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Detailed LC-MS/MS instrumentation settings for global %5-mC and %5-hmC analysis

Background: Posttranslational histone modifications (PTHMs) are altered by arsenic, an environmental carcinogen. PTHMs are also influenced by nutritional methyl donors involved in one-carbon metabolism (OCM), which may protect against epigenetic dysregulation.Methods: We measured global levels of three PTHMs, which are dysregulated in cancers (H3K36me2, H3K36me3, H3K79me2), in peripheral blood mononuclear cells (PBMC) from 324 participants enrolled in the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults. Sex-specific associations between several blood OCM indices (folate, vitamin B12, choline, betaine, homocysteine) and PTHMs were examined at baseline using regression models, adjusted for multiple tests by controlling for the false discovery rate (PFDR). We also evaluated the effects of folic acid supplementation (400 μg/d for 12 weeks), compared with placebo, on PTHMs.Results: Associations between choline and H3K36me2 and between vitamin B12 and H3K79me2 differed significantly by sex (Pdiff < 0.01 and PFDR < 0.05), and among women, plasma vitamin B12 was positively associated with H3K79me2 (PFDR < 0.01). Folic acid supplementation did not alter any of the PTHMs examined (PFDR = 0.80).Conclusions: OCM indices may influence PTHMs in a sex-dependent manner, and folic acid supplementation, at this dose and duration, does not alter PTHMs in PBMCs.Impact: This is the first study to examine the influences of OCM indices on PTHMs in a population that may have increased susceptibility to cancer development due to widespread exposure to arsenic-contaminated drinking water and a high prevalence of hyperhomocysteinemia. Cancer Epidemiol Biomarkers Prev; 26(2); 261–9. ©2016 AACR.

Supplementary Table S1. Baseline characteristics of FACT participants with vs. without PTHM measures;Supplementary Table S2. Baseline characteristics of FACT participants with vs. without RBC folate measures; Supplementary Table S3. Associations (β (95% CI)) between OCM indices and PTHMs by sex in FACT participants, comparing models additionally adjusting for BMI; Supplementary Table S4. Associations (β (95% CI)) between OCM indices and PTHMs by sex in FACT participants, comparing models additionally adjusting for blood arsenic; Supplementary Table S5. Associations (β (95% CI))a between OCM indices and PTHMs by sex in FACT participants, comparing nutrients in model alone vs. included simultaneously;Supplementary Table S6. Associationsa between plasma OCM indices and PTHMs stratified by age and sex;Supplementary Table S7. Associationsa between plasma OCM indices and PTHMs stratified by blood arsenic and sex; Supplementary Table S8. Associationsa between changes in OCM indices and changes in PTHMs from baseline to week 12; Supplementary Figure S1. Sex-Specific Associations between OCM Indices and PTHMs in FACT Participants with RBC Folate Measures

Table S1. Percentages for select baseline characteristic for 20,033 HEALS participants and subsetted based on those who have metabolite data (4794) and those who had metabolite data and were genotyped (2060). Supplemental Material, Table S2. Odds ratios and 95% confidence intervals for the association between baseline characteristics and skin lesion status (prevalent and incident (n=1,575) vs. none (n=1,780)). Supplemental Material, Table S3. Odds ratios and 95% confidence intervals for the association between quartiles of PCs and skin lesion status (prevalent+incident (n=1575) vs. none (n=1780))

Background: Depletion of global 5-hydroxymethylcytosine (5-hmC) is observed in human cancers and is strongly implicated in skin cancer development. Although arsenic (As)—a class I human carcinogen linked to skin lesion and cancer risk—is known to be associated with changes in global %5-methylcytosine (%5-mC), its influence on 5-hmC has not been widely studied.Methods: We evaluated associations of As in drinking water, urine, and blood with global %5-mC and %5-hmC in two studies of Bangladeshi adults: (i) leukocyte DNA in the Nutritional Influences on Arsenic Toxicity study (n = 196; 49% male, 19–66 years); and (ii) peripheral blood mononuclear cell DNA in the Folate and Oxidative Stress study (n = 375; 49% male, 30–63 years).Results: Overall, As was not associated with global %5-mC or %5-hmC. Sex-specific analyses showed that associations of As exposure with global %5-hmC were positive in males and negative in females (P for interaction < 0.01). Analyses examining interactions by elevated plasma total homocysteine (tHcys), an indicator of B-vitamin deficiency, found that tHcys also modified the association between As and global %5-hmC (P for interaction < 0.10).Conclusion: In two samples, we observed associations between As exposure and global %5-hmC in blood DNA that were modified by sex and tHcys.Impact: Our findings suggest that As induces sex-specific changes in 5-hmC, an epigenetic mark that has been associated with cancer. Future research should explore whether altered %5-hmC is a mechanism underlying the sex-specific influences of As on skin lesion and cancer outcomes. Cancer Epidemiol Biomarkers Prev; 24(11); 1748–57. ©2015 AACR.

