Effects of Inorganic Arsenic, Methylated Arsenicals, and Arsenobetaine on Atherosclerosis in the apoE−/− Mouse Model and the Role of As3mt-Mediated Methylation

Abstract

Background:Arsenic is metabolized through a series of oxidative methylation reactions by arsenic (3) methyltransferase (As3MT) to yield methylated intermediates. Although arsenic exposure is known to increase the risk of atherosclerosis, the contribution of arsenic methylation and As3MT remains undefined.Objectives:Our objective was to define whether methylated arsenic intermediates were proatherogenic and whether arsenic biotransformation by As3MT was required for arsenic-enhanced atherosclerosis.Methods:We utilized the apoE−/− mouse model to compare atherosclerotic plaque size and composition after inorganic arsenic, methylated arsenical, or arsenobetaine exposure in drinking water. We also generated apoE−/−/As3mt−/− double knockout mice to test whether As3MT-mediated biotransformation was required for the proatherogenic effects of inorganic arsenite. Furthermore, As3MT expression and function were assessed in in vitro cultures of plaque-resident cells. Finally, bone marrow transplantation studies were performed to define the contribution of As3MT-mediated methylation in different cell types to the development of atherosclerosis after inorganic arsenic exposure.Results:We found that methylated arsenicals, but not arsenobetaine, are proatherogenic and that As3MT is required for arsenic to induce reactive oxygen species and promote atherosclerosis. Importantly, As3MT was expressed and functional in multiple plaque-resident cell types, and transplant studies indicated that As3MT is required in extrahepatic tissues to promote atherosclerosis.Conclusion:Taken together, our findings indicate that As3MT acts to promote cardiovascular toxicity of arsenic and suggest that human AS3MT SNPs that correlate with enzyme function could predict those most at risk to develop atherosclerosis among the millions that are exposed to arsenic. https://doi.org/10.1289/EHP806

Rare, Protein-Altering Variants in AS3MT and Arsenic Metabolism Efficiency: A Multi-Population Association Study

“…In addition, KO mice are at an increased risk for arsenic toxicities ( Douillet et al. 2017 ; Negro Silva et al. 2017 ; Yokohira et al.…”

Use of a Mouse Model and Human Umbilical Vein Endothelial Cells to Investigate the Effect of Arsenic Exposure on Vascular Endothelial Function and the Associated Role of Calpains

“…Previous studies showed that As exposure could cause molecular and cellular events relevant to atherogenesis in cultured endothelial cells (Simeonova and Luster 2004) and also increase atherosclerotic plaque formation in ApoE−/− mice (Negro Silva et al. 2017).…”

Screening of House Dust from Chinese Homes for Chemicals with Liver X Receptors Binding Activities and Characterization of Atherosclerotic Activity Using an in Vitro Macrophage Cell Line and ApoE−/− Mice

“…All experiments related to animals were approved by the institutional animal care and use committee of Peking University and followed the guidelines for animal experiments of the university as well as for experimental animals in China. The biological effect size of the animal experiments was based on the previous paper (Negro Silva et al. 2017).…”

“…Because the formation of atherosclerosis lesions required a long time, the exposure period used in the present study was based on previous studies in which the effects of chemicals on formation of atherosclerosis lesions were observed after an exposure period of 12–15 weeks (Li et al. 2009; Negro Silva et al. 2017; Shi et al.…”