood exposure to As with higher BP in adolescents, which may be exacerbated by higher BMI at adolescence.

Early life and adolescent arsenic exposure from drinking water and blood pressure in adolescence

ObjectivesEvidence of the association between inorganic arsenic (As) exposure, especially early-life exposure, and blood pressure (BP) in adolescence is limited. We examined the association of As exposure during early childhood, childhood, and adolescence with BP in adolescence. MethodsWe conducted a cross-sectional study of 726 adolescents aged 14–17 (mean 14.75) years whose mothers were participants in the Bangladesh Health Effects of Arsenic Longitudinal Study (HEALS). Adolescents' BP was measured at the time of their recruitment between December 2012 and December 2016. We considered maternal urinary As (UAs), repeatedly measured during childhood, as proxy measures of early childhood (<5 years old, A1) and childhood (5–12 years old, A2) exposure. Adolescents’ current UAs was collected at the time of recruitment (14–17 years of age, A3). ResultsEvery doubling of UAs at A3 and maternal UAs at A1 was positively associated with a difference of 0.7-mmHg (95% confidence interval [CI]: 0.1, 1.3) and a 0.7-mmHg (95% CI: 0.05, 1.4) in SBP, respectively. These associations were stronger in adolescents with a BMI above the median (17.7 kg/m2) than those with a BMI below the median (P for interaction = 0.03 and 0.03, respectively). There was no significant association between any of the exposure measures and DBP. The Weighted Quantile Sum (WQS) regression confirmed that adolescents’ UAs at A3 and maternal UAs at A1 contributed the most to the overall effect of As exposure at three life stages on SBP. Mixture analyses using Bayesian Kernel Machine Regression identified UAs at A3 as a significant contributor to SBP and DBP independent of other concurrent blood levels of cadmium, lead, manganese, and selenium. ConclusionOur findings suggest an association of current exposure and early childhood exposure to As with higher BP in adolescents, which may be exacerbated by higher BMI at adolescence.

Changes in human peripheral blood mononuclear cell (HPBMC) populations and T-cell subsets associated with arsenic and polycyclic aromatic hydrocarbon exposures in a Bangladesh cohort.

Exposures to environmental arsenic (As) and polycyclic aromatic hydrocarbons (PAH) have been shown to independently cause dysregulation of immune function. Little data exists on the associations between combined exposures to As and PAH with immunotoxicity in humans. In this work we examined associations between As and PAH exposures with lymphoid cell populations in human peripheral blood mononuclear cells (PBMC), as well as alterations in differentiation and activation of B and T cells. Two hundred men, participating in the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh, were selected for the present study based on their exposure to As from drinking water and their cigarette smoking status. Blood and urine samples were collected from study participants. We utilized multiparameter flow cytometry in PBMC to identify immune cells (B, T, monocytes, NK) as well as the T-helper (Th) cell subsets (Th1, Th2, Th17, and Tregs) following ex vivo activation. We did not find evidence of interactions between As and PAH exposures. However, individual exposures (As or PAH) were associated with changes to immune cell populations, including Th cell subsets. Arsenic exposure was associated with an increase in the percentage of Th cells, and dose dependent changes in monocytes, NKT cells and a monocyte subset. Within the Th cell subset we found that Arsenic exposure was also associated with a significant increase in the percentage of circulating proinflammatory Th17 cells. PAH exposure was associated with changes in T cells, monocytes and T memory (Tmem) cells and with changes in Th, Th1, Th2 and Th17 subsets all of which were non-monotonic (dose dependent). Alterations of immune cell populations caused by environmental exposures to As and PAH may result in adverse health outcomes, such as changes in systemic inflammation, immune suppression, or autoimmunity.