Background: Exposure to inorganic arsenic (iAs), a class I carcinogen, affects several hundred million people worldwide. Once absorbed, iAs is converted to monomethylated (MMA) and then dimethylated forms (DMA), with methylation facilitating urinary excretion. The abundance of each species in urine relative to their sum (iAs%, MMA%, and DMA%) varies across individuals, reflecting differences in arsenic metabolism capacity.Methods: The association of arsenic metabolism phenotypes with participant characteristics and arsenical skin lesions was characterized among 4,794 participants in the Health Effects of Arsenic Longitudinal Study (Araihazar, Bangladesh). Metabolism phenotypes include those obtained from principal component (PC) analysis of arsenic species.Results: Two independent PCs were identified: PC1 appears to represent capacity to produce DMA (second methylation step), and PC2 appears to represent capacity to convert iAs to MMA (first methylation step). PC1 was positively associated (P AS3MT region polymorphisms were strongly associated with PC1, but not PC2. Patterns of association for most variables were similar for PC1 and DMA%, and for PC2 and MMA% with the exception of arsenic exposure and SNP associations.Conclusions: Two distinct arsenic metabolism phenotypes show unique associations with age, sex, BMI, 10q24.32 polymorphisms, and skin lesions.Impact: This work enhances our understanding of arsenic metabolism kinetics and toxicity risk profiles. Cancer Epidemiol Biomarkers Prev; 25(2); 381–90. ©2015 AACR.

Exposure to inorganic arsenic (As) is recognized as risk factor for basal cell carcinoma (BCC). We have followed-up 7000 adults for 6 years who were exposed to As and had manifest As skin toxicity. Of them, 1.7% developed BCC (males = 2.2%, females = 1.3%). In this study, we compared transcriptome-wide RNA sequencing data from the very first 26 BCC cases and healthy skin tissue from independent 16 individuals. Genes in “ cell carcinoma pathway”, “Hedgehog signaling pathway”, and “Notch signaling pathway” were overexpressed in BCC, confirming the findings from earlier studies in BCC in other populations known to be exposed to As. However, we found that the overexpression of these known pathways was less pronounced in patients with high As exposure (urinary As creatinine ratio (UACR) > 192 µg/gm creatinine) than patients with low UACR. We also found that high UACR was associated with impaired DNA replication pathway, cellular response to different DNA damage repair mechanisms, and immune response. Transcriptomic data were not strongly suggestive of great potential for immune checkpoint inhibitors; however, it suggested lower chance of platinum drug resistance in BCC patients with high UACR compared high platinum drug resistance potential in patients with lower UACR.

Background Arsenic exposure increases the risk of several cancers in humans and contributes to genomic instability. Somatic loss of the Y chromosome (LoY) is a potential biomarker of genomic instability and cancer risk. Smoking is associated with LoY, but few other carcinogens have been investigated. We tested the cross-sectional association between arsenic exposure and LoY in leukocytes among genotyped Bangladeshi men (age 20–70 years) from the Health Effects of Arsenic Longitudinal Study. Methods We extracted the median of logR-ratios from probes on the Y chromosome (mLRR-chrY) from genotyping arrays (n = 1364) and estimated the percentage of cells with LoY (% LoY) from mLRR-chrY. We evaluated the association between arsenic exposure (measured in drinking water and urine) and LoY using multivariable linear and logistic regression models. The association between LoY and incident arsenic-induced skin lesions was also examined. Results Ten percent of genotyped men had LoY in at least 5% of cells and % LoY increased with age. Among men randomly selected for genotyping (n = 778), higher arsenic in drinking water, arsenic consumed and urinary arsenic were associated with increased % LoY (P = 0.006, P = 0.06 and P = 0.13, respectively). LoY was associated with increased risk of incident skin lesions (P = 0.008). Conclusion Arsenic exposure was associated with increased LoY, providing additional evidence that arsenic contributes to genomic instability. LoY was associated with developing skin lesions, a risk factor for cancer, suggesting that LoY may be a biomarker of susceptibility in arsenic-exposed populations. The effect of arsenic on somatic events should be further explored in cancer-prone tissue types.

