Maternal serum concentrations of one-carbon metabolism factors modify the association between biomarkers of arsenic methylation efficiency and birth weight.

BACKGROUND: Inorganic arsenic (iAs) is a ubiquitous metalloid and drinking water contaminant. Prenatal exposure is associated with birth outcomes across multiple studies. During metabolism, iAs is sequentially methylated to mono- and di-methylated arsenical species (MMAs and DMAs) to facilitate whole body clearance. Inefficient methylation (e.g., higher urinary % MMAs) is associated with increased risk of certain iAs-associated diseases. One-carbon metabolism factors influence iAs methylation, modifying toxicity in adults, and warrant further study during the prenatal period. The objective of this study was to evaluate folate, vitamin B12, and homocysteine as modifiers of the relationship between biomarkers of iAs methylation efficiency and birth outcomes. METHODS: Data from the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort (2011-2012)  with maternal urine and cord serum arsenic biomarkers and maternal serum folate, vitamin B12, and homocysteine concentrations were utilized. One-carbon metabolism factors were dichotomized using clinical cutoffs and median splits. Multivariable linear regression models were fit to evaluate associations between each biomarker and birth outcome overall and within levels of one-carbon metabolism factors. Likelihood ratio tests of full and reduced models were used to test the significance of statistical interactions on the additive scale (α = 0.10). RESULTS: Among urinary biomarkers, % U-MMAs was most strongly associated with birth weight (ß = - 23.09, 95% CI: - 44.54, - 1.64). Larger, more negative mean differences in birth weight were observed among infants born to women who were B12 deficient (ß = - 28.69, 95% CI: - 53.97, - 3.42) or experiencing hyperhomocysteinemia (ß = - 63.29, 95% CI: - 154.77, 28.19). Generally, mean differences in birth weight were attenuated among infants born to mothers with higher serum concentrations of folate and vitamin B12 (or lower serum concentrations of homocysteine). Effect modification by vitamin B12 and homocysteine was significant on the additive scale for some associations. Results for gestational age were less compelling, with an approximate one-week mean difference associated with C-tAs (ß = 0.87, 95% CI: 0, 1.74), but not meaningful otherwise. CONCLUSIONS: Tissue distributions of iAs and its metabolites (e.g., % MMAs) may vary according to serum concentrations of folate, vitamin B12 and homocysteine during pregnancy. This represents a potential mechanism through which maternal diet may modify the harms of prenatal exposure to iAs.

Effects of ALAD genotype on the relationship between lead exposure and anthropometry in a Cohort of Mexican children.

OBJECTIVES: Lead exposure is associated with children's growth, but this relationship may depend on the presence of susceptibility factors, including genetic variation. Blood lead levels (BLL) differ by ALAD (aminolevulinic acid dehydratase) genotype. We investigated the association between BLL and growth in Mexican first-graders with different ALAD genotypes. METHODS: Children between the ages of 6-8 years (n = 602) attending first grade in schools within the vicinity of a metal foundry in Torreón, Mexico were enrolled into a randomized controlled trial (RCT) testing the efficacy of iron and/or zinc supplementation on blood lead levels (BLL) and cognition. BLL and anthropometry were assessed at baseline (height, height-for-age z-score (HAZ), knee height, head circumference), after 6 (head circumference) and 12 months (height, HAZ, knee height). Children with ALAD1-1 and ALAD1-2/2-2 were compared. The study sample included 538 and 470 participants who had complete data at baseline and follow-up, respectively. Separate multivariable linear regression models adjusted for covariates were used to test the association between BLL at baseline and each anthropometric measure. Covariates included age, sex, hemoglobin, crowding, and maternal education. BLL x ALAD genotype interaction term was tested. RESULTS: Median BLL (10.1 µg/dL) did not differ by ALAD genotype. After covariate adjustment, baseline BLL was inversely associated with baseline height, HAZ, and knee height. The association (ß [95% CI]) between BLL and baseline height (-0.38[-0.68, -0.09]), HAZ (-0.07[-0.12, -0.02]) and knee height (-0.14[-0.25, -0.02]), was somewhat stronger in children with ALAD1-2/2-2 than ALAD1-1 (-0.09[-0.16, -0.02], -0.02[-0.03, -0.004] and -0.04[-0.06, -0.01], respectively). No associations between BLL and growth at 6 or 12 months were detected irrespective of ALAD genotype. CONCLUSIONS: BLL was adversely associated with anthropometric measures among Mexican children. ALAD genotype may be a susceptibility factor for the effects of lead on child growth.

