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.

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

[This corrects the article DOI: 10.1371/journal.pgen.1007984.].

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.

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.

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.

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

OBJECTIVES: Evidence 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. 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), 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). RESULTS: Every 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. CONCLUSION: 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.

Exposure to arsenic in utero is associated with various types of DNA damage and micronuclei in newborns: a birth cohort study.

BACKGROUND: Growing evidence indicates that in utero arsenic exposures in humans may increase the risk of adverse health effects and development of diseases later in life. This study aimed to evaluate potential health risks of in utero arsenic exposure on genetic damage in newborns in relation to maternal arsenic exposure. METHODS: A total of 205 pregnant women residing in arsenic-contaminated areas in Hanam province, Vietnam, were recruited. Prenatal arsenic exposure was determined by arsenic concentration in mother's toenails and urine during pregnancy and in umbilical cord blood collected at delivery. Genetic damage in newborns was assessed by various biomarkers of early genetic effects including oxidative/nitrative DNA damage (8-hydroxydeoxyguanosine, 8-OHdG, and 8-nitroguanine), DNA strand breaks and micronuclei (MN) in cord blood. RESULTS: Maternal arsenic exposure, measured by arsenic levels in toenails and urine, was significantly increased (p <  0.05) in subjects residing in areas with high levels of arsenic contamination in drinking water. Cord blood arsenic level was significantly increased in accordance with maternal arsenic exposure (p <  0.001). Arsenic exposure in utero is associated with genotoxic effects in newborns indicated as increased levels of 8-OHdG, 8-nitroguanine, DNA strand breaks and MN frequency in cord blood with increasing levels of maternal arsenic exposure. Maternal toenail arsenic level was significantly associated with all biomarkers of early genetic effects, while cord blood arsenic levels associated with DNA strand breaks and MN frequency. CONCLUSIONS: In utero arsenic exposure is associated with various types of genetic damage in newborns potentially contributing to the development of diseases, including cancer, later in life.

Correction to: Exposure to arsenic in utero is associated with various types of DNA damage and micronuclei in newborns: a birth cohort study.

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

Screening for gene-environment (G×E) interaction using omics data from exposed individuals: an application to gene-arsenic interaction.

Identifying gene-environment interactions is a central challenge in the quest to understand susceptibility to complex, multi-factorial diseases. Developing an understanding of how inter-individual variability in inherited genetic variation alters the effects of environmental exposures will enhance our knowledge of disease mechanisms and improve our ability to predict disease and target interventions to high-risk sub-populations. Limited progress has been made identifying gene-environment interactions in the epidemiological setting using existing statistical approaches for genome-wide searches for interaction. In this paper, we describe a novel two-step approach using omics data to conduct genome-wide searches for gene-environment interactions. Using existing genome-wide SNP data from a large Bangladeshi cohort study specifically designed to assess the effect of arsenic exposure on health, we evaluated gene-arsenic interactions by first conducting genome-wide searches for SNPs that modify the effect of arsenic on molecular phenotypes (gene expression and DNA methylation features). Using this set of SNPs showing evidence of interaction with arsenic in relation to molecular phenotypes, we then tested SNP-arsenic interactions in relation to skin lesions, a hallmark characteristic of arsenic toxicity. With the emergence of additional omics data in the epidemiologic setting, our approach may have the potential to boost power for genome-wide interaction research, enabling the identification of interactions that will enhance our understanding of disease etiology and our ability to develop interventions targeted at susceptible sub-populations.

A study of telomere length, arsenic exposure, and arsenic toxicity in a Bangladeshi cohort.