Urinary As (uAs) is a biomarker of As exposure. Urinary creatinine (uCr) or specific gravity (SG) are used to correct uAs for urine dilution. However, uCr is correlated with As methylation, whereas SG has limitations in individuals with kidney damage. We aimed to evaluate which urine dilution correction methods for uAs most accurately predicted blood As (bAs). We used data from the Folic Acid and Creatine Trial (FACT; N = 541) and Folate and Oxidative Stress (FOX; N = 343) study in Bangladesh. Three linear regression models were assessed using uAs (1) adjusted for uCr or SG as separate covariates, (2) standardized for uCr or SG, i.e., uAs/uCr, and (3) adjusted for residual corrected uCr or SG following adjustment for age, sex and BMI. Median uAs/bAs for FACT and FOX were 114/8.4 and 140/12.3 µg/L. In FACT, two-fold increases in uAs adjusted for uCr or SG were related to 34% and 22% increases in bAs, respectively, with similar patterns in FOX. Across methods, models with uCr consistently had lower AIC values than SG. The uAs associations with bAs were stronger after adjustment for uCr vs. SG. Decisions regarding urine dilution methods should consider whether the study outcomes are influenced by factors such as methylation or medical conditions.

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 (

Following publication of the original article [1], the author reported that incorrect version of Tables 1, 3, 5 and 6 were published.

Background: Concentrations 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. Objectives: We 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. Methods: We 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. Results: Urinary 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. Conclusions: Arsenic 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., NIEHS grant P42 ES10349.

BACKGROUND: Arsenic exposure through drinking water persists in many regions. Inorganic As (InAs) is methylated to monomethyl-arsenical species (MMAs) and dimethyl-arsenical species (DMAs), facilitating urinary excretion. Arsenic methylation is dependent on one-carbon metabolism, which is influenced by nutritional factors such as folate and creatine. OBJECTIVE: This study investigated the effects of folic acid (FA) and/or creatine supplementation on the proportion of As metabolites in urine. DESIGN: In a 24-wk randomized, double-blinded, placebo-controlled trial, 622 participants were assigned to receive FA (400 or 800 μg per day), 3 g creatine per day, 400 μg FA + 3 g creatine per day, or placebo. The majority of participants were folate sufficient; all received As-removal water filters. From wk 12–24, half of the participants receiving FA received placebo. RESULTS: Among groups receiving FA, the mean decrease in ln(%InAs) and %MMAs and increase in %DMAs exceeded those of the placebo group at wk 6 and 12 (P

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, n=2,434), Strong Heart Study (SHS, n=868), and New Hampshire Skin Cancer Study (NHSCS, n=666). We assessed the collective effects of rare (allele frequency

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 2000-2001 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.

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 dimethyla...

Background Water-borne arsenic (As) exposure is a global health problem. Once ingested, inorganic As (iAs) is methylated to mono-methyl (MMA) and dimethyl (DMA) arsenicals via one-carbon metabolism (OCM). People with higher relative percentage of MMA (MMA%) in urine (inefficient As methylation), have been shown to have a higher risk of cardiovascular disease and several cancers but appear to have a lower risk of diabetes and obesity in populations from the US, Mexico, and Taiwan. It is unknown if this opposite pattern with obesity is present in Bangladesh, a country with lower adiposity and higher As exposure in drinking water. Objective To characterize the association between body mass index (BMI) and As methylation in Bangladeshi adults and adolescents participating in the Folic Acid and Creatine Trial (FACT); Folate and Oxidative Stress (FOX) study; and Metals, Arsenic, and Nutrition in Adolescents Study (MANAS). Methods Arsenic species (iAs, MMA, DMA) were measured in urine and blood. Height and weight were measured to calculate BMI. The associations between concurrent BMI with urine and blood As species were analyzed using linear regression models, adjusting for nutrients involved in OCM such as choline. In FACT, we also evaluated the prospective association between weight change and As species. Results Mean BMIs were 19.2/20.4, 19.8/21.0, and 17.7/18.7 kg/m2 in males/females in FACT, FOX, and MANAS, respectively. BMI was associated with As species in female but not in male participants. In females, after adjustment for total urine As, age, and plasma folate, the adjusted mean differences (95% confidence) in urinary MMA% and DMA% for a 5 kg/m2 difference in BMI were −1.21 (−1.96, −0.45) and 2.47 (1.13, 3.81), respectively in FACT, −0.66 (−1.56, 0.25) and 1.43 (−0.23, 3.09) in FOX, and −0.59 (−1.19, 0.02) and 1.58 (−0.15, 3.30) in MANAS. The associations were attenuated after adjustment for choline. Similar associations were observed with blood As species. In FACT, a 1-kg of weight increase over 2 to 10 (mean 5.4) years in males/females was prospectively associated with mean DMA% that was 0.16%/0.19% higher. Discussion BMI was negatively associated with MMA% and positively associated with %DMA in females but not males in Bangladesh; associations were attenuated after plasma choline adjustment. These findings may be related to the role of body fat on estrogen levels that can influence one-carbon metabolism, e.g. by increasing choline synthesis. Research is needed to determine whether the associations between BMI and As species are causal and their influence on As-related health outcomes.