Circulating miRNAs Associated with Arsenic Exposure.

Arsenic (As) is a toxic metalloid. Inorganic arsenic (iAs) is a form of As commonly found in drinking water and in some foods. Overwhelming evidence suggests that people chronically exposed to iAs are at risk of developing cancer or cardiovascular, neurological, and metabolic diseases. Although the mechanisms underlying iAs-associated illness remain poorly characterized, a growing body of literature raises the possibility that microRNAs (miRNAs), post-transcriptional gene suppressors, may serve as mediators and/or early indicators of the pathologies associated with iAs exposure. To characterize the circulating miRNA profiles of individuals chronically exposed to iAs, samples of plasma were collected from 109 healthy residents of the city of Zimapán and the Lagunera area in Mexico, the regions with historically high exposures to iAs in drinking water. These plasma samples were analyzed for small RNAs using high-throughput sequencing and for iAs and its methylated metabolites. Associations between plasma levels of arsenic species and miRNAs were evaluated. Six circulating miRNAs (miRs-423-5p, -142-5p -2, -423-5p +1, -320c-1, -320c-2, and -454-5p), two of which have been previously linked to cardiovascular disease and diabetes (miRs-423-5p, -454-5p), were found to be significantly correlated with plasma MAs. No miRNAs were associated with plasma iAs or DMAs after correction for multiple testing. These miRNAs may represent mechanistic links between iAs exposure and disease or serve as markers of disease risks associated with this exposure.

Iron and Zinc Supplementation Does Not Impact Urinary Arsenic Excretion in Mexican School Children.

OBJECTIVE: To examine the role of iron and zinc in arsenic excretion and metabolism in children. STUDY DESIGN: An analysis of urinary arsenic (UAs) concentrations from a double-blind randomized trial originally testing the efficacy of iron and zinc for lowering blood lead levels in children. A 2 × 2 factorial design was used, with children randomized individually, stratified by sex and classroom, to receive 30?mg ferrous fumarate (n?=?148), 30?mg zinc oxide (n?=?144), iron and zinc together (n?=?148), or placebo (n?=?151). Of the 602 children enrolled, 527 completed the 6-month treatment, and 485 had both baseline and final UAs values. The baseline total UAs concentration ranged from 3.2 to 215.9?µg/L. RESULTS: At baseline, children in the highest tertile of serum ferritin concentration had higher excretion of dimethylarsinic acid (DMA; 1.93?±?0.86%; P?

Neonatal Metabolomic Profiles Related to Prenatal Arsenic Exposure.

Prenatal inorganic arsenic (iAs) exposure is associated with health effects evident at birth and later in life. An understanding of the relationship between prenatal iAs exposure and alterations in the neonatal metabolome could reveal critical molecular modifications, potentially underpinning disease etiologies. In this study, nuclear magnetic resonance (NMR) spectroscopy-based metabolomic analysis was used to identify metabolites in neonate cord serum associated with prenatal iAs exposure in participants from the Biomarkers of Exposure to ARsenic (BEAR) pregnancy cohort, in Gómez Palacio, Mexico. Through multivariable linear regression, ten cord serum metabolites were identified as significantly associated with total urinary iAs and/or iAs metabolites, measured as %iAs, %monomethylated arsenicals (MMAs), and %dimethylated arsenicals (DMAs). A total of 17 metabolites were identified as significantly associated with total iAs and/or iAs metabolites in cord serum. These metabolites are indicative of changes in important biochemical pathways such as vitamin metabolism, the citric acid (TCA) cycle, and amino acid metabolism. These data highlight that maternal biotransformation of iAs and neonatal levels of iAs and its metabolites are associated with differences in neonate cord metabolomic profiles. The results demonstrate the potential utility of metabolites as biomarkers/indicators of in utero environmental exposure.

Sex differences in the reduction of arsenic methylation capacity as a function of urinary total and inorganic arsenic in Mexican children.