The association between gut microbiome and anthropometric measurements in Bangladesh

ABSTRACTOur objective was to investigate the relationship between the gut microbiota and anthropometric measurements among 248 participants from the Health Effects of Arsenic Longitudinal Study (HEALS) in Bangladesh. Our cohort represents a unique population that allows for the investigation of the gut microbiota and anthropometric measurements in lean individuals. We measured height, weight, arm, thigh, hip, and waist circumferences, and collected fecal samples. Microbial DNA was extracted from the stool samples and sequenced by 16S rRNA gene sequencing. We examined associations between relative abundance of individual bacterial taxa from phylum to genus levels and anthropometric measurements. We found that higher BMI, mid-upper arm circumference, waist circumference, and waist-to-hip ratio were associated with a lower alpha diversity of fecal bacteria. Relative abundance of the genus Oscillospira and the family S24-7 were inversely related to all measurements after correction for multiple testing. Relative abundance of genus Acidaminococcus and family Ruminococcaceae were also associated with several measurements. The positive associations of the genus Acidaminococcus with BMI, as well as waist and hip circumferences, were stronger in women than in men. Our data in this lean Bangladeshi population found a correlation between Oscillospira and leanness, as measured using multiple anthropometric measures.

Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults.

Background:Arsenic exposure affects people worldwide, including in Bangladesh. Arsenic exposure increases the risk of cancer and other chronic diseases, and one potential mechanism of arsenic toxicity is epigenetic dysregulation.Objective:We assessed associations between arsenic exposure and genome-wide DNA methylation measured at baseline among 396 Bangladeshi adults participating in the Health Effects of Arsenic Longitudinal Study (HEALS) who were exposed by drinking naturally contaminated well water.Methods:Methylation in whole blood DNA was measured at using the Illumina InfiniumMethylationEPIC (EPIC) array. To assess associations between arsenic exposure and CpG methylation, we used linear regression models adjusted for covariates and surrogate variables (SVs) (capturing unknown technical and biologic factors). We attempted replication and conducted a meta-analysis using an independent dataset of from 400 Bangladeshi individuals with arsenical skin lesions.Results:We identified 34 CpGs associated with creatinine-adjusted urinary arsenic []. Sixteen of these CpGs annotated to the array, and 10 associations were replicated (). The top two CpGs annotated upstream of the ABR gene (cg01912040, cg10003262). All urinary arsenic–associated CpGs were also associated with arsenic concentration measured in drinking water (). Meta-analysis ( samples) identified 221 urinary arsenic–associated CpGs (). The arsenic-associated CpGs from the meta-analysis were enriched in non-CpG islands and shores () and depleted in promoter regions (). Among the arsenic-associated CpGs (), we observed significant enrichment of genes annotating to the reactive oxygen species pathway, inflammatory response, and tumor necrosis factor () signaling via nuclear factor kappa-B () hallmarks ().Conclusions:The novel and replicable associations between arsenic exposure and DNA methylation at specific CpGs observed in this work suggest that epigenetic alterations should be further investigated as potential mediators in arsenic toxicity and as biomarkers of exposure and effect in exposed populations. https://doi.org/10.1289/EHP3849

Thyroid hormones and neurobehavioral functions among adolescents chronically exposed to groundwater with geogenic arsenic in Bangladesh

Groundwater, the major source of drinking water in Bengal Delta Plain, is contaminated with geogenic arsenic (As) enrichment affecting millions of people. Children exposed to tubewell water containing As may be associated with thyroid dysfunction, which in turn may impact neurodevelopmental outcomes. However, data to support such relationship is sparse. The purpose of this study was to examine if chronic water As (WAs) from Holocene alluvial aquifers in this region was associated with serum thyroid hormone (TH) and if TH biomarkers were related to neurobehavioral (NB) performance in a group of adolescents. A sample of 32 healthy adolescents were randomly drawn from a child cohort in the Health Effects of Arsenic Longitudinal Study (HEALS) in Araihazar, Bangladesh. Half of these participants were consistently exposed to low WAs (<10 μg/L) and the remaining half had high WAs exposure (≥10 μg/L) since birth. Measurements included serum total triiodothyronine (tT3), free thyroxine (fT4), thyrotropin (TSH) and thyroperoxidase antibodies (TPOAb); concurrent WAs and urinary arsenic (UAs); and adolescents' NB performance. WAs and UAs were positively and significantly correlated with TPOAb but were not correlated with TSH, tT3 and fT4. After accounting for covariates, both WAs and UAs demonstrated positive but non-significant relationships with TSH and TPOAb and negative but non-significant relationships with tT3 and fT4. TPOAb was significantly associated with reduced NB performance indicated by positive associations with latencies in simple reaction time (b = 82.58; p < 0.001) and symbol digit (b = 276.85; p = 0.005) tests. TSH was significantly and negatively associated with match-to-sample correct count (b = −0.95; p = 0.05). Overall, we did not observe significant associations between arsenic exposure and TH biomarkers although the relationships were in the expected directions. We observed TH biomarkers to be related to reduced NB performance as hypothesized. Our study indicated a possible mechanism of As-induced neurotoxicity, which requires further investigations for confirmatory findings.

