Influence of folic acid and vitamin B12 supplementation on arsenic methylation: A double-blinded, placebo-controlled trial in Bangladeshi children.

BACKGROUND: Inorganic arsenic is metabolized to monomethyl- (MMAs) and dimethyl- (DMAs) species via one-carbon metabolism (OCM); this facilitates urinary arsenic elimination. OCM is influenced by folate and vitamin B12 and previous randomized control trials (RCTs) showed that folic acid (FA) supplementation increases arsenic methylation in adults. This RCT investigated the effects of FA + B12 supplementation on arsenic methylation in children, a key developmental stage where OCM supports growth. METHODS: A total of 240 participants (8-11 years, 53 % female) drinking from wells with arsenic concentrations > 50 µg/L, were encouraged to switch to low arsenic wells and were randomized to receive 400 µg FA + 5 µg B12 or placebo daily for 12-weeks. Urine and blood samples were collected at baseline, week 1 (only urine) and week 12. Generalized estimated equation (GEE) models were used to assess treatment effects on arsenic species in blood and urine. RESULTS: At baseline, the mean ± SD total blood and urinary arsenic were 5.3 ± 2.9 µg/L and 91.2 ± 89.5 µg/L. Overall, total blood and urine arsenic decreased by 11.7% and 17.6%, respectively, at the end of follow up. Compared to placebo, the supplementation group experienced a significant increase in the concentration of blood DMAs by 14.0% (95% CI 5.0, 25.0) and blood secondary methylation index (DMAs/MMAs) by 0.19 (95% CI: 0.09, 0.35) at 12 weeks. Similarly, there was a 1.62% (95% CI: 0.43, 20.83) significantly higher urinary %DMAs and -1.10% (95% CI: -1.73, -0.48) significantly lower urinary %MMAs in the supplementatio group compared to the placebo group after 1 week. The direction of the changes in the urinary %iAs, %MMAs, and %DMAs at week 12 were consistent with those at week 1, though estimates were not significant. Treatment effects were stronger among participants with higher baseline blood arsenic concentrations. Results were consistent across males and females, and participants with higher and lower folate and B12 status at baseline. CONCLUSION: This RCT confirms that FA + B12 supplementation increases arsenic methylation in children as reflected by decreased MMAs and increased DMAs in blood and urine. Nutritional interventions may improve arsenic methylation and elimination in children, potentially reducing arsenic toxicity while also improving nutritional status.

Safety and utility of CardioMEMS device for remote pulmonary artery monitoring in paediatric Fontan patients: a case series.

Background: Patients with single ventricle congenital heart disease who undergo total cavo-pulmonary anastomosis (Fontan surgery) suffer from elevated pulmonary artery pressure (PAP), which leads to multiple adverse sequelae. Traditionally, the Fontan pressures are assessed via invasive haemodynamic catheterization that exposes these medically fragile patients to the risks of vascular injury and anaesthesia. While the CardioMEM remote PAP monitor has been extensively used in adults with heart failure, the safety of this device has not been established in children. Case summary: We report safety and utility of this device in eight paediatric Fontan patients. Our patients ranged from 9 to 18 years of age. There were no reported complications related to the implantation of the CardioMEMS device in our population. Discussion: This is the first case series of safety of CardioMEMS device in paediatric Fontan Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation patients. Our experience indicates that the device may be safely utilized for the management of Fontan-related complications in this vulnerable population.

Transapical Delivery of a Sapien Valve for Transcatheter Aortic Valve Replacement in an 11-Year-Old Patient with Truncus Arteriosus.

Complex congenital heart defects may necessitate repeated surgical interventions throughout a patient's lifetime. Each subsequent procedure exposes patients to a greater cumulative risk, thus adding to the potential morbidity and mortality of the surgery. Transcatheter interventions can help mitigate the surgical risk for many defects and can delay or mitigate the need for surgery. This case report describes the rare use of a transapically delivered transcatheter aortic valve replacement (TAVR) therapy in a high-risk pediatric patient to postpone the need for surgery and potentially reduce the number of lifelong surgical interventions. The case highlights how transcatheter aortic valve therapies can be considered for non-standard, higher risk pediatric patients to postpone the need for surgical valve replacement and may serve as a paradigm shift in the care of complex patients with aortic valve pathology.

The Folic Acid and Creatine Trial: Treatment Effects of Supplementation on Arsenic Methylation Indices and Metabolite Concentrations in Blood in a Bangladeshi Population.