Chronic arsenic (As) exposure decreases adult and children's ability to methylate inorganic As (iAs); however, few studies have examined children's sex differences. We measured urinary concentrations of iAs, monomethylarsonic (MMA), and dimethylarsinic (DMA) acids, and calculated the primary (PMI: MMA/iAs) and secondary (SMI: DMA/MMA) methylation capacity indexes in 591 children 6-8 years in Torreón, Mexico. We determined iAs, MMA, and DMA by hydride generation cryotrapping AAS. Lineal regression models estimated associations between methylation capacity and total As (TAs) or iAs. Interactions with sex were tested at p<0.10. Boys had significantly higher TAs levels, (58.4µg/L) than girls (46.2µg/L). We observed negative associations between TAs and PMI (ß=-0.039; p<0.18) and SMI (ß=-0.08; p=0.002) with significant sex differences; PMI reduction was significant in boys (ß=-0.09; p=0.02) but not in girls (ß=0.021; p=0.63), p for interaction=0.06. In contrast, SMI reduction was significantly more pronounced in girls. Furthermore, negative associations PMI (ß=-0.19; p<0.001) and SMI (ß=-0.35; p<0.001) were a function of urinary iAs levels, independently of TAs; however, the reduction in PMI was more pronounced in boys (ß=-0.24; p<0.001; girls ß=-0.15; p<0.001), p for interaction=0.04. A significant negative association was observed between SMI and iAs levels without significant sex differences. TAs and iAs associations with metabolite percentages were in good agreement with those observed with methylation indexes. Our results suggest that iAs plays an important role in reducing As methylation ability and that significant sex differences are present in As metabolism. These differences merit further investigation to confirm our findings and their potential implications for arsenic toxicity in children.

The relationship between blood lead levels and occupational exposure in a pregnant population.

BACKGROUND: Pregnant women exposed to lead are at risk of suffering reproductive damages, such as miscarriage, preeclampsia, premature delivery and low birth weight. Despite that the workplace offers the greatest potential for lead exposure, there is relatively little information about occupational exposure to lead during pregnancy. This study aims to assess the association between blood lead levels and occupational exposure in pregnant women from Durango, Mexico. METHODS: A cross-sectional study was carried out in a population of 299 pregnant women. Blood lead was measured in 31 women who worked in jobs where lead is used (exposed group) and 268 who did not work in those places (control group). Chi-square test was applied to compare exposed and control groups with regard to blood lead levels. Odds ratio (OR) and 95% confidence intervals (CI) were calculated. Multivariable regression analysis was applied to determine significant predictors of blood lead concentrations in the exposed group. RESULTS: Exposed women had higher blood lead levels than those in the control group (4.00 ± 4.08 µg/dL vs 2.65 ± 1.75 µg/dL, p = 0.002). Furthermore, women in the exposed group had 3.82 times higher probability of having blood lead levels ≥ 5 µg/dL than those in the control group. Wearing of special workwear, changing clothes after work, living near a painting store, printing office, junkyard or rubbish dump, and washing the workwear together with other clothes resulted as significant predictors of elevated blood lead levels in the exposed group. CONCLUSIONS: Pregnant working women may be at risk of lead poisoning because of occupational and environmental exposure. The risk increases if they do not improve the use of protective equipment and their personal hygiene.

Identification of novel gene targets and putative regulators of arsenic-associated DNA methylation in human urothelial cells and bladder cancer.

There is strong epidemiologic evidence linking chronic exposure to inorganic arsenic (iAs) to myriad adverse health effects, including cancer of the bladder. We set out to identify DNA methylation patterns associated with arsenic and its metabolites in exfoliated urothelial cells (EUCs) that originate primarily from the urinary bladder, one of the targets of arsenic-induced carcinogenesis. Genome-wide, gene-specific promoter DNA methylation levels were assessed in EUCs from 46 residents of Chihuahua, Mexico, and the relationship was examined between promoter methylation profiles and the intracellular concentrations of total arsenic and arsenic species. A set of 49 differentially methylated genes was identified with increased promoter methylation associated with EUC tAs, iAs, and/or monomethylated As (MMAs) enriched for their roles in metabolic disease and cancer. Notably, no genes had differential methylation associated with EUC dimethylated As (DMAs), suggesting that DMAs may influence DNA methylation-mediated urothelial cell responses to a lesser extent than iAs or MMAs. Further analysis showed that 22 of the 49 arsenic-associated genes (45%) are also differentially methylated in bladder cancer tissue identified using The Cancer Genome Atlas repository. Both the arsenic- and cancer-associated genes are enriched for the binding sites of common transcription factors known to play roles in carcinogenesis, demonstrating a novel potential mechanistic link between iAs exposure and bladder cancer.