BACKGROUND: Chronic arsenic exposure is associated with increased risk for arsenical skin lesions, cancer, and other adverse health outcomes. One potential mechanism of arsenic toxicity is telomere dysfunction. However, prior epidemiological studies of arsenic exposure, telomere length (TL), and skin lesion are small and cross-sectional. We investigated the associations between arsenic exposure and TL and between baseline TL and incident skin lesion risk among individuals participating in the Health Effects of Arsenic Longitudinal Study in Bangladesh (2000-2009). METHODS: Quantitative PCR was used to measure the average TL of peripheral blood DNA collected at baseline. The association between baseline arsenic exposure (well water and urine) and TL was estimated in a randomly-selected subcohort (n = 1469). A nested case-control study (466 cases and 464 age- and sex-matched controls) was used to estimate the association between baseline TL and incident skin lesion risk (diagnosed < 8 years after baseline). RESULTS: No association was observed between arsenic exposure (water or urine) and TL. Among incident skin lesion cases and matched controls, we observed higher skin lesion risk among individuals with shorter TL (Ptrend = 1.5 × 10-5) with odds ratios of 2.60, 1.59, and 1.10 for the first (shortest), second, and third TL quartiles compared to the fourth (longest). CONCLUSIONS: Arsenic exposure was not associated with TL among Bangladeshi adults, suggesting that leukocyte TL may not reflect a primary mode of action for arsenic's toxicity. However, short TL was associated with increased skin lesion risk, and may be a biomarker of arsenic susceptibility modifying arsenic's effect on skin lesion risk.

Arsenic exposures alter clinical indicators of anemia in a male population of smokers and non-smokers in Bangladesh.

Drinking water arsenic (WAs) exposure has been linked to a number of detrimental health outcomes including anemia, primarily among pregnant women. Little is known about the effects of arsenic (As) on hematological disorders among men. We have examined the role of As exposure on hematological indicators of anemia in a group of men exposed to a wide range of As in their drinking water. We conducted a cross-sectional investigation among 119 healthy men in the Health Effects of As Longitudinal Study (HEALS) cohort, in rural Bangladesh. The participants are part of an ongoing study focused on evaluating the influence of As and smoking on immune function. Samples were collected at recruitment and analyzed for water As, urinary As (UAs) and UAs metabolites to assess As exposure. Blood samples were also collected at recruitment and assayed immediately for hematological parameters. We found that increased WAs levels were associated with decreased red blood cell counts [ß=-0.13, p<0.0001] as well as hematocrit packed cell volumes [ß=-0.68, p=0.008] following adjustment for age, smoking, body mass index and polycyclic aromatic hydrocarbon-DNA adducts. Other measures of As exposure (UAs and its metabolites) demonstrated similar associations. Slightly stronger effects were observed among smokers. We also observed an effect of As on hemoglobin among smokers in relation to UAs [ß=-0.54, p<0.05]. Our analysis revealed effects of As exposure on hematological indicators of anemia in a group of healthy male smokers and non-smokers.

Associations between prenatal arsenic exposure with adverse pregnancy outcome and child mortality.

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.

Association between genome-wide copy number variation and arsenic-induced skin lesions: a prospective study.

BACKGROUND: Exposure to arsenic in drinking water is a global health problem and arsenic-induced skin lesions are hallmark of chronic arsenic toxicity. We and others have reported germline genetic variations as risk factors for such skin lesions. The role of copy number variation (CNV) in the germline DNA in this regard is unknown. METHODS: From a large prospectively followed-up cohort, exposed to arsenic, we randomly selected 2171 subjects without arsenic-induced skin lesions at enrollment and genotyped their whole blood DNA samples on Illumina Cyto12v2.1 SNP chips to generate DNA copy number. Participants were followed up every 2 years for a total of 8 years, especially for the development of skin lesions. In Cox regression models, each CNV segment was used as a predictor, accounting for other potential covariates, for incidence of skin lesions. RESULT: The presence of genomic deletion(s) in a number of genes (OR5J2, GOLGA6L7P, APBA2, GALNTL5, VN1R31P, PHKG1P2, SGCZ, ZNF658) and lincRNA genes (RP11-76I14.1, CTC-535 M15.2, RP11-73B2.2) were associated with higher risk [HR between 1.67 (CI 1.3-2.1) and 2.15 (CI 1.5-2.9) for different CNVs] for development of skin lesions independent of gender, age, and arsenic exposure. Some deletions had stronger effect in a specific gender (ZNF658 in males, SGCZ in females) and some had stronger effect in higher arsenic exposure (lincRNA CTD-3179P9.1) suggesting a possible gene-environment interaction. CONCLUSION: This first genome-wide CNV study in a prospectively followed-up large cohort, exposed to arsenic, suggests that DNA deletion in several genes and lincRNA genes may predispose an individual to a higher risk of development of arsenic-induced skin lesions.

