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Variants in AS3MT, the gene encoding arsenic (+3 oxidation state) methyltranserase, have been shown to influence patterns of inorganic arsenic (iAs) metabolism. Several studies have suggested that capacity to metabolize iAs may vary depending on levels of iAs exposure. However, it is not known whether the influence of variants in AS3MT on iAs metabolism also vary by level of exposure. We investigated, in a population of Mexican adults exposed to drinking water As, whether associations between 7 candidate variants in AS3MT and urinary iAs metabolites were consistent with prior studies, and whether these associations varied depending on the level of exposure. Overall, associations between urinary iAs metabolites and AS3MT variants were consistent with the literature. Referent genotypes, defined as the genotype previously associated with a higher percentage of urinary dimethylated As (DMAs%), were associated with significant increases in the DMAs% and ratio of DMAs to monomethylated As (MAs), and significant reductions in MAs% and iAs%. For 3 variants, associations between genotypes and iAs metabolism were significantly stronger among subjects exposed to water As >50 versus ≤50 ppb (water As X genotype interaction P < .05). In contrast, for 1 variant (rs17881215), associations were significantly stronger at exposures ≤50 ppb. Results suggest that iAs exposure may influence the extent to which several AS3MT variants affect iAs metabolism. The variants most strongly associated with iAs metabolism--and perhaps with susceptibility to iAs-associated disease--may vary in settings with exposure level. [ABSTRACT FROM AUTHOR]

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 (β = - 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 (β = - 28.69, 95% CI: - 53.97, - 3.42) or experiencing hyperhomocysteinemia (β = - 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 (β = 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. [ABSTRACT FROM AUTHOR]

Chronic exposure to inorganic arsenic (iAs), a common drinking water and food contaminant, has been associated with an increased risk of type 2 diabetes in population studies worldwide. Several mechanisms underlying the diabetogenic effects of iAs have been proposed through laboratory investigations. We have previously shown that exposure to arsenite (iAs(III)) or its methylated trivalent metabolites, methylarsonite (MAs(III)) and dimethylarsinite (DMAs(III)), inhibits glucose-stimulated insulin secretion (GSIS) in pancreatic islets, without significant effects on insulin expression or insulin content. The goal of the present study was to determine if iAs(III) and/or its metabolites inhibit Ca2+ influx, an essential mechanism that regulates the release of insulin from β cells in response to glucose. We found that in vitro exposures for 48 h to non-cytotoxic concentrations of iAs(III), MAs(III), and DMAs(III) impaired Ca2+ influx in isolated murine pancreatic islets stimulated with glucose. MAs(III) and DMAs(III) were more potent inhibitors of Ca2+ influx than iAs(III). These arsenicals also inhibited Ca2+ influx and GSIS in islets treated with depolarizing levels of potassium chloride in the absence of glucose. Treatment with Bay K8644, a Cav1.2 channel agonist, did not restore insulin secretion in arsenical-exposed islets. Tolbutamide, a KATP channel blocker, prevented inhibition of insulin secretion in MAs(III)- and DMAs(III)-exposed islets, but only marginally in islets exposed to iAs(III). Our findings suggest that iAs(III), MAs(III), and DMAs(III) inhibit glucose-stimulated Ca2+ influx in pancreatic islets, possibly by interfering with KATP and/or Cav1.2 channel function. Notably, the mechanisms underlying inhibition of GSIS by iAs(III) may differ from those of its trivalent methylated metabolites. [ABSTRACT FROM AUTHOR]

BACKGROUND: Chronic exposure to inorganic arsenic (iAs) has been associated with type 2 diabetes (T2D). However, potential sex divergence and the underlying mechanisms remain understudied. iAs is not metabolized uniformly across species, which is a limitation of typical exposure studies in rodent models. The development of a new “humanized” mouse model overcomes this limitation. In this study, we leveraged this model to study sex differences in the context of iAs exposure. OBJECTIVES: The aim of this study was to determine if males and females exhibit different liver and adipose molecular profiles and metabolic phenotypes in the context of iAs exposure. METHODS: Our study was performed on wild-type (WT) 129S6/SvEvTac and humanized arsenic +3 methyl transferase (human AS3MT) 129S6/SvEvTac mice treated with 400 ppb of iAs via drinking water ad libitum. After 1 month, mice were sacrificed and the liver and gonadal adipose depots were harvested for iAs quantification and sequencing-based microRNA and gene expression analysis. Serum blood was collected for fasting blood glucose, fasting plasma insulin, and homeostatic model assessment for insulin resistance (HOMA-IR). RESULTS: We detected sex divergence in liver and adipose markers of diabetes (e.g., miR-34a, insulin signaling pathways, fasting blood glucose, fasting plasma insulin, and HOMA-IR) only in humanized (not WT) mice. In humanized female mice, numerous genes that promote insulin sensitivity and glucose tolerance in both the liver and adipose are elevated compared to humanized male mice. We also identified Klf11 as a putative master regulator of the sex divergence in gene expression in humanized mice. DISCUSSION: Our study underscored the importance of future studies leveraging the humanized mouse model to study iAs-associated metabolic disease. The findings suggested that humanized males are at increased risk for metabolic dysfunction relative to humanized females in the context of iAs exposure. Future investigations should focus on the detailed mechanisms that underlie the sex divergence. [ABSTRACT FROM AUTHOR]