Relationship between blood lead levels and hematological indices in pregnant women.

Several studies have revealed a negative association between blood lead levels and hematological impairment. In this cross-sectional study, we examined the relationship between blood lead levels and hematological indices in 292 pregnant women from Durango, Mexico. Apparently healthy pregnant women, aged 14-41 years and at 3-41 weeks of gestation, were recruited between June 2007 and May 2008. Blood lead and hematological indices were measured. The mean blood lead was 2.79 ± 2.16 µg/dL, and lead levels ≥ 5 µg/dL were detected in 25 women (8.6%). Hemoglobin, hematocrit, and red blood cells count were significantly higher in pregnant women with a blood lead concentration of ≥ 5 µg/dL than the group with lower blood lead levels (p < .05). Mean corpuscular volume and mean corpuscular hemoglobin were not significantly related to lead levels. Hemoglobin and hematocrit showed a non-significant positive correlation with blood lead, but the correlation between red blood cell count and blood lead levels was statistically significant (r = 0.185, p = .002). The findings suggest that a positive association between blood lead and some hematological indices may occur at relatively low blood lead concentration (mean < 5 µg/dL).

Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation.

Biotransformation of inorganic arsenic (iAs) is one of the factors that determines the character and magnitude of the diverse detrimental health effects associated with chronic iAs exposure, but it is unknown how iAs biotransformation may impact the epigenome. Here, we integrated analyses of genome-wide, gene-specific promoter DNA methylation levels of peripheral blood leukocytes with urinary arsenical concentrations of subjects from a region of Mexico with high levels of iAs in drinking water. These analyses revealed dramatic differences in DNA methylation profiles associated with concentrations of specific urinary metabolites of arsenic (As). The majority of individuals in this study had positive indicators of As-related disease, namely pre-diabetes mellitus or diabetes mellitus (DM). Methylation patterns of genes with known associations with DM were associated with urinary concentrations of specific iAs metabolites. Future studies will determine whether these DNA methylation profiles provide mechanistic insight into the development of iAs-associated disease, predict disease risk, and/or serve as biomarkers of iAs exposure in humans.

Identification of the GST-T1 and GST-M1 null genotypes using high resolution melting analysis.

Glutathione S-transferases, including GST-T1 and GST-M1, are known to be involved in the phase II detoxification pathways for xenobiotics as well as in the metabolism of endogenous compounds. Polymorphisms in these genes have been linked to an increased susceptibility to carcinogenesis and associated with risk factors that predispose to certain inflammatory diseases. In addition, GST-T1 and GST-M1 null genotypes have been shown to be responsible for interindividual variations in the metabolism of arsenic, a known human carcinogen. To assess the specific GST genotypes in the Mexican population chronically exposed to arsenic, we have developed a multiplex High Resolution Melting PCR (HRM-PCR) analysis using a LightCycler480 instrument. This method is based on analysis of the PCR product melting curve that discriminates PCR products according to their lengths and base sequences. Three pairs of primers that specifically recognize GST-T1, GST-M1, and ß-globin, an internal control, to produce amplicons of different length were designed and combined with LightCycler480 High Resolution Melting Master Mix containing ResoLight, a completely saturating DNA dye. Data collected from melting curve analysis were evaluated using LightCycler480 software to determine specific melting temperatures of individual melting curves representing target genes. Using this newly developed multiplex HRM-PCR analysis, we evaluated GST-T1 and GST-M1 genotypes in 504 DNA samples isolated from the blood of individuals residing in Zimapan, Lagunera, and Chihuahua regions in Mexico. We found that the Zimapan and Lagunera populations have similar GST-T1 and GST-M1 genotype frequencies which differ from those of the Chihuahua population. In addition, 14 individuals have been identified as carriers of the double null genotype, i.e., null genotypes in both GST-T1 and GST-M1 genes. Although this procedure does not distinguish between biallelic (+/+) and monoallelic (+/-) genotypes, it can be used in an automated workflow as a simple, sensitive, and time and money saving procedure for rapid identification of the GST-T1 and GST-M1 positive or null genotypes.

