Arsenic exposure and non-carcinogenic health effects.

Inorganic arsenic (iAs) exposure is a serious health problem that affects more than 140 million individuals worldwide, mainly, through contaminated drinking water. Acute iAs poisoning produces several symptoms such as nausea, vomiting, abdominal pain, and severe diarrhea, whereas prolonged iAs exposure increased the risk of several malignant disorders such as lung, urinary tract, and skin tumors. Another sensitive endpoint less described of chronic iAs exposure are the non-malignant health effects in hepatic, endocrine, renal, neurological, hematological, immune, and cardiovascular systems. The present review outlines epidemiology evidence and possible molecular mechanisms associated with iAs-toxicity in several non-carcinogenic disorders.

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.

[Overweight and obesity in indigenous nahuas from Ixtaczoquitlán, Veracruz, Mexico]. / Sobrepeso y obesidad en indígenas nahuas de Ixtaczoquitlán, Veracruz, México.

The study was aimed at determining the prevalence of overweight and obesity in indigenous nahuas from Ixtaczoquitlán, Veracruz, Mexico. For this purpose, a cross-cut study was conducted between 2010 and 2011, in which the body mass index (BMI) was calculated. To define overweight and obesity, the categories of the World Health Organization (WHO) and the Mexican Official Standard (NOM, Spanish acronym) were used. 227 nahuas (77,5% women) were included. According to WHO’s guidelines, the rate for overweight among nahuas was 41%, and 36.5% for obesity; according to NOM, it was 11.4 and 69.2% respectively. In conclusion, the prevalence of overweight and obesity among indigenous nahuas is high. Studies should be conducted to determine the prevalence and risk factors in order to develop prevention strategies based on this information to improve the health quality of these populations.

Sobrepeso y obesidad en indígenas nahuas de Ixtaczoquitlán, Veracruz, México / Overweight and obesity in indigenous nahuas from Ixtaczoquitlán, Veracruz, Mexico

El estudio tuvo como objetivo determinar la frecuencia de sobrepeso y obesidad en indígenas nahuas de Ixtaczoquitlán, Veracruz, México. Para ello, se realizó un estudio transversal entre los años 2010-2011; donde se calculó el índice de masa corporal (IMC). Para la definición de sobrepeso y obesidad se emplearon las categorías de la Organización Mundial de la Salud (OMS) y los de la Norma Oficial Mexicana (NOM). Se incluyó 227 nahuas (77,5% mujeres). Según los lineamientos de la OMS, la proporción de nahuas con sobrepeso fue de 41%, y de obesidad 36,5%; y según la NOM fue de 11,4 y 69,2% respectivamente. En conclusión, la frecuencia de sobrepeso y obesidad en indígenas nahuas es alta. Deben realizarse estudios enfocados a determinar la prevalencia y factores de riesgo y, con ello, desarrollar estrategias de prevención que mejoren la calidad de salud de estas poblaciones.

The study was aimed at determining the prevalence of overweight and obesity in indigenous nahuas from Ixtaczoquitlán, Veracruz, Mexico. For this purpose, a cross-cut study was conducted between 2010 and 2011, in which the body mass index (BMI) was calculated. To define overweight and obesity, the categories of the World Health Organization (WHO) and the Mexican Official Standard (NOM, Spanish acronym) were used. 227 nahuas (77,5% women) were included. According to WHO’s guidelines, the rate for overweight among nahuas was 41%, and 36.5% for obesity; according to NOM, it was 11.4 and 69.2% respectively. In conclusion, the prevalence of overweight and obesity among indigenous nahuas is high. Studies should be conducted to determine the prevalence and risk factors in order to develop prevention strategies based on this information to improve the health quality of these populations.

Dose-dependent urinary phenotype of inorganic arsenic methylation in mice with a focus on trivalent methylated metabolites.