Background Over 57 million people in Bangladesh are chronically exposed to arsenic-contaminated drinking water. Ingested inorganic arsenic (InAs) undergoes hepatic methylation generating monomethyl- (MMAs) and dimethyl- (DMAs) arsenic species in a process that facilitates urinary As (uAs) elimination. One-carbon metabolism (OCM), a biochemical pathway that is influenced by folate and vitamin B12, facilitates the methylation of As. OCM also supports nucleotide and amino acid synthesis, particularly during periods of rapid growth such as adolescence. While folate supplementation increases As methylation and lowers blood As (bAs) in adults, little data is available for adolescents. Objectives To examine the associations between OCM-related micronutrients and As methylation in Bangladeshi adolescents chronically exposed to As-contaminated drinking water. Methods We conducted a cross-sectional study of 679 Bangladeshi adolescents, including 320 boys and 359 girls aged 14–16 years. Nutritional status was assessed by red blood cell (RBC) folate, plasma folate, plasma B12 and homocysteine (Hcys). Arsenic-related outcomes included blood arsenic (bAs), urinary arsenic (uAs), and urinary arsenic metabolites expressed as a percentage of total urinary As: %InAs, %MMAs, %DMAs. Results Boys had significantly lower B12, higher Hcys, higher bAs, higher uAs, higher %MMAs, and a trend toward lower RBC folate compared to girls. Therefore, regression analyses controlling for water As and BMI were sex stratified. Among girls, RBC folate was inversely associated with bAs, plasma B12 was inversely associated with uAs, and plasma Hcys was inversely associated with %MMA. Among boys, plasma folate was inversely associated with %InAs and positively associated with %DMA, RBC folate was inversely associated with %InAs and positively associated with %MMA, while Hcys was positively associated with %InAs. Conclusions These findings suggest that associations between OCM nutritional status, bAs, and distribution of As metabolites in adolescents are similar to previously reported observations in adults and in children. The As methylation findings are statistically significant among boys but not among girls; this may be related to estrogen which more strongly influences OCM in females. The inverse association between Hcys and %MMA in girls is somewhat unexpected given that Hcys is known to be an indicator of impaired OCM and low folate/B12 in adults. Overall, these results indicate that the associations between OCM-related micronutrients and arsenic methylation in adolescents are generally similar to prior findings in adults, though these associations may differ by sex. Additionally, these findings suggest that more investigation into the role of Hcys in adolescent physiology is needed, perhaps particularly for girls. Additional studies are needed to evaluate the impact of OCM and As methylation on As-related adverse health outcomes (such as cancer and cardiovascular disease) in people exposed to As during adolescence.

Supplemental Digital Content is available in the text., Background: Hypertension in later life, a significant risk factor for cardiovascular disease, has been linked to elevated blood pressure in early life. Exposure to metals may influence childhood blood pressure; however, previous research is limited and has mainly focused on evaluating the toxicity of single metal exposures. This study evaluates the associations between exposure to metal mixtures and blood pressure among Bangladeshi children age 5–7 years. Methods: We investigated the associations of 17 toenail metal concentrations with blood pressure using linear regression models. Principal component analysis (PCA), weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) were conducted as secondary analyses. Results: Associations were observed for selenium with diastolic blood pressure (per doubling of exposure β = 2.91, 95% confidence interval [CI] = 1.08, 4.75), molybdenum with systolic (β = 0.33, 95% CI = 0.05, 0.61) and diastolic blood pressure (β = 0.39, 95% CI = 0.12, 0.66), tin with systolic blood pressure (β = –0.33, 95% CI = –0.60, –0.06), and mercury with systolic (β = –0.83, 95% CI = –1.49, –0.17) and diastolic blood pressure (β = –0.89, 95% CI = –1.53, –0.26). Chromium was associated with diastolic blood pressure among boys only (β = 1.10, 95% CI = 0.28, 1.92, P for interaction = 0.02), and copper was associated with diastolic blood pressure among girls only (β = –1.97, 95% CI = –3.63, –0.32, P for interaction = 0.01). These findings were largely robust to the secondary analyses that utilized mixture modeling approaches (PCA, WQS, and BKMR). Conclusions: Future prospective studies are needed to investigate further the impact of early life exposure to metal mixtures on children’s blood pressure trajectories and cardiovascular disease risk later in life.