A missense variant in FTCD is associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

Inorganic arsenic (iAs) is a carcinogen, and exposure to iAs via food and water is a global public health problem. iAs-contaminated drinking water alone affects >100 million people worldwide, including ~50 million in Bangladesh. Once absorbed into the blood stream, most iAs is converted to mono-methylated (MMA) and then di-methylated (DMA) forms, facilitating excretion in urine. Arsenic metabolism efficiency varies among individuals, in part due to genetic variation near AS3MT (arsenite methyltransferase; 10q24.32). To identify additional arsenic metabolism loci, we measured protein-coding variants across the human exome for 1,660 Bangladeshi individuals participating in the Health Effects of Arsenic Longitudinal Study (HEALS). Among the 19,992 coding variants analyzed exome-wide, the minor allele (A) of rs61735836 (p.Val101Met) in exon 3 of FTCD (formiminotransferase cyclodeaminase) was associated with increased urinary iAs% (P = 8x10-13), increased MMA% (P = 2x10-16) and decreased DMA% (P = 6x10-23). Among 2,401 individuals with arsenic-induced skin lesions (an indicator of arsenic toxicity and cancer risk) and 2,472 controls, carrying the low-efficiency A allele (frequency = 7%) was associated with increased skin lesion risk (odds ratio = 1.35; P = 1x10-5). rs61735836 is in weak linkage disequilibrium with all nearby variants. The high-efficiency/major allele (G/Valine) is human-specific and eliminates a start codon at the first 5´-proximal Kozak sequence in FTCD, suggesting selection against an alternative translation start site. FTCD is critical for catabolism of histidine, a process that generates one-carbon units that can enter the one-carbon/folate cycle, which provides methyl groups for arsenic metabolism. In our study population, FTCD and AS3MT SNPs together explain ~10% of the variation in DMA% and support a causal effect of arsenic metabolism efficiency on arsenic toxicity (i.e., skin lesions). In summary, this work identifies a coding variant in FTCD associated with arsenic metabolism efficiency, providing new evidence supporting the established link between one-carbon/folate metabolism and arsenic toxicity.

Changes in arsenic exposure in Araihazar, Bangladesh from 2001 through 2015 following a blanket well testing and education campaign

BackgroundConcentrations of arsenic (As) are elevated in a large proportion of wells in Bangladesh but are spatially variable even within a village. This heterogeneity can enable exposed households to switch to a nearby well lower in As in response to blanket (area-wide) well As testing. ObjectivesWe document the evolution of As exposure in Araihazar, Bangladesh following a blanket well testing and education campaign, as well as the installation of a considerable number of low As community wells. MethodsWe use well water and urinary As data collected between 2000 and 2008, along with household interviews extending through 2016, within a 25 km2 area of Araihazar upazila for nearly 12,000 participants enrolled in the Health Effects of Arsenic Longitudinal Study (HEALS). We observe changes in participants' well water and urinary As concentrations following interventions to lower their exposure and use logistic regression to determine the factors associated with participants' decisions to switch primary household wells. ResultsUrinary As for participants drinking from wells with >100 μg/L As at baseline declined from a mean of 226 μg/L at baseline to 173 μg/L two years later, and further declined to 139 μg/L over 8 years. For comparison, urinary As concentrations for participants drinking from wells with ≤10 μg/L As remained close to 50 μg/L throughout. Whereas the interventions only partially reduced exposure, well status with respect to As was predictive of well-switching decisions for at least a decade after the initial testing. Participants with high-As wells were 7 times more likely to switch wells over the first two years and 1.4–1.8 times more likely to switch wells over the ensuing decade. ConclusionsArsenic exposure gradually declined following blanket well testing, an education campaign, and the installation of community wells but remained almost three times higher than for a subgroup of the participants drinking from wells with ≤10 μg/L. In addition, the number of participants with unknown As concentrations in their primary household wells increased substantially over time, indicating the importance of additional well testing as new wells continue to be installed, in addition to other means of reducing As exposure.