Epigenetic changes in individuals with arsenicosis.

Inorganic arsenic (iAs) is an environmental toxicant currently poisoning millions of people worldwide, and chronically exposed individuals are susceptible to arsenicosis or arsenic poisoning. Using a state-of-the-art technique to map the methylomes of our study subjects, we identified a large interactome of hypermethylated genes that are enriched for their involvement in arsenic-associated diseases, such as cancer, heart disease, and diabetes. Notably, we have uncovered an arsenic-induced tumor suppressorome, a complex of 17 tumor suppressors known to be silenced in human cancers. This finding represents a pivotal clue in unraveling a possible epigenetic mode of arsenic-induced disease.

Follow-up study on lead exposure in children living in a smelter community in northern Mexico.

BACKGROUND: To study the changes of children lead exposure in the city of Torreon during the last five years, after environmental and public health interventions, using the timeline of lead in blood concentration as the biomarker of exposure and its relation to lead in soil concentrations. METHODS: This follow-up study started in 2001 and consisted of 232 children living in nine neighborhoods in Torreon. Children were tested at 0, 6, 12 and 60 months. Lead in blood concentrations, Hemoglobin, Zinc-Protoporphyrin, anthropometric measures and socioeconomic status questionnaire was supplied to the parents. RESULTS: Median and range of lead in blood concentrations obtained at 0, 6, 12, 60 months were: 10.12 µg/dl (1.9 - 43.8), 8.75 µg/dl (1.85 - 41.45), 8.4 µg/dl (1.7 - 35.8) and 4.4 µg/dl (1.3 - 30.3), respectively. The decrease of lead in blood levels was significantly related to ages 0, 6, 12 and 60 months of the follow-up study. The timeline of B-Pb was associated with the timeline of lead in soil concentrations. CONCLUSIONS: B-Pb levels have significantly decreased in the group of children studied. This could be explained by a) environmental interventions by authorities and the smelter companies, b) normal changes in hygienic habits as children age and c) lead redistribution from blood to hard tissues.

Exposure to arsenic in drinking water is associated with increased prevalence of diabetes: a cross-sectional study in the Zimapán and Lagunera regions in Mexico.

BACKGROUND: Human exposures to inorganic arsenic (iAs) have been linked to an increased risk of diabetes mellitus. Recent laboratory studies showed that methylated trivalent metabolites of iAs may play key roles in the diabetogenic effects of iAs. Our study examined associations between chronic exposure to iAs in drinking water, metabolism of iAs, and prevalence of diabetes in arsenicosis-endemic areas of Mexico. METHODS: We used fasting blood glucose (FBG), fasting plasma insulin (FPI), oral glucose tolerance test (OGTT), glycated hemoglobin (HbA1c), and insulin resistance (HOMA-IR) to characterize diabetic individuals. Arsenic levels in drinking water and urine were determined to estimate exposure to iAs. Urinary concentrations of iAs and its trivalent and pentavalent methylated metabolites were measured to assess iAs metabolism. Associations between diabetes and iAs exposure or urinary metabolites of iAs were estimated by logistic regression with adjustment for age, sex, hypertension and obesity. RESULTS: The prevalence of diabetes was positively associated with iAs in drinking water (OR 1.13 per 10 ppb, p < 0.01) and with the concentration of dimethylarsinite (DMAsIII) in urine (OR 1.24 per inter-quartile range, p = 0.05). Notably, FPI and HOMA-IR were negatively associated with iAs exposure (ß -2.08 and -1.64, respectively, p < 0.01), suggesting that the mechanisms of iAs-induced diabetes differ from those underlying type-2 diabetes, which is typically characterized by insulin resistance. CONCLUSIONS: Our study confirms a previously reported, but frequently questioned, association between exposure to iAs and diabetes, and is the first to link the risk of diabetes to the production of one of the most toxic metabolites of iAs, DMAsIII.