The human GABAB receptor-a member of the class C family of G-protein-coupled receptors (GPCRs)-mediates inhibitory neurotransmission and has been implicated in epilepsy, pain and addiction1. A unique GPCR that is known to require heterodimerization for function2-6, the GABAB receptor has two subunits, GABAB1 and GABAB2, that are structurally homologous but perform distinct and complementary functions. GABAB1 recognizes orthosteric ligands7,8, while GABAB2 couples with G proteins9-14. Each subunit is characterized by an extracellular Venus flytrap (VFT) module, a descending peptide linker, a seven-helix transmembrane domain and a cytoplasmic tail15. Although the VFT heterodimer structure has been resolved16, the structure of the full-length receptor and its transmembrane signalling mechanism remain unknown. Here we present a near full-length structure of the GABAB receptor, captured in an inactive state by cryo-electron microscopy. Our structure reveals several ligands that preassociate with the receptor, including two large endogenous phospholipids that are embedded within the transmembrane domains to maintain receptor integrity and modulate receptor function. We also identify a previously unknown heterodimer interface between transmembrane helices 3 and 5 of both subunits, which serves as a signature of the inactive conformation. A unique 'intersubunit latch' within this transmembrane interface maintains the inactive state, and its disruption leads to constitutive receptor activity.

Methylation of ingested inorganic arsenic (InAs) to monomethyl- (MMAs) and dimethyl-arsenical species (DMAs) facilitates urinary arsenic elimination. Folate and creatine supplementation influenced arsenic methylation in a randomized controlled trial. Here, we examine if baseline status of one-carbon metabolism nutrients (folate, choline, betaine, and vitamin B12) modified the effects of FA and creatine supplementation on changes in homocysteine, guanidinoacetate (GAA), total blood arsenic, and urinary arsenic metabolite proportions and indices. Study participants (N = 622) received 400 or 800 μg FA, 3 g creatine, 400 μg FA + 3 g creatine, or placebo daily for 12 weeks. Relative to placebo, FA supplementation was associated with greater mean increases in %DMAs among participants with betaine concentrations below the median than those with levels above the median (FDR

There are limited data examining the consequences of environmental exposure to arsenic on the immune system in adults, particularly among smokers. Smoking has been shown to exacerbate or contribute to impaired immune function in men chronically exposed to arsenic. In contrast, vitamin D (VitD) is known to have a positive influence on innate and adaptive immune responses. The effect of circulating VitD on arsenic-associated immune dysfunction is not known. Here we examine the relationship of arsenic exposure and T cell proliferation (TCP), a measure of immune responsiveness, and circulating VitD among adult men and women in Bangladesh. Arsenic exposure was assessed using total urinary arsenic as well as urinary arsenic metabolites all adjusted for urinary creatinine. TCP was measured ex vivo in cryopreserved peripheral blood mononuclear cells from 614 adult participants enrolled in the Bangladesh Health Effects of Arsenic Longitudinal Study; serum VitD was also evaluated. The influence of cigarette smoking on arsenic-induced TCP modulation was assessed only in males as there was an inadequate number of female smokers. These studies show that arsenic suppressed TCP in males. The association was significantly strong in male smokers and to a lesser extent in male non-smokers. Interestingly, we found a strong protective effect of high/sufficient serum VitD levels on TCP among non-smoking males. Furthermore, among male smokers with low serum VitD (⊔20 ng/ml), we found a strong suppression of TCP by arsenic. On the other hand, high VitD (>20 ng/ml) was found to attenuate effects of arsenic on TCP among male-smokers. Overall, we found a strong protective effect of VitD, when serum levels were >20 ng/ml, on arsenic-induced inhibition of TCP in men, irrespective of smoking status. To our knowledge this is the first large study of immune function in healthy adult males and females with a history of chronic arsenic exposure.