BACKGROUND: Chronic arsenic (As) exposure is a global environmental health issue. Inorganic As (InAs) undergoes methylation to monomethyl (MMAs) and dimethyl-arsenical species (DMAs); full methylation to DMAs facilitates urinary excretion and is associated with reduced risk for As-related health outcomes. Nutritional factors, including folate and creatine, influence one-carbon metabolism, the biochemical pathway that provides methyl groups for As methylation. OBJECTIVE: Our aim was to investigate the effects of supplementation with folic acid (FA), creatine, or the two combined on the concentrations of As metabolites and the primary methylation index (PMI: MMAs/InAs) and secondary methylation index (SMI: DMAs/MMAs) in blood in Bangladeshi adults having a wide range of folate status. METHODS: In a randomized, double-blinded, placebo (PBO)-controlled trial, 622 participants were recruited independent of folate status and assigned to one of five treatment arms: a) PBO (n=102), b) 400µg FA/d (400FA; n=153), c) 800µg FA/d (800FA; n=151), d) 3g creatine/d (creatine; n=101), or e) 3g creatine+400µg of FA/d (creatine+400FA; n=103) for 12 wk. For the following 12 wk, half of the FA participants were randomly switched to the PBO while the other half continued FA supplementation. All participants received As-removal water filters at baseline. Blood As (bAs) metabolites were measured at weeks 0, 1, 12, and 24. RESULTS: At baseline, 80.3% (n=489) of participants were folate sufficient (≥9 nmol/L in plasma). In all groups, bAs metabolite concentrations decreased, likely due to filter use; for example, in the PBO group, blood concentrations of MMAs (bMMAs) (geometric mean±geometric standard deviation) decreased from 3.55±1.89µg/L at baseline to 2.73±1.74 at week 1. After 1 wk, the mean within-person increase in SMI for the creatine+400FA group was greater than that of the PBO group (p=0.05). The mean percentage decrease in bMMAs between baseline and week 12 was greater for all treatment groups compared with the PBO group [400FA: -10.4 (95% CI: -11.9, -8.75), 800FA: -9.54 (95% CI: -11.1, -7.97), creatine: -5.85 (95% CI: -8.59, -3.03), creatine+400FA: -8.44 (95% CI: -9.95, -6.90), PBO: -2.02 (95% CI: -4.03, 0.04)], and the percentage increase in blood DMAs (bDMAs) concentrations for the FA-treated groups significantly exceeded that of PBO [400FA: 12.8 (95% CI: 10.5, 15.2), 800FA: 11.3 (95% CI: 8.95, 13.8), creatine+400FA: 7.45 (95% CI: 5.23, 9.71), PBO: -0.15 (95% CI: -2.85, 2.63)]. The mean decrease in PMI and increase in SMI in all FA groups significantly exceeded PBO (p<0.05). Data from week 24 showed evidence of a reversal of treatment effects on As metabolites from week 12 in those who switched from 800FA to PBO, with significant decreases in SMI [-9.0% (95% CI: -3.5, -14.8)] and bDMAs [-5.9% (95% CI: -1.8, -10.2)], whereas PMI and bMMAs concentrations continued to decline [-7.16% (95% CI: -0.48, -14.3) and -3.1% (95% CI: -0.1, -6.2), respectively] for those who remained on 800FA supplementation. CONCLUSIONS: FA supplementation lowered bMMAs and increased bDMAs in a sample of primarily folate-replete adults, whereas creatine supplementation lowered bMMAs. Evidence of the reversal of treatment effects on As metabolites following FA cessation suggests short-term benefits of supplementation and underscores the importance of long-term interventions, such as FA fortification. https://doi.org/10.1289/EHP11270.

Sequencing-based fine-mapping and in silico functional characterization of the 10q24.32 arsenic metabolism efficiency locus across multiple arsenic-exposed populations.

Inorganic arsenic is highly toxic and carcinogenic to humans. Exposed individuals vary in their ability to metabolize arsenic, and variability in arsenic metabolism efficiency (AME) is associated with risks of arsenic-related toxicities. Inherited genetic variation in the 10q24.32 region, near the arsenic methyltransferase (AS3MT) gene, is associated with urine-based measures of AME in multiple arsenic-exposed populations. To identify potential causal variants in this region, we applied fine mapping approaches to targeted sequencing data generated for exposed individuals from Bangladeshi, American Indian, and European American populations (n = 2,357, 557, and 648 respectively). We identified three independent association signals for Bangladeshis, two for American Indians, and one for European Americans. The size of the confidence sets for each signal varied from 4 to 85 variants. There was one signal shared across all three populations, represented by the same SNP in American Indians and European Americans (rs191177668) and in strong linkage disequilibrium (LD) with a lead SNP in Bangladesh (rs145537350). Beyond this shared signal, differences in LD patterns, minor allele frequency (MAF) (e.g., rs12573221 ~13% in Bangladesh ~0.2% among American Indians), and/or heterogeneity in effect sizes across populations likely contributed to the apparent population specificity of the additional identified signals. One of our potential causal variants influences AS3MT expression and nearby DNA methylation in numerous GTEx tissue types (with rs4919690 as a likely causal variant). Several SNPs in our confidence sets overlap transcription factor binding sites and cis-regulatory elements (from ENCODE). Taken together, our analyses reveal multiple potential causal variants in the 10q24.32 region influencing AME, including a variant shared across populations, and elucidate potential biological mechanisms underlying the impact of genetic variation on AME.