Toxicity in Goats Exposed to Arsenic in the Region Lagunera, Northern Mexico.

The Region Lagunera, a region in northeast Mexico, is undergoing significant problems with the quality of its groundwater, which exceeds the permissible limits of contaminants and/or heavy metals stipulated in Mexican legislation. The present study evaluated chronic toxicity in male goats exposed to arsenic via one ex situ Group 1 (n = 5) and one in situ female goats Group 3 (n = 10). The treatment in Group 1 was carried out in the La Laguna experimental field of the Instituto Nacional de Investigaciones Forestales, Agrícolas y Pecuarias (INIFAP), located in Matamoros, Coahuila, Mexico. Sodium arsenite (2 mg/kg) was orally administered for 84 days to five male Creole goats, aged between four and five years old and weighing between 60 and 70 kg, in order to determine its effect on urine toxicity, libido, and physiological condition, an untreated group (n = 5) was included (Group 2). The experiment in group 3 was conducted on ten female Creole goats, aged between four and six years old and weighing between 40 and 49 kg, in both the contaminated sampling area in the rural community of El Venado and the control sampling area in the rural community of Nuevo Reynosa (Group 4 (n = 5)), in which the arsenic levels were measured in the urine of the exposed goats, as was their physiological condition. Significant differences (p < 0.01) between the groups were found in both the arsenic concentration in the urine and the physiological condition observed in both experimental groups.

Association of AS3MT polymorphisms and the risk of premalignant arsenic skin lesions.

Exposure to naturally occurring inorganic arsenic (iAs), primarily from contaminated drinking water, is considered one of the top environmental health threats worldwide. Arsenic (+3 oxidation state) methyltransferase (AS3MT) is the key enzyme in the biotransformation pathway of iAs. AS3MT catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to trivalent arsenicals, resulting in the production of methylated (MAs) and dimethylated arsenicals (DMAs). MAs is a susceptibility factor for iAs-induced toxicity. In this study, we evaluated the association of the polymorphism in AS3MT gene with iAs metabolism and with the presence of arsenic (As) premalignant skin lesions. This is a case-control study of 71 cases with skin lesions and 51 controls without skin lesions recruited from a iAs endemic area in Mexico. We measured urinary As metabolites, differentiating the trivalent and pentavalent arsenical species, using the hydride generation atomic absorption spectrometry. In addition, the study subjects were genotyped to analyze three single nucleotide polymorphisms (SNPs), A-477G, T14458C (nonsynonymus SNP; Met287Thr), and T35587C, in the AS3MT gene. We compared the frequencies of the AS3MT alleles, genotypes, and haplotypes in individuals with and without skin lesions. Marginal differences in the frequencies of the Met287Thr genotype were identified between individuals with and without premalignant skin lesions (p=0.055): individuals carrying the C (TC+CC) allele (Thr) were at risk [odds ratio=4.28; 95% confidence interval (1.0-18.5)]. Also, individuals with C allele of Met287Thr displayed greater percentage of MAs in urine and decrease in the percentage of DMAs. These findings indicate that Met287Thr influences the susceptibility to premalignant As skin lesions and might be at increased risk for other adverse health effects of iAs exposure.

Evaluation of plasma arsenicals as potential biomarkers of exposure to inorganic arsenic.

Exposure to inorganic arsenic (iAs) remains a global public health problem. Urinary arsenicals are the current gold-standard for estimating both iAs exposure and iAs metabolism. However, the distribution of these arsenicals may differ between the urine and target organs. Instead, plasma arsenicals may better represent internal dose and capture target organ exposure to arsenicals. Drinking water iAs, plasma and urinary arsenicals were quantified in individuals living in the Zimapan and Lagunera regions of Mexico. The relationship between drinking water iAs and plasma arsenicals was examined using both Spearman correlations and multivariable linear regression models. In addition, the distribution of arsenicals in plasma and urine was examined and the association between plasma and urinary arsenicals was assessed using both Spearman correlations and multivariable linear regression models. Levels of iAs in drinking water were significantly associated with plasma arsenicals in unadjusted and adjusted analyses and the strength of these associations was similar to that of drinking water iAs and urinary arsenicals. These results suggest that plasma arsenicals are reliable biomarkers of iAs exposure via drinking water. However, there were notable differences between the profiles of arsenicals in the plasma and the urine. Key differences between the proportions of arsenicals in plasma and urine may indicate that urine and plasma arsenicals reflect different aspects of iAs toxicokinetics, including metabolism and excretion.