Households with pregnancies and young children are a priority group for outreach on private well water screening due to the widespread occurrence and toxicity of common groundwater contaminants such as arsenic. Given the trusted role of health care providers as communicators of health risk, Columbia University investigators and New Jersey government partners collaborated with Hunterdon Healthcare to offer free well testing to residents of Hunterdon County, a hot spot for naturally occurring arsenic in New Jersey. Through practice-based test kit distribution and online patient portal messages, supported by a public multimedia campaign, we tested 433 private wells and alerted 50 families about elevated arsenic found in their drinking water. These health care-facilitated outreach strategies allowed for targeting based on geographic and demographic risk and suggested opportunities to better leverage communication channels, such as incorporating questions on home water source into the electronic medical record.

Background and Aims. Epidemiologic cross-sectional studies examining the relationship between environmental lead (Pb) exposure and erythropoietin (EPO) production have reported contrasting results. It is unknown, however, if exposure to Pb earlier in life has an effect on EPO production later in life. Here, using a prospective study, we evaluate the association between prenatal, early childhood, and concurrent Pb exposure and EPO concentration in young adulthood. Methods. From our prospective birth cohort study in Mitrovica (a mining town) and Pristina (a control town), Kosovo, from 1985 to 1998, we located and assessed blood lead concentration (BPb) and serum EPO in 101 participants (mean age 24.9 years) in 2011. We examined the association between BPb and EPO, stratified by hemoglobin (Hgb), and controlling for potential confounders. Results. These results resemble the findings in the original full cohort at 4.5 and 6.5 years of age, at which time we reported that the maintenance of a normal Hgb required increased EPO production among participants exposed to high levels of environmental Pb. In contrast, when the original cohort was 9.5 and 12 years of age, they were no longer capable of hyper-production of EPO in order to maintain normal levels of Hgb, suggestive of cumulative toxicity to the peritubular cells of the kidney that are responsible for EPO synthesis. Conclusion. Our results, along with previously reported findings on this cohort, suggest that a dramatic reduction of Pb exposure may allow for a reversal of the impact that prolonged Pb exposure may have on EPO production.

Background: Exposure to inorganic arsenic (As) from drinking water is associated with modest deficits in intellectual function in young children; it is unclear whether deficits occur during adolescence, when key brain functions are more fully developed. Objectives: We sought to determine the degree to which As exposure is associated with adolescent intelligence, and the contributory roles of lead, cadmium, manganese and selenium. Methods: We recruited a cross-section of 726 14–16 year olds (mean age = 14.8 years) whose mothers are participants in the Bangladesh Health Effects of Arsenic Longitudinal Study (HEALS), and whose household well water As levels, which varied widely, were well characterized. Using a culturally modified version of the WISC-IV, we examined raw Full Scale scores, and Verbal Comprehension, Perceptual Reasoning, Working Memory and Processing Speed Indices. Blood levels of As (BAs), Mn, Pb, Cd and Se were assessed at the time of the visit, as was creatinine-adjusted urinary As (UAs/Cr). Results: Linear regression analyses revealed that BAs was significantly negatively associated with all WISC-IV scores except for Perceptual Reasoning. With UAs/Cr as the exposure variable, we observed significantly negative associations for all WISC-IV scores. Except for Se, blood levels of other metals, were also associated with lower WISC-IV scores. Controlling for covariates, doubling BAs, or UAs/Cr, was associated with a mean decrement (95% CI) of 3.3 (1.1, 5.5), or 3.0 (1.2, 4.5) points, respectively, in raw Full scale scores with a sample mean of 177.6 (SD = 36.8). Confirmatory analyses using Bayesian Kernel Machine Regression, which identifies important mixture members, supported these findings; the primary contributor of the mixture was BAs, followed by BCd. Conclusions: Our data indicate that the adverse consequences of As exposure on neurodevelopment observed in other cross-sectional studies of younger children are also apparent during adolescence. They also implicate Cd as a neurotoxic element that deserves more attention. Keywords: Arsenic exposure, Metal mixtures, Cognitive test scores, Intellectual function, Adolescence

Hundreds of millions of people worldwide are exposed to arsenic via contaminated water. The goal of this study was to identify whether arsenic-associated lung function deficits resemble obstructive- or restrictive-like lung disease, in order to help illuminate a mechanistic pathway and identify at-risk populations. We recently published a qualitative systematic review outlining the body of research on arsenic and non-malignant respiratory outcomes. Evidence from several populations, at different life stages, and at different levels of exposure showed consistent associations of arsenic exposure with chronic lung disease mortality, respiratory symptoms, and lower lung function levels. The published review, however, only conducted a broad qualitative description of the published studies without considering specific spirometry patterns, without conducting a meta-analysis, and without evaluating the dose-response relationship. We searched PubMed and Embase for studies on environmental arsenic exposure and lung function. We performed a meta-analysis using inverse-variance-weighted random effects models to summarize adjusted effect estimates for arsenic and forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. Across nine studies, median water arsenic levels ranged from 23 to 860 μg/L. The pooled estimated mean difference (MD) comparing the highest category of arsenic exposure (ranging from > 11 to > 800 μg/L) versus the lowest (ranging from