Inorganic arsenic (iAs) exposure has been associated with the increased risk of various forms of cancer and of non-cancerous diseases. Metabolic conversions of iAs that yield highly toxic and genotoxic methylarsonite (MAsIII) and dimethylarsinite (DMAsIII) may play a significant role in determining the extent and character of toxic and cancer-promoting effects of iAs exposure. However, in vivo research involving the production of MAsIII and DMAsIII remains an area of ongoing investigation and debate. The results of metabolic and toxicity studies using mice have been entirely applicable to other species including humans. The goal of this study was to investigate the phenotype for the trivalent and pentavalent arsenic metabolites in relation to arsenite dose via immediate analysis of fresh urine samples, while preventing the oxidation of unstable methylated AsIII-containing metabolites. Female mice (C57BL/6) received sodium arsenite by gavage at doses of 0, 3, 6 or 10 mg As/kg/day for 9 days, after which trivalent methylated arsenicals were detected in 100% of urine samples; these arsenicals were not detected in the urine of control mice. The amount of DMAsIII detected in urine depended on the dose of arsenite administered and was determined to be 50.2%, 31.4% and 16.5% of the total urinary arsenic in mice exposed to 3, 6, or 10 mg/kg/day, respectively. This relationship is consistent with the hypothesis of inhibition or saturation of iAs methylation. Understanding the in vivo production of MAsIII and DMAsIII in mice exposed to iAs could aid in developing a biologically based dose-response model for iAs.

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.

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.

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.

Chronic arsenic exposure increases TGFalpha concentration in bladder urothelial cells of Mexican populations environmentally exposed to inorganic arsenic.

Inorganic arsenic (iAs) is a well-established carcinogen and human exposure has been associated with a variety of cancers including those of skin, lung, and bladder. High expression of transforming growth factor alpha (TGF-alpha) has associated with local relapses in early stages of urinary bladder cancer. iAs exposures are at least in part determined by the rate of formation and composition of iAs metabolites (MAs(III), MAs(V), DMAs(III), DMAs(V)). This study examines the relationship between TGF-alpha concentration in exfoliated bladder urothelial cells (BUC) separated from urine and urinary arsenic species in 72 resident women (18-51 years old) from areas exposed to different concentrations of iAs in drinking water (2-378 ppb) in central Mexico. Urinary arsenic species, including trivalent methylated metabolites were measured by hydride generation atomic absorption spectrometry method. The concentration of TGF-alpha in BUC was measured using an ELISA assay. Results show a statistically significant positive correlation between TGF-alpha concentration in BUC and each of the six arsenic species present in urine. The multivariate linear regression analyses show that the increment of TGF-alpha levels in BUC was importantly associated with the presence of arsenic species after adjusting by age, and presence of urinary infection. People from areas with high arsenic exposure had a significantly higher TGF-alpha concentration in BUC than people from areas of low arsenic exposure (128.8 vs. 64.4 pg/mg protein; p<0.05). Notably, exfoliated cells isolated from individuals with skin lesions contained significantly greater amount of TGF-alpha than cells from individuals without skin lesions: 157.7 vs. 64.9 pg/mg protein (p=0.003). These results suggest that TGF-alpha in exfoliated BUC may serve as a susceptibility marker of adverse health effects on epithelial tissue in arsenic-endemic areas.

Urinary trivalent methylated arsenic species in a population chronically exposed to inorganic arsenic.

Chronic exposure to inorganic arsenic (iAs) has been associated with increased risk of various forms of cancer and of noncancerous diseases. Metabolic conversions of iAs that yield highly toxic and genotoxic methylarsonite (MAsIII) and dimethylarsinite (DMAsIII) may play a significant role in determining the extent and character of toxic and cancer-promoting effects of iAs exposure. In this study we examined the relationship between urinary profiles of MAsIII and DMAsIII and skin lesion markers of iAs toxicity in individuals exposed to iAs in drinking water. The study subjects were recruited among the residents of an endemic region of central Mexico. Drinking-water reservoirs in this region are heavily contaminated with iAs. Previous studies carried out in the local populations have found an increased incidence of pathologies, primarily skin lesions, that are characteristic of arseniasis. The goal of this study was to investigate the urinary profiles for the trivalent and pentavalent As metabolites in both high- and low-iAs-exposed subjects. Notably, methylated trivalent arsenicals were detected in 98% of analyzed urine samples. On average, the major metabolite, DMAsIII, represented 49% of total urinary As, followed by DMAsV (23.7%), iAsV (8.6%), iAsIII (8.5%), MAsIII (7.4%), and MAsV (2.8%). More important, the average MAsIII concentration was significantly higher in the urine of exposed individuals with skin lesions compared with those who drank iAs-contaminated water but had no skin lesions. These data suggest that urinary levels of MAsIII, the most toxic species among identified metabolites of iAs, may serve as an indicator to identify individuals with increased susceptibility to toxic and cancer-promoting effects of arseniasis.