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

Abstract

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