Background and Aims. Epidemiologic studies examining the relationship between environmental lead (Pb) exposure and blood pressure (BP) generally report small associations between blood lead concentration (BPb) and BP. However, these studies are predominantly cross-sectional. In addition, no epidemiologic studies evaluate associations between either current or past Pb exposure and serum levels of markers of systemic inflammation and endothelial dysfunction, including soluble vascular adhesion molecule (sVCAM-1) and soluble intercellular cell adhesion molecule (sICAM-1).We prospectively investigate these associations later in life.Methods. From our original prospective birth cohort study in Mitrovica (a mining town) and Prishtina (a control town), Kosovo, from 1985 to 1998, we located and assessed BPb and BP in 101 participants (mean age of 24.9 years old) in 2011.Results. We found highly statistically significant association between concurrent BPb and sVCAM-1 in men and a marginally significant association between concurrent PBb and sICAM.-1 in women. We did not find evidence of mediation.Conclusion. Current study results, along with previously reported findings on this cohort, provide evidence for the hypothesis that exposure to Pb leads to small increases in sBP and perhaps to increased circulating levels of sVCAM-1 and sICAM-1 later in life.

Despite a recent increase in e-cigarette use, the adverse human health effects of exposure to e-cigarette aerosol, especially on the central nervous system (CNS), remain unclear. Multiple neurotoxic metals have been identified in e-cigarette aerosol. However, it is unknown whether those metals accumulate in the CNS at biologically meaningful levels. To answer this question, two groups of mice were whole-body exposed twice a day, 5 days a week, for two months, to either a dose of e-cigarette aerosol equivalent to human secondhand exposure, or a 5-fold higher dose. After the last exposure, the olfactory bulb, anterior and posterior frontal cortex, striatum, ventral midbrain, cerebellum, brainstem, remaining brain tissue and spinal cord were collected for metal quantification by inductively coupled plasma mass spectrometry and compared to tissues from unexposed control mice. The two-month exposure caused significant accumulation of several neurotoxic metals in various brain areas - for some metals even at the low exposure dose. The most striking increases were measured in the striatum. For several metals, including Cr, Cu, Fe, Mn, and Pb, similar accumulations are known to be neurotoxic in mice. Decreases in some essential metals were observed across the CNS. Our findings suggest that chronic exposure to e-cigarette aerosol could lead to CNS neurotoxic metal deposition and endogenous metal dyshomeostasis, including potential neurotoxicity. We conclude that e-cigarette-mediated metal neurotoxicity may pose long-term neurotoxic and neurodegenerative risks for e-cigarette users and bystanders.

Summary: Background: In 2006, the current US Environmental Protection Agency (EPA) maximum contaminant level for arsenic in public water systems (10 μg/L) took effect. We aimed to assess national trends in water arsenic exposure in the USA, hypothesising that urinary arsenic concentrations would decrease over time in individuals using public water systems but not in those using well water (which is not federally regulated). We further estimated the expected number of avoided skin or lung and bladder cancer cases. Methods: In this analysis of the 2003â14 cycles of the National Health and Nutrition Examination Survey (NHANES), we used data for dimethylarsinate (DMA), the main metabolite of inorganic arsenic in human beings, and total urine arsenic to reflect water arsenic exposure in survey participants. To isolate exposure to water arsenic, we expanded a residual-based method to remove tobacco and dietary sources of urinary DMA and total arsenic. We also applied EPA risk-assessment approaches to estimate the expected annual number of avoided skin or lung and bladder cancer cases comparing arsenic exposure in 2013â14 with 2003â04. Findings: We obtained data from 14â127 individuals who participated in the NHANES between 2003 and 2014. Among public water users, fully adjusted geometric means of DMA decreased from 3·01 μg/L in 2003â04 to 2·49 μg/L in 2013â14 (17% reduction; 95% CI 10â24; p-trend

