Effects of Arsenite Exposure during Fetal Development on Energy Metabolism and Susceptibility to Diet-Induced Fatty Liver Disease in Male Mice

BACKGROUND: Chronic exposure to arsenicals at various life stages and across a range of exposures has been implicated in cardiometabolic and liver disease, but disease predisposition from developmental exposures remains unclear. OBJECTIVES: In utero and post-weaning exposure to trivalent arsenic (As(III)) was examined on the background of a Western-style diet to determine whether As(III) exposure affects metabolic disease. METHODS: Male Swiss Webster mice were exposed to 100 ppb As(III) in utero, after weaning, or both. Ad libitum access to a Western-style diet was provided after weaning, and the plasma metabolome, liver histopathology, liver enzyme activity, and gene expression were analyzed. RESULTS: Hepatic lipid composition and histopathology revealed that developmental As(III) exposure exacerbated Western-style diet–induced fatty liver disease. Continuous As(III) exposure increased cardiometabolic risk factors including increased body weight, insulin resistance, hyperglycemia, and plasma triglycerides. As(III) exposure produced a decrease in the intermediates of glycolysis and the TCA cycle while increasing ketones. Hepatic isocitrate dehydrogenase activity was also decreased, which confirmed disruption of the TCA cycle. Developmental As(III) exposure increased the expression of genes involved in fatty acid synthesis, lipogenesis, inflammation, and packaging of triglycerides, suggesting an increased acetyl coenzyme A (acetyl-CoA) load. CONCLUSIONS: In utero and continuous early-life exposure to As(III) disrupted normal metabolism and elevated the risk for fatty liver disease in mice maintained on a high-fat diet. Our findings suggest that individuals exposed to As(III) during key developmental periods and who remain exposed to As(III) on the background of a Western-style diet may be at increased risk for metabolic disease later in life. CITATION: Ditzel EJ, Nguyen T, Parker P, Camenisch TD. 2016. Effects of arsenite exposure during fetal development on energy metabolism and susceptibility to diet-induced fatty liver disease in male mice. Environ Health Perspect 124:201–209; http://dx.doi.org/10.1289/ehp.1409501