Supplementation with Folic Acid, but Not Creatine, Increases Plasma Betaine, Decreases Plasma Dimethylglycine, and Prevents a Decrease in Plasma Choline in Arsenic-Exposed Bangladeshi Adults.

BACKGROUND: Folic acid (FA) supplementation facilitates urinary excretion of arsenic, a human carcinogen. A better understanding of interactions between one-carbon metabolism intermediates may improve the ability to design nutrition interventions that further facilitate arsenic excretion. OBJECTIVE: The objective was to determine if FA and/or creatine supplementation increase choline and betaine and decrease dimethylglycine (DMG). METHODS: We conducted a secondary analysis of the Folic Acid and Creatine Trial, a randomized trial in arsenic-exposed Bangladeshi adults (n = 605, aged 24-55 y, 50.3% male) who received arsenic-removal water filters. We examined treatment effects of FA and/or creatine supplementation on plasma choline, betaine, and DMG concentrations, measured by LC-tandem mass spectrometry at baseline and at week 12. Group comparisons were between 1) 400 and 800 µg FA/d (FA400 and FA800, respectively) compared with placebo, 2) creatine (3 g/d) compared with placebo, and 3) creatine plus FA400 compared with FA400. RESULTS: Choline decreased in the placebo group (-6.6%; 95% CI: -10.2%, -2.9%) but did not change in the FA groups (FA400: 2.5%; 95% CI: -0.9%, 6.1%; FA800: 1.4%; 95% CI: -2.5%, 5.5%; P < 0.05). Betaine did not change in the placebo group (-3.5%; 95% CI: -9.3%, 2.6%) but increased in the FA groups (FA400: 14.1%; 95% CI: 9.4%, 19.0%; FA800: 13.0%; 95% CI: 7.2%, 19.1%; P < 0.01). The decrease in DMG was greater in the FA groups (FA400: -26.7%; 95% CI: -30.9%, -22.2%; FA800: -27.8%; 95% CI: -31.8%, -23.4%) than in the placebo group (-12.3%; 95% CI: -18.1%, -6.2%; P < 0.01). The percentage change in choline, betaine, and DMG did not differ between creatine treatment arms and their respective reference groups. CONCLUSION: Supplementation for 12 wk with FA, but not creatine, increases plasma betaine, decreases plasma DMG, and prevents a decrease in plasma choline in arsenic-exposed Bangladeshi adults. This trial was registered at clinicaltrials.gov as NCT01050556.

Inorganic arsenic and respiratory health, from early life exposure to sex-specific effects: A systematic review.

This systematic review synthesizes the diverse body of epidemiologic research accrued on inorganic arsenic exposure and respiratory health effects. Twenty-nine articles were identified that examined the relationship between inorganic arsenic exposure and respiratory outcomes (i.e. lung function, symptoms, acute respiratory infections, chronic non-malignant lung diseases, and non-malignant lung disease mortality). There was strong evidence of a general association between arsenic and non-malignant respiratory illness, including consistent evidence on lung function impairment, acute respiratory tract infections, respiratory symptoms, and non-malignant lung disease mortality. Overall, early life exposure (i.e. in utero and/or early-childhood) had a marked effect throughout the lifespan. This review also identified some research gaps, including limited evidence at lower levels of exposure (water arsenic <100µg/L), mixed evidence of sex differences, and some uncertainty on arsenic and any single non-malignant respiratory disease or pathological process. Common limitations, including potential publication bias; non-comparability of outcome measures across included articles; incomplete exposure histories; and limited confounder control attenuated the cumulative strength of the evidence as it relates to US populations. This systematic review provides a comprehensive assessment of the epidemiologic evidence and should be used to guide future research on arsenic's detrimental effects on respiratory health.

Arsenite accumulation in the mouse eye.