Somatic loss of the Y chromosome is associated with arsenic exposure among Bangladeshi men.

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.

Interaction of Arsenic Exposure and Transcriptomic Profile in Basal Cell Carcinoma.

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.

Exposure to arsenic and level of Vitamin D influence the number of Th17 cells and production of IL-17A in human peripheral blood mononuclear cells in adults.

There is limited evidence on the effects of environmental exposure to arsenic (As) on the immune system in adults. In a population-based study, we have found that urinary As (UAs), and its metabolites [inorganic As (InAs), monomethylated arsenicals (MMA+3/+5), and dimethylated arsenicals (DMA+3/+5)] modulate or influence the number of T-helper 17 (Th17) cells and IL-17A cytokine production. In non-smoking women, we observed that UAs and DMA+3/+5 were associated with changes in Th17 cell numbers in a nonlinear fashion. In smoking males, we found that UAs was associated with a significant decrease of Th17 cell numbers. Similar association was observed among non-smoking males. Likewise, UAs, DMA+3/+5 and MMA+3/+5 were associated with diminished production of IL-17A among non-smoking males. When stratified by Vitamin D levels defined as sufficient (≥20 ng/ml) and insufficient (<20 ng/ml), we found a substancial decrease in Th17 cell numbers among those with insufficient levels. Individuals with sufficient VitD levels demonstrated significant inhibition of IL-17A production in non-smoking males. Collectively, we find that exposure to As via drinking water is associated with alterations in Th17 numbers and IL-17A production, and that these associations may be modified by Vitamin D status. Our findings have significance for health outcomes associated with As exposure.

Mixed metals exposure and cognitive function in Bangladeshi adolescents.

BACKGROUND: Over 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. OBJECTIVES: To examine the associations between mixed metals exposure and cognitive function in Bangladeshi adolescents. METHODS: The 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. RESULTS: Linear 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. CONCLUSIONS: Overall, 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.

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 2000-2001 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.

Symmetric activation and modulation of the human calcium-sensing receptor.

The human extracellular calcium-sensing (CaS) receptor controls plasma Ca2+ levels and contributes to nutrient-dependent maintenance and metabolism of diverse organs. Allosteric modulation of the CaS receptor corrects disorders of calcium homeostasis. Here, we report the cryogenic-electron microscopy reconstructions of a near-full-length CaS receptor in the absence and presence of allosteric modulators. Activation of the homodimeric CaS receptor requires a break in the transmembrane 6 (TM6) helix of each subunit, which facilitates the formation of a TM6-mediated homodimer interface and expansion of homodimer interactions. This transformation in TM6 occurs without a positive allosteric modulator. Two modulators with opposite functional roles bind to overlapping sites within the transmembrane domain through common interactions, acting to stabilize distinct rotamer conformations of key residues on the TM6 helix. The positive modulator reinforces TM6 distortion and maximizes subunit contact to enhance receptor activity, while the negative modulator strengthens an intact TM6 to dampen receptor function. In both active and inactive states, the receptor displays symmetrical transmembrane conformations that are consistent with its homodimeric assembly.

Exposure to e-cigarette aerosol over two months induces accumulation of neurotoxic metals and alteration of essential metals in mouse brain.

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.

Urinary arsenic and relative telomere length in 5-7 year old children in Bangladesh.

BACKGROUND: Telomere length has been associated with the occurrence and progression of common chronic and age-related diseases, and in younger populations, may represent a biomarker of disease susceptibility. Early childhood is a critical period for telomere biology as this period is characterized by a rapid decline in telomere length due to a large turnover of highly proliferative cells and may represent a period of unique sensitivity to environmental insults. Arsenic (As) exposure has been associated with both telomere lengthening and shortening in adults and children and some evidence suggests the effects may differ by level and timing of exposure. OBJECTIVES: Given the lack of clarity across studies, we investigated the association between urinary As and leukocyte telomere length among 476 five- to seven-year-old children enrolled in the Bangladesh Environmental Research in Children's Health (BiRCH) cohort. METHODS: In a series of multivariable models, adjusted for key covariates, we examined associations between urinary As and relative telomere length (RTL) of whole blood DNA. RESULTS: We observed small but consistent, negative associations between urinary As and RTL, such that a doubling of urinary As was associated with a -0.017 (95% CI: -0.030, -0.005; p = 0.0056) decrease in RTL, in fully adjusted models. We also observed a somewhat stronger inverse relationship between urinary As concentration and RTL among children born to fathers ≥ 30 years of age at the time of birth, than those < 30 years; however, we did not observe a statistically significant interaction. DISCUSSION: Our study suggests that As influences RTL, with detectable associations in early to mid-childhood. Further studies are needed to confirm our findings and investigate the potential long-term impacts of telomere shortening in childhood on later life health outcomes. Additional studies exploring how dose and timing of exposure may relate to RTL are critical to understanding As's relationship to telomere length.