Exposure to low-dose arsenic in early life alters innate immune function in children

Early-life exposure to arsenic (As) increases risks of respiratory diseases/infections in children. However, data on the ability of the innate immune system to combat bacterial infections in the respiratory tracts of As-exposed children are scarce. To evaluate whether persistent low-dose As exposure alters innate immune function among children younger than 5 years-of-age, mothers and participating children (N = 51) that were members of the Health Effects of Arsenic Longitudinal Study (HEALS) cohort in rural Bangladesh were recruited. Household water As, past and concurrent maternal urinary As (U-As) as well as child U-As were all measured at enrollment. In addition, U-As metabolites were evaluated. Innate immune function was examined via measures of cathelicidin LL-37 in plasma, ex vivo monocyte-derived-macrophage (MDM)-mediated killing of Streptococcus pneumoniae (Spn), and serum bactericidal antibody (SBA) responses against Haemophilus influenzae type b (Hib). Cyto-/chemokines produced by isolated peripheral blood mononuclear cells (PBMC) were assayed using a Multiplex system. Multivariable linear regression analyses revealed that maternal (p < 0.01) and child (p = 0.02) U-As were positively associated with plasma LL-37 levels. Decreased MDM-mediated Spn killing (p = 0.05) and SBA responses (p = 0.02) were seen to be each associated with fractions of mono-methylarsonic acid (MMA; a U-As metabolite) in the children. In addition, U-As levels were seen to be negatively associated with PBMC formation of fractalkine and IL-7, and positively associated with that for IL-13, IL-17 and MIP-1α. These findings suggested that early-life As exposure may disrupt the innate host defense pathway in these children. It is possible that such disruptions may have health consequences later in life.

Urinary metals and metal mixtures in Bangladesh: Exploring environmental sources in the Health Effects of Arsenic Longitudinal Study (HEALS)

IntroductionEnvironmental exposure to toxic metals and metalloids is pervasive and occurs from multiple sources. The Health Effects of Arsenic Longitudinal Study (HEALS) is an ongoing prospective study predominantly focused on understanding health effects associated with arsenic exposure from drinking water. The goal of this project was to measure a suite of elements in urine to better understand potential exposure patterns and to identify common environmental sources of exposure among this semi-rural Bangladeshi population. MethodsIn a random sample of 199 adult HEALS participants (50% female), the concentrations of 15 urinary elements (As, Ba, Cd, Co, Cs, Cu, Mn, Mo, Ni, Pb, Se, Sr, Tl, W, Zn) were assessed by Inductively-Coupled Plasma Mass Spectrometry (ICP-MS) to assess commonalities with sociodemographic characteristics and potential sources of exposure. We used principal component analysis (PCA) with varimax normalized rotations, and hierarchical cluster analysis (CA), using Ward's method with Euclidean distances, to evaluate these relationships. ResultsPCA and CA showed similar patterns, suggesting 6 principal components (PC) and 5 clusters: 1)PC: Sr-Ni-Cs/ CA: Sr-Ni-Co; 2) Pb-Tl/Pb-Tl-Se-Cs; 3) As-Mo-W/As-Mo-W; 4) Ba-Mn/Ba-Mn; 5) Cu-Zn/Cu-Zn-Cd; and 6) Cd. There was a strong significant association between the As-Mo-W PC/cluster and water arsenic levels (p < 0.001) and between the Cd PC and betel nut use (p = 0.003). The Sr-Ni-Cs PC was not related to any of the socio-demographic characteristics investigated, including smoking status and occupation. The first PC, Sr-Ni-Cs, explained 21% of the variability; the third PC, As-Mo-W, explained 12.5% of the variability; and the sixth PC, Cd, explained 10% of the variability. Day laborers appeared to have the highest exposure. ConclusionsGroundwater and betel nut use are likely important sources of metal and metalloid exposure in this population. These findings will guide future exposure assessment research in Bangladesh and future epidemiologic research investigating the degree to which metal mixtures play a role in disease development.

