Millions of people in various geographical regions, including the US, are exposed to unsafe levels of inorganic arsenic (iAs) in drinking water. The research of the effects of chronic exposure to iAs has commonly focused on its carcinogenic potency. However, epidemiologic studies indicate that iAs exerts other adverse effects that do not involve cancer. Several studies in arseniasis-endemic areas of Taiwan, Bangladesh, and Mexico have linked chronic exposures to high or moderate levels of iAs in drinking water to an increased risk for type 2 diabetes mellitus (T2D). Although results of epidemiologic studies in low-exposure areas or occupational settings have been inconclusive, laboratory research shows that exposures to iAs can produce symptoms that are consistent with T2D. In our preliminary studies, mice chronically exposed to iAs in drinking water developed impaired glucose tolerance. The major fraction of arsenic retained in tissues of these mice, including liver, pancreas, adipose and skeletal muscle tissues, was represented by methylated arsenicals, the products of the methylation of iAs by arsenic (3+ oxidation state) methyltransferase (AS3MT). Our in vitro studies showed that methylated trivalent arsenicals are more potent than iAs as inhibitors of insulin signaling and insulin-stimulated glucose uptake in cultured adipocytes. Notably, concentrations of arsenicals that inhibit glucose uptake by adipocytes and arsenic concentrations in tissues of mice that developed impaired glucose tolerance after exposure to iAs in drinking water are similar to arsenic concentrations in livers of residents in the arseniasis areas of Bangladesh. These results suggest that the formation of methylated trivalent arsenicals in the course of iAs metabolism may be a determining factor for development of T2D in individuals exposed to iAs in drinking water and that insulin-activated signal transduction pathway is the key target for these arsenicals. Based on these findings, we propose a translational research project that will examine diabetogenic effects of iAs in cultured cells, laboratory mice, and in humans. The main goals of this project are (i) to further characterize the association between iAs exposure and T2D, (ii) to identify molecular mechanisms for the diabetogenic effects of iAs exposure, (iii) to evaluate the roles specific metabolites of iAs play in these effects, and (iv) to characterize AS3MT polymorphisms that are associated with the increased production of these metabolites. Results of this project will advance knowledge in the area of environmental toxicology of As that has not been systematically studied, providing novel information that will improve the risk assessment of diabetes in arseniasis-endemic areas and the identification of individuals with increased susceptibility to the diabetogenic effects of chronic exposures to iAs.
Millions of people worldwide are exposed to arsenic in drinking water. Previous epidemiologic studies have linked chronic exposures to arsenic to an increased risk for type 2 diabetes mellitus. We propose a translational research project that will examine diabetogenic effects of arsenic in cultured cells, laboratory mice, and in humans. The goals of this project are to identify mechanisms by which exposures to arsenic induce diabetes and to characterize genetic polymorphisms that are associated with increased risk of diabetes for individuals exposed to arsenic in drinking water.
|Currier, Jenna M; Ishida, María C; González-Horta, Carmen et al. (2014) Associations between arsenic species in exfoliated urothelial cells and prevalence of diabetes among residents of Chihuahua, Mexico. Environ Health Perspect 122:1088-94|
|Musil, Stanislav; Matoušek, Tomáš; Currier, Jenna M et al. (2014) Speciation analysis of arsenic by selective hydride generation-cryotrapping-atomic fluorescence spectrometry with flame-in-gas-shield atomizer: achieving extremely low detection limits with inexpensive instrumentation. Anal Chem 86:10422-8|
|Douillet, Christelle; Currier, Jenna; Saunders, Jesse et al. (2013) Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets. Toxicol Appl Pharmacol 267:11-5|
|Matousek, Tomas; Currier, Jenna M; Trojankova, Nikola et al. (2013) Selective hydride generation- cryotrapping- ICP-MS for arsenic speciation analysis at picogram levels: analysis of river and sea water reference materials and human bladder epithelial cells. J Anal At Spectrom 28:1456-1465|
|Drobna, Zuzana; Del Razo, Luz M; Garcia-Vargas, Gonzalo G et al. (2013) Environmental exposure to arsenic, AS3MT polymorphism and prevalence of diabetes in Mexico. J Expo Sci Environ Epidemiol 23:151-5|
|Drobna, Zuzana; Del Razo, Luz Maria; Garcia-Vargas, Gonzalo et al. (2012) Identification of the GST-T1 and GST-M1 null genotypes using high resolution melting analysis. Chem Res Toxicol 25:216-24|
|Del Razo, Luz M; Garcia-Vargas, Gonzalo G; Valenzuela, Olga L et al. (2011) Exposure to arsenic in drinking water is associated with increased prevalence of diabetes: a cross-sectional study in the Zimapan and Lagunera regions in Mexico. Environ Health 10:73|
|Paul, David S; Walton, Felecia S; Saunders, R Jesse et al. (2011) Characterization of the impaired glucose homeostasis produced in C57BL/6 mice by chronic exposure to arsenic and high-fat diet. Environ Health Perspect 119:1104-9|
|Paul, David S; Devesa, Vicenta; Hernandez-Zavala, Araceli et al. (2008) Environmental arsenic as a disruptor of insulin signaling. Met Ions Biol Med 10:1-7|
|Paul, David S; Hernandez-Zavala, Araceli; Walton, Felecia S et al. (2007) Examination of the effects of arsenic on glucose homeostasis in cell culture and animal studies: development of a mouse model for arsenic-induced diabetes. Toxicol Appl Pharmacol 222:305-14|