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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. https://doi.org/10.1289/EHP12785, Introduction Chronic exposure to inorganic arsenic (iAs) is associated with numerous health complications, including but not limited to cancer, metabolic disease, and cardiovascular disease. (1-3) iAs, depending on the duration [...]

Background: Chronic exposure to inorganic arsenic (iAs) is a significant public health problem. Methylation of iAs by arsenic methyltransferase (AS3MT) controls iAs detoxification and modifies risks of iAs-induced diseases. Mechanisms underlying these diseases have been extensively studied using animal models. However, substantive differences between humans and laboratory animals in efficiency of iAs methylation have hindered the translational potential of the laboratory studies. Objectives: The goal of this study was to determine whether humanization of the As3mt gene confers a human-like pattern of iAs metabolism in mice. Methods: We generated a mouse strain in which the As3mt gene along with the adjacent Borcs7 gene was humanized by syntenic replacement. We compared expression of the mouse As3mt and the human AS3MT and the rate and pattern of iAs metabolism in the wild-type and humanized mice. Results: AS3MT expression in mouse tissues closely modeled that of human and differed substantially from expression of AS3MT. Detoxification of iAs was much less efficient in the humanized mice than in wild-type mice. Profiles for iAs and its methylated metabolites in tissues and excreta of the humanized mice were consistent with those reported in humans. Notably, the humanized mice expressed both the full-length AS3MT that catalyzes iAs methylation and the human-specific [AS3MT.sup.d2d3] splicing variant that has been linked to schizophrenia. Conclusions: These results suggest that AS3MT is the primary genetic locus responsible for the unique pattern of iAs metabolism in humans. Thus, the humanized mouse strain can be used to study the role of iAs methylation in the pathogenesis of iAs-induced diseases, as well as to evaluate the role of [AS3MT.sup.d2d3] in schizophrenia. https://doi.org/10.1289/EHP6943, Introduction Inorganic arsenic (iAs) is the chemical form of As commonly found in drinking water (ATSDR 2007) and in some foods (Cubadda et al. 2017). Chronic exposure to iAs has [...]

BACKGROUND: Increased prevalences of diabetes mellitus have been reported among individuals chronically exposed to inorganic arsenic (iAs). However, the mechanisms underlying the diabetogenic effects of iAs have not been characterized. [...]

BACKGROUND: Exposure to arsenic (As) concentrations in drinking water > 150 µg/L has been associated with risk of diabetes and cardiovascular disease, but little is known about the effects of lower exposures. OBJECTIVE: This study aimed to examine whether moderate As exposure, or indicators of individual As metabolism at these levels of exposure, are associated with cardiometabolic risk. METHODS: We analyzed cross-sectional associations between arsenic exposure and multiple markers of cardiometabolic risk using drinking-water As measurements and urinary As species data obtained from 1,160 adults in Chihuahua, Mexico, who were recruited in 2008-2013. Fasting blood glucose and lipid levels, the results of an oral glucose tolerance test, and blood pressure were used to characterize cardiometabolic risk. Multivariable logistic, multinomial, and linear regression were used to assess associations between cardiometabolic outcomes and water As or the sum of inorganic and methylated As species in urine. RESULTS: After multivariable adjustment, concentrations in the second quartile of water As (25.5 to < 47.9 µg/L) and concentrations of total speciated urinary As (< 55.8 µg/L) below the median were significantly associated with elevated triglycerides, high total cholesterol, and diabetes. However, moderate water and urinary As levels were also positively associated with HDL cholesterol. Associations between arsenic exposure and both dysglycemia and triglyceridemia were higher among individuals with higher proportions of dimethylarsenic in urine. CONCLUSIONS: Moderate exposure to As may increase cardiometabolic risk, particularly in individuals with high proportions of urinary dimethylarsenic. In this cohort, As exposure was associated with several markers of increased cardiometabolic risk (diabetes, triglyceridemia, and cholesterolemia), but exposure was also associated with higher rather than lower HDL cholesterol. http://dx.doi.org/10.1289/ehp.1408742, Introduction There is growing evidence that chronic exposure to inorganic As (iAs) may increase the risk of cardiometabolic (CM) disorders, including diabetes mellitus (DM) and cardiovascular diseases (CVD) (Kuo et [...]