Metal Exposure as a Mixture and Intellectual Function in Adolescence in Bangladesh

Background: Exposure to inorganic arsenic (As) is associated with modest deficits in intellectual function in young children. Few studies have examined associations in adolescence or whether co-exposure to other metals such as manganese (Mn), lead (Pb), cadmium (Cd), and selenium (Se) affects the association.Objective: We evaluated whether concurrent exposure to As (as creatinine-adjusted urinary As (UAs/Cr)), the afore-listed metals in blood, and maternal UAs/Cr at baseline, a proxy for peri-natal As exposure, were associated with adolescent intellectual function.Methods: The sample comprises 726 14-16-year-olds whose mothers are participants in the Bangladesh Health Effects of Arsenic Longitudinal Study (HEALS). We used a culturally modified version of the Wechsler Intelligence Scale for Children (WISC-IV) to measure Full Scale raw scores and Bayesian Kernel Machine Regression (BKMR) to investigate the joint effects of the metals mixture on these scores. BKMR uses a flexible kernel function to identify important mixture members while accounting for the correlated exposure structure, to estimate potentially nonlinear exposure-response functions, and to evaluate complex and potentially non-additive interactions.Results: Adolescent UAs/Cr, followed by Cd, were the two most important metals in the mixture, with posterior inclusion probabilities of 95.2% and 83.2%, respectively. Both adolescent UAs/Cr and Cd were significantly associated with decreased Full Scale scores. No significant interactions between metals were observed. The overall mixture (i.e., simultaneous exposure to all metals) was consistently significantly associated with decreased Full Scale scores.Conclusion: Our findings indicate that adolescent exposure to the metals mixtures, and predominantly to As and Cd, may be neurotoxic and deserves more attention.

The Impact of Arsenic Exposure on Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults

Background: Arsenic exposure affects &amp;gt;200 million people worldwide, including ~56 million in Bangladesh. Arsenic exposure increases the risk of chronic disease, and one potential mechanism of arsenic toxicity is epigenetic dysregulation of DNA methylation.Objective: We assessed associations between arsenic exposure and genome-wide DNA methylation among 396 Bangladeshi adults participating in the Health Effects of Arsenic Longitudinal Study (HEALS), who were exposed by drinking naturally-contaminated well water.Methods: Methylation in whole blood DNA was measured at ~850,000 CpGs using the Illumina EPIC array. To assess associations between arsenic exposure and CpG methylation, we used multivariate linear regression models adjusted for covariates and surrogate variables (capturing unknown technical and biologic factors). We attempted replication and conducted a meta-analysis using an independent set of 400 exposed Bangladeshi adults with data on ~450,000 CpGs.Results: We identified nine CpGs associated with urine arsenic exposure (Bonferroni-corrected threshold p&amp;lt;6.5x10-8). Four of these CpGs annotated to the 450K array and all robustly replicated (p&amp;lt;10-3). The top two CpGs annotated upstream of ABR (cg01912040, cg10003262). All urine arsenic-associated CpGs were also associated with arsenic measured in drinking water (p&amp;lt;0.05). Meta-analysis (n&amp;#61;796) identified 33 urine arsenic-associated CpGs (Bonferroni-corrected threshold p&amp;lt;1.3x10-7). Among meta-analysis arsenic associated CpGs, gene-specific expression and methylation was associated for six CpGs (p&amp;lt;0.05) and associated CpGs annotated to three genes (EFNA1, SPSB1, SQSTM1) in the TNF&amp;#945; signaling via NF&amp;#954;B pathway (enrichment p&amp;#61;7.7x10-4).Conclusions: The robust associations between arsenic exposure and DNA methylation observed in this work suggest that epigenetic alterations may be important mediators in arsenic toxicity and could be further investigated as biomarkers of exposure and effect in exposed populations.

Identifying Environmental Sources of Metal Mixtures in Bangladesh: A Pilot Study from the Health Effects of Arsenic Longitudinal Study (HEALS)

Identifying Environmental Sources of Metal Mixtures in Bangladesh: A Pilot Study from the Health Effects of Arsenic Longitudinal Study (HEALS)