Correction to: Maternal one carbon metabolism and arsenic methylation in a pregnancy cohort in Mexico.

A correction to this paper has been published and can be accessed via link at the top of the paper.

One-carbon metabolism nutrient intake and the association between body mass index and urinary arsenic metabolites in adults in the Chihuahua cohort.

BACKGROUND: Exposure to inorganic arsenic (iAs) via drinking water is a serious global health threat. Various factors influence susceptibility to iAs-associated health outcomes, including differences in iAs metabolism. Previous studies have shown that obesity is associated with iAs metabolism. It has been hypothesized that this association can be explained by confounding from nutritional factors involved in one-carbon metabolism, such as folate or other B vitamins, whose intake may differ across BMI categories and is known be associated with iAs metabolism. However, no studies have explored whether this association is confounded by nutritional factors. METHODS: We investigated the relationship between body mass index (BMI) and the distribution of urinary arsenic species in a cross-sectional cohort of 1166 adults living in Chihuahua, Mexico from 2008 to 2013. Nutrient intake related to one-carbon metabolism, including folate, vitamin B2, and vitamin B12, was assessed using a food frequency questionnaire developed for Mexican populations. Multivariable linear regression was used to estimate the association between BMI and the distribution of urinary arsenic metabolites. Effect modification by drinking water iAs level and sex was also examined. RESULTS: After adjusting for potential confounders, including age, educational attainment, smoking, alcohol consumption, seafood consumption, water iAs, and sex, BMI was negatively associated with the proportion of urinary inorganic arsenic (%U-iAs) and urinary monomethylated arsenic (%U-MMAs) and positively associated with urinary dimethylated arsenic (%U-DMAs). This relationship was not influenced by additional adjustment for folate, vitamin B2, or vitamin B12 intake. Additionally, there was significant effect modification by both drinking water iAs level and sex. CONCLUSIONS: This study provides further evidence for an association between BMI and arsenic metabolism. However, contrary to previous hypotheses, these results suggest that this association is not confounded by the intake of micronutrients involved in one-carbon metabolism.

Speciation of arsenic in exfoliated urinary bladder epithelial cells from individuals exposed to arsenic in drinking water.

BACKGROUND: The concentration of arsenic in urine has been used as a marker of exposure to inorganic As (iAs). Relative proportions of urinary metabolites of iAs have been identified as potential biomarkers of susceptibility to iAs toxicity. However, the adverse effects of iAs exposure are ultimately determined by the concentrations of iAs metabolites in target tissues. OBJECTIVE: In this study we examined the feasibility of analyzing As species in cells that originate in the urinary bladder, a target organ for As-induced cancer in humans. METHODS: Exfoliated bladder epithelial cells (BECs) were collected from urine of 21 residents of Zimapan, Mexico, who were exposed to iAs in drinking water. We determined concentrations of iAs, methyl-As (MAs), and dimethyl-As (DMAs) in urine using conventional hydride generation-cryotrapping-atomic absorption spectrometry (HG-CT-AAS). We used an optimized HG-CT-AAS technique with detection limits of 12-17 pg As for analysis of As species in BECs. RESULTS: All urine samples and 20 of 21 BEC samples contained detectable concentrations of iAs, MAs, and DMAs. Sums of concentrations of these As species in BECs ranged from 0.18 to 11.4 ng As/mg protein and in urine from 4.8 to 1,947 ng As/mL. We found no correlations between the concentrations or ratios of As species in BECs and in urine. CONCLUSION: These results suggest that urinary levels of iAs metabolites do not necessarily reflect levels of these metabolites in the bladder epithelium. Thus, analysis of As species in BECs may provide a more effective tool for risk assessment of bladder cancer and other urothelial diseases associated with exposures to iAs.