Background: Inorganic arsenic (iAs) is a diabetogen. Interindividual differences in iAs metabolism have been linked to susceptibility to diabetes in iAs-exposed populations. Dietary folate intake has been shown to influence iAs metabolism, but to our knowledge its role in iAs-associated diabetes has not been studied. OBJECTIVE: The goal of this study was to assess how folate intake, combined with low-fat (LFD) and high-fat diets (HFD), affects the metabolism and diabetogenic effects of iAs in wild-type (WT) mice and in As3mi-knockout (KO) mice that have limited capacity for iAs detoxification. Methods: Male and female WT and KO mice were exposed to 0 or 100ppb iAs in drinking water. Mice were fed the LFD containing 0.2 mg/kg or 10mg/kg folate for 24 weeks, followed by the HFD with the same folate levels for 13 weeks. Metabolic phenotype and iAs metabolism were examined before and after switching to the HFD. Results: iAs exposure had little effect on the phenotype of mice fed LFD regardless of folate intake. High folate intake stimulated iAs metabolism, but only in WT females. KO mice accumulated more fat than WT mice and were insulin resistant, with males more insulin resistant than females despite similar %fat mass. Feeding the HFD increased adiposity and insulin resistance in all mice. However, iAs-exposed male and female WT mice with low folate intake were more insulin resistant than unexposed controls. High folate intake alleviated insulin resistance in both sexes, but stimulated iAs metabolism only in female mice. Conclusions: Exposure to 100 ppb iAs in drinking water resulted in insulin resistance in WT mice only when combined with a HFD and low folate intake. The protective effect of high folate intake may be independent of iAs metabolism, at least in male mice. KO mice were more prone to developing insulin resistance, possibly due to the accumulation of iAs in tissues. https://doi.org/10.1289/EHP3951, Introduction Chronic exposure to inorganic arsenic (iAs) is a global public health problem. Over 200 million people worldwide are exposed to iAs in drinking water at levels higher than 10 [...]

Background: A growing number of studies link chronic exposure to inorganic arsenic (iAs) with the risk of diabetes. Many of these studies assessed iAs exposure by measuring arsenic (As) species in urine. However, this approach has been criticized because of uncertainties associated with renal function and urine dilution in diabetic individuals. Objectives: Our goal was to examine associations between the prevalence of diabetes and concentrations of As species in exfoliated urothelial cells (EUC) as an alternative to the measures of As in urine. Methods: We measured concentrations of trivalent and pentavalent iAs methyl-As (MAs) and dimethyl-As (DMAs) species in EUC from 374 residents of Chihuahua, Mexico, who were exposed to iAs in drinking water. We used fasting plasma glucose, glucose tolerance tests, and self-reported diabetes diagnoses or medication to identify diabetic participants. Associations between As species in EUC and diabetes were estimated using logistic and linear regression, adjusting for age, sex, and body mass index. Results: Interquartile-range increases in trivalent, but not pentavalent, As species in EUC were positively and significantly associated with diabetes, with ORs of 1.57 (95% CI: 1.19, 2.07) for iAsIn, 1.63 (1.24, 2.15) for [Mas.sup.III], and 1.31 (0.96, 1.84) for [DMAs.sup.III]. DMAs/MAs and DMAs/iAs ratios were negatively associated with diabetes (OR = 0.62; 95% CI: 0.47, 0.83 and OR = 0.72; 95% CI: 0.55, 0.96, respectively). Conclusions: Our data suggest that uncertainties associated with measures of As species in urine may be avoided by using As species in EUC as markers of iAs exposure and metabolism. Our results provide additional support to previous findings suggesting that trivalent As species may be responsible for associations between diabetes and chronic iAs exposure. http://dx.doi.org/10.1289/ehp.1307756, Introduction Arsenic (As), and specifically its inorganic forms (iAs) [arsenite ([iAs.sup.III]) and arsenate ([iAs.sup.V)], are naturally occurring drinking-water contaminants. Epidemiologic evidence (James et al. 2013; Kuo et al. 2013; Maull [...]