Background Chronic arsenic exposure is a public health concern in many parts of the world, with elevated concentrations in groundwater posing a threat to millions of people. Arsenic is associated with various cancers and an array of chronic diseases; however, the relationship with adverse pregnancy outcomes and child mortality is less established. Objectives We evaluated associations between individual-level prenatal arsenic exposure with adverse pregnancy outcomes and child mortality in a pregnancy study among 498 women nested in a larger population-based cohort in rural Bangladesh. Methods Creatinine-adjusted urinary total arsenic concentration, a comprehensive measure of exposure from water, food, and air sources, reflective of the prenatal period was available for participants. Self-reported pregnancy outcomes (livebirth, stillbirth, spontaneous/elective abortion) were ascertained. Generalized estimating equations, accounting for multiple pregnancies of participants, were used to estimate odds ratios and 95% confidence intervals in relation to adverse pregnancy outcomes. Vital status of livebirths was subsequently ascertained through November 2015. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals in relation to child mortality. Results We observed a significant association between prenatal arsenic exposure and the risk of stillbirth (greater than median; adjusted OR = 2.50; 95% CI = 1.04, 6.01). We also observed elevated risk of child mortality (greater than median; adjusted HR = 1.92; 95% CI = 0.78, 4.68) in relation to prenatal arsenic exposure. Conclusions Prospective studies should continue to evaluate prenatal and early life health effects of arsenic exposure and arsenic remediation strategies for women of child-bearing age.

Telomeres are tandem repeat sequences at the end of chromosomes that bind proteins to protect chromosome ends. Telomeres shorten with age, and shorter leukocyte telomere length (TL) has been associated with overall mortality in numerous studies. However, this association has not been tested in populations outside of Europe and the U.S. We assessed the association between TL and subsequent mortality using data on 744 mortality cases and 761 age-/sex-matched controls sampled from >27,000 participants from three longitudinal Bangladeshi cohorts: Health Effects of Arsenic Longitudinal Study (HEALS), HEALS Expansion (HEALS-E), and Bangladesh Vitamin E and Selenium Trial (BEST). We used conditional logistic regression to estimate odds ratios (ORs) for the association between a standardized TL variable and overall mortality, as well as mortality from chronic diseases, respiratory diseases, circulatory diseases, and cancer. In HEALS and BEST, we observed an association between shorter TL and increased overall mortality (P=0.03 and P=0.03), mortality from chronic disease (P=0.01 and P=0.03) and mortality from circulatory disease (P=0.03 and P=0.04). Results from pooled analyses of all cohorts were consistent with HEALS and BEST. This is the first study demonstrating an association between short TL and increased mortality in a population of non-European ancestry.

Background: Posttranslational histone modifications (PTHMs) are altered by arsenic, an environmental carcinogen. PTHMs are also influenced by nutritional methyl donors involved in one-carbon metabolism (OCM), which may protect against epigenetic dysregulation. Methods: We measured global levels of three PTHMs, which are dysregulated in cancers (H3K36me2, H3K36me3, H3K79me2), in peripheral blood mononuclear cells (PBMC) from 324 participants enrolled in the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults. Sex-specific associations between several blood OCM indices (folate, vitamin B12, choline, betaine, homocysteine) and PTHMs were examined at baseline using regression models, adjusted for multiple tests by controlling for the false discovery rate (PFDR). We also evaluated the effects of folic acid supplementation (400 μg/d for 12 weeks), compared with placebo, on PTHMs. Results: Associations between choline and H3K36me2 and between vitamin B12 and H3K79me2 differed significantly by sex (Pdiff < 0.01 and Conclusions: OCM indices may influence PTHMs in a sex-dependent manner, and folic acid supplementation, at this dose and duration, does not alter PTHMs in PBMCs. Impact: This is the first study to examine the influences of OCM indices on PTHMs in a population that may have increased susceptibility to cancer development due to widespread exposure to arsenic-contaminated drinking water and a high prevalence of hyperhomocysteinemia. Cancer Epidemiol Biomarkers Prev; 26(2); 261–9. ©2016 AACR.

Falls are the most common cause of injury in older adults. Being homebound further increases the risk of falling. The cause of falls is often multifactorial. A home-based provider’s approach to a patient with frequent falls begins with an assessment to identify environmental, physical, and medical fall hazards. Next, an individualized home exercise program (HEP), designed and implemented in collaboration with a home health physical therapist, is an evidence-based strategy for reducing fall risk. The HEP should focus on improving range of motion, strength, balance, and gait. Medical providers and occupational therapists also have important roles in reducing the risk of future falls by addressing medical concerns and mitigating fall hazards within the home.