Elevated arsenic (As) concentrations in drinking water are a major worldwide public health concern. Exposure to As is associated with carcinogenesis, skin lesions, cardiovascular disease, cognitive deficits, and other disorders. However, little is known regarding chronic As-mediated effects on the eye. Oxidative stress is believed to be an important factor in As-related pathology and is also implicated in certain eye diseases such as cataract. Thus, elevated exposure to arsenic could potentially be a contributing factor for ocular pathology. A pilot study was therefore initiated to determine whether As could be detected in eye tissue of mice exposed to sodium arsenite in drinking water. Total As concentrations were determined by inductively coupled plasma-mass spectroscopy in whole eyes, lens, liver, heart, lung, kidneys, spleen, brain, and hair from mice given 0, 10, 50, or 250 ppm sodium arsenite in their drinking water for 4 wk or 0, 10 or 50 ppm for 6 mo. Dose-dependent increases in As concentration were observed in all organs and tissues. Surprisingly, As concentrations in the eye and lens were significantly higher than those in liver, lung, heart, spleen, and brain and similar to that found in kidneys. The relatively high concentration in the eye, and the lens in particular, suggests As exposure may be a contributing factor in cataract formation in parts of the world where As in drinking water is endemic.

Low-Dose Creatine Supplementation Lowers Plasma Guanidinoacetate, but Not Plasma Homocysteine, in a Double-Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND: Creatine synthesis from guanidinoacetate consumes ~50% of s-adenosylmethionine (SAM)-derived methyl groups, accounting for an equivalent proportion of s-adenosylhomocysteine (SAH) and total homocysteine (tHcys) synthesis. Dietary creatine inhibits the synthesis of guanidinoacetate, thereby lowering plasma tHcys in rats. OBJECTIVE: We tested the hypotheses that creatine supplementation lowers plasma guanidinoacetate, increases blood SAM, lowers blood SAH, and lowers plasma tHcys. METHODS: Bangladeshi adults were randomly assigned to receive 1 of 4 treatments for 12 wk: placebo (n = 101), 3 g/d creatine (Cr; n = 101), 400 µg/d folic acid (FA; n = 153), or 3 g/d creatine plus 400 µg/d folic acid (Cr+FA; n = 103). The outcomes of plasma guanidinoacetate and tHcys, as well as whole blood SAM and SAH, were analyzed at baseline and week 12 by HPLC. Treatment effects of creatine supplementation were examined with the use of the group comparisons of Cr vs. placebo and Cr+FA vs. FA. RESULTS: Plasma guanidinoacetate declined by 10.6% (95% CI: 4.9, 15.9) in the Cr group while increasing nonsignificantly in the placebo group (3.7%; 95% CI: -0.8, 8.5) (Pgroup difference = 0.0002). Similarly, plasma guanidinoacetate declined by 9.0% (95% CI: 3.4, 14.2) in the Cr+FA group while increasing in the FA group (7.0%; 95% CI: 2.0, 12.2) (Pgroup difference < 0.0001). Plasma tHcys declined by 23.4% (95% CI: 19.5, 27.1) and 21.0% (95% CI: 16.4, 25.2) in the FA and Cr+FA groups, respectively (Pgroup difference = 0.41), with no significant changes in the placebo or Cr groups (Pgroup difference = 0.35). A decrease in guanidinoacetate over time was associated with a decrease in tHcys over time in the Cr+FA group (ß = 0.30; 95% CI: 0.17, 0.43; P < 0.0001). CONCLUSIONS: Our findings indicate that whereas creatine supplementation downregulates endogenous creatine synthesis, this may not on average lower plasma tHcys in humans. However, tHcys did decrease in those participants who experienced a decline in plasma guanidinoacetate while receiving creatine plus folic acid supplementation. This trial was registered at clinicaltrials.gov as NCT01050556.

Renal function is associated with indicators of arsenic methylation capacity in Bangladeshi adults.