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, 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 <1%), 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 [ß=-9.4 (95% CI: -13.9, -4.8)], SHS [ß=-6.9 (95% CI: -13.6, -0.2)], and NHSCS [ß=-8.7 (95% CI: -15.6, -2.2)]. In meta-analyses across cohorts, DMA% was 8.7% lower in carriers [ß=-8.7 (95% CI: -11.9, -5.4)]. 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.

Exposure to metal mixtures in relation to blood pressure among children 5-7 years old: An observational study in Bangladesh.

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 ß = 2.91, 95% confidence interval [CI] = 1.08, 4.75), molybdenum with systolic (ß = 0.33, 95% CI = 0.05, 0.61) and diastolic blood pressure (ß = 0.39, 95% CI = 0.12, 0.66), tin with systolic blood pressure (ß = -0.33, 95% CI = -0.60, -0.06), and mercury with systolic (ß = -0.83, 95% CI = -1.49, -0.17) and diastolic blood pressure (ß = -0.89, 95% CI = -1.53, -0.26). Chromium was associated with diastolic blood pressure among boys only (ß = 1.10, 95% CI = 0.28, 1.92, P for interaction = 0.02), and copper was associated with diastolic blood pressure among girls only (ß = -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.

Association between body mass index and arsenic methylation in three studies of Bangladeshi adults and adolescents.

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.

Nutrition, one-carbon metabolism and arsenic methylation in Bangladeshi adolescents.

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.

Urinary arsenic is associated with wasting and underweight status in young children in rural Bangladesh.

BACKGROUND: Deficits in child growth are associated with poor cognitive outcomes and an increased risk for infection and mortality globally. One hundred forty million people are chronically exposed to arsenic from contaminated drinking water worldwide. While arsenic exposure has been associated with cognitive developmental delays in children, there is limited research on the association between arsenic exposure and growth deficits in young children. PURPOSE: The objective of this study was to assess the association between chronic arsenic exposure and deficits in growth among children under 5 years in a rural setting in Bangladesh. METHODS: Urinary arsenic measurements were collected from 465 children between the ages of 28 days-59 months in rural Matlab, Bangladesh, and analyzed by graphite furnace atomic absorption. Height and weight measurements were collected from children according to World Health Organization child growth standards. A z-score cutoff2 standard deviations below the mean was used to define stunting (height-for-age z-score), underweight (weight-for-age z-score), and wasting (weight-for-height z-score). RESULTS: Children under 5 years with urinary arsenic concentrations in the third tertile (greater than 31 µg per liter (µg/L)) had a two times higher odds of being underweight after adjustment for age, creatinine, paternal education, breastfeeding, number of individuals using the same sleeping room, and physician-diagnosed pneumonia (Odds Ratio (OR): 2.29 (95% Confidence Interval (CI): 1.16, 4.52)). Children under 2 years of age had a two times higher odds of being wasted after adjustment for age, creatinine, paternal education, breastfeeding, number of individuals using the same sleeping room, and physician-diagnosed pneumonia (OR: 2.85 (95% CI: 1.18, 6.89)). CONCLUSIONS: These findings suggest that arsenic exposure is associated with an increased odds of being wasted and underweight among young children in rural Bangladesh.

Betaine and choline status modify the effects of folic acid and creatine supplementation on arsenic methylation in a randomized controlled trial of Bangladeshi adults.

PURPOSE: 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. METHODS: 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. RESULTS: 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 < 0.05). 400 µg FA/day was associated with a greater decrease in homocysteine among participants with plasma folate concentrations below, compared with those above, the median (FDR < 0.03). Creatine treatment was associated with a significant decrease in %MMAs among participants with choline concentrations below the median (P = 0.04), but not among participants above the median (P = 0.94); this effect did not significantly differ between strata (P = 0.10). CONCLUSIONS: Effects of FA and creatine supplementation on arsenic methylation capacity were greater among individuals with low betaine and choline status, respectively. The efficacy of FA and creatine interventions to facilitate arsenic methylation may be modified by choline and betaine nutritional status. CLINICAL TRIAL REGISTRATION: Clinical Trial Registry Identifier: NCT01050556, U.S. National Library of Medicine, https://clinicaltrials.gov ; registered January 15, 2010.