Biochar is widely used for water and soil remediation in part because of its local availability and low production cost. However, its effectiveness depends on physicochemical properties related to its feedstock and pyrolysis temperature, as well as the environmental conditions of its use site. Furthermore, biochar is susceptible to natural aging caused by changes in soil or sediment moisture, which can alter its redox properties and interactions with contaminants such as arsenic (As). In this study, we investigated the effect of pyrolysis temperature and biochar application on the release and transformations of As in contaminated sediments subjected to redox fluctuations. Biochar application and pyrolysis temperature played an important role in As species availability, As methylation, and dissolved organic carbon concentration. Furthermore, successive flooding cycles that induced reductive conditions in sediments increased the As content in the solution by up to seven times. In the solid phase, the application of biochar and the flooding cycle altered the spatial distribution and speciation of carbon, iron (Fe) and As. In general, the application of biochar decreased the reduction of Fe(III) and As(V) after the first cycle of flooding. Our results demonstrate that the flooding cycle plays an important role in the reoxidation of biochar to the point of enhancing the immobilization of As. [Display omitted] • The application of biochar affects the reduction of As methylation. • The redox fluctuation may favor the effectiveness of biochar. • The pyrolysis temperature affects the spatial distribution of carbon contents. • The application of biochar favors the reduction and dispersion of Fe(III) minerals. [ABSTRACT FROM AUTHOR]

Chronic exposure to inorganic arsenic (iAs) has been linked to diabetes in both humans and mice, but the role of iAs exposure prior to conception and its transgenerational effects are understudied. The present study investigated transgenerational effects of preconception iAs exposure in C57BL/6J mice, focusing on metabolic phenotypes of G1 and G2 offspring. Body composition and diabetes indicators, including fasting blood glucose, fasting plasma insulin, glucose tolerance, and indicators of insulin resistance and beta cell function, were examined in both generations. The results suggest that the preconception iAs exposure in the parental (G0) generation induced diabetic phenotypes in G1 and G2 offspring in a sex-dependent manner. G1 females from iAs-exposed parents developed insulin resistance while no significant effects were found in G1 males. In the G2 generation, insulin resistance was observed only in males from iAs-exposed grandparents and was associated with higher bodyweights and adiposity. Similar trends were observed in G2 females from iAs-exposed grandparents, but these did not reach statistical significance. Thus, preconception iAs exposure altered metabolic phenotype across two generations of mouse offspring. Future research will investigate the molecular mechanisms underlying these transgenerational effects, including epigenomic and transcriptomic profiles of germ cells and tissues from G0, G1 and G2 generations. [ABSTRACT FROM AUTHOR]

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 (β -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. [ABSTRACT FROM AUTHOR]

Although mice are widely used to study adverse effects of inorganic arsenic (iAs), higher rates of iAs methylation in mice than in humans may limit their utility as a model organism. A recently created 129S6 mouse strain in which the Borcs7/As3mt locus replaces the human BORCS7/AS3MT locus exhibits a human-like pattern of iAs metabolism. Here, we evaluate dosage dependency of iAs metabolism in humanized (Hs) mice. We determined tissue and urinary concentrations and proportions of iAs, methylarsenic (MAs), and dimethylarsenic (DMAs) in male and female Hs and wild-type (WT) mice that received 25- or 400-ppb iAs in drinking water. At both exposure levels, Hs mice excrete less total arsenic (tAs) in urine and retain more tAs in tissues than WT mice. Tissue tAs levels are higher in Hs females than in Hs males, particularly after exposure to 400-ppb iAs. Tissue and urinary fractions of tAs present as iAs and MAs are significantly greater in Hs mice than in WT mice. Notably, tissue tAs dosimetry in Hs mice resembles human tissue dosimetry predicted by a physiologically based pharmacokinetic model. These data provide additional support for use of Hs mice in laboratory studies examining effects of iAs exposure in target tissues or cells. [ABSTRACT FROM AUTHOR]

Arsenic (+3 oxidation state) methyltransferase is the key enzyme in the methylation pathway for inorganic arsenic. We have recently shown that As3mt knockout (KO) has a profound effect on metabolomic profiles in mice. Phosphatidylcholine species (PCs) were the largest group of metabolites altered in both plasma and urine. The present study used targeted analysis to investigate the KO-associated changes in PC profiles in the liver, the site of PC synthesis. Results show that As3mt KO has a systemic effect on PC metabolism and that this effect is sex dependent. [ABSTRACT FROM AUTHOR]