BACKGROUND: Arsenic (As) methylation capacity in epidemiologic studies is typically indicated by the proportions of inorganic As (%InAs), monomethylarsonic acid (%MMA), and dimethylarsinic acid (%DMA) in urine as a fraction of total urinary As. The relationship between renal function and indicators of As methylation capacity has not been thoroughly investigated. OBJECTIVES: Our two aims were to examine (1) associations between estimated glomerular filtration rate (eGFR) and %As metabolites in blood and urine, and (2) whether renal function modifies the relationship of blood %As metabolites with respective urinary %As metabolites. METHODS: In a cross-sectional study of 375 As-exposed Bangladeshi adults, we measured blood and urinary As metabolites, and calculated eGFR from plasma cystatin C. RESULTS: In covariate-adjusted linear models, a 1 ml/min/1.73 m(2) increase in eGFR was associated with a 0.39% increase in urinary %InAs (p<0.0001) and a mean decrease in urinary %DMA of 0.07 (p=0.0005). In the 292 participants with measurable blood As metabolites, the associations of eGFR with increased blood %InAs and decreased blood %DMA did not reach statistical significance. eGFR was not associated with urinary or blood %MMA in covariate-adjusted models. For a given increase in blood %InAs, the increase in urinary %InAs was smaller in those with reduced eGFR, compared to those with normal eGFR (p=0.06); this effect modification was not observed for %MMA or %DMA. CONCLUSIONS: Urinary excretion of InAs may be impaired in individuals with reduced renal function. Alternatively, increased As methylation capacity (as indicated by decreased urinary %InAs) may be detrimental to renal function.

Arsenic exposure, telomere length, and expression of telomere-related genes among Bangladeshi individuals.

BACKGROUND: Inorganic arsenic is a carcinogen whose mode of action may involve telomere dysfunction. Recent epidemiological studies suggest that chronic arsenic exposure is associated with longer telomeres and altered expression of telomere-related genes in peripheral blood. In this study, we evaluated the association of urinary arsenic concentration with expression of telomere-related genes and telomere length in Bangladeshi individuals with a wide range of arsenic exposure through naturally contaminated drinking water. METHODS: We used linear regression models to estimate associations between urinary arsenic and array-based expression measures for 69 telomere related genes using mononuclear cell RNA samples from 1799 individuals. Association between arsenic exposure and a qPCR-based telomere length measure was assessed among 167 individuals. RESULTS: Urinary arsenic was positively associated with expression of WRN, and negatively associated with TERF2, DKC1, TERF2IP and OBFC1 (all P<0.00035, Bonferroni-corrected threshold). We detected interaction between urinary arsenic and arsenic metabolism efficiency in relation to expression of WRN (P for interaction =0.00008). In addition, we observed that very high arsenic exposure was associated with longer telomeres compared to very low exposure (P=0.02). DISCUSSION: Our findings suggest that arsenic's carcinogenic mode of action may involve alteration of telomere maintenance and/or telomere damage. This study extends our knowledge regarding the effect of arsenic on telomere length and expression of telomere-related genes.

Arsenic exposure is associated with pediatric pneumonia in rural Bangladesh: a case control study.

BACKGROUND: Pneumonia is the leading cause of death for children under 5 years of age globally, making research on modifiable risk factors for childhood pneumonia important for reducing this disease burden. Millions of children globally are exposed to elevated levels of arsenic in drinking water. However, there is limited data on the association between arsenic exposure and respiratory infections, particularly among pediatric populations. METHODS: This case control study of 153 pneumonia cases and 296 controls 28 days to 59 months of age in rural Bangladesh is the first to assess whether arsenic exposure is a risk factor for pneumonia in a pediatric population. Cases had physician diagnosed World Health Organization defined severe or very severe pneumonia. Urine collected during hospitalization (hospital admission time point) and 30 days later (convalescent time point) from cases and a single specimen from community controls was tested for urinary arsenic by graphite furnace atomic absorption. RESULTS: The odds for pneumonia was nearly double for children with urinary arsenic concentrations higher than the first quartile (≥6 µg/L) at the hospital admission time point (Odd Ratio (OR):1.88 (95% Confidence Interval (CI): 1.01, 3.53)), after adjustment for urinary creatinine, weight for height, breastfeeding, paternal education, age, and number of people in the household. This was consistent with findings at the convalescent time point where the adjusted OR for children with urinary arsenic concentrations greater than the first quartile (≥6 µg/L) was 2.32 (95% CI: 1.33, 4.02). CONCLUSION: We observed a nearly two times higher odds of pneumonia for children with creatinine adjusted urinary arsenic concentrations greater than the first quartile (≥6 µg/L) at the hospital admission time point. This novel finding suggests that low to moderate arsenic exposure may be a risk factor for pneumonia in children under 5 years of age.