Background: Exposure to arsenic is a major concern in the United States and worldwide, since this metalloid has been associated with a number of ailments, including cardiovascular and metabolic diseases. Environmental exposures to toxicants throughout fetal development have been shown to play a critical role as triggers of adult disease. Methods: This study aimed to evaluate the contribution of fetal arsenic exposure to the onset of metabolic syndrome. Swiss Webster mice were exposed to either 100 ppb sodium arsenite or sodium chloride via the dam's drinking water from embryonic day 6 until birth. Weight and metabolic end-points were evaluated throughout the 36 week study. Retroorbital bleeds and blood plasma analyses were done to evaluate glucose, lipids, triglycerides and liver enzymes. Livers were evaluated histologically to assess extent and progression of nonalcoholic fatty liver disease. Cardiovascular outcomes such as blood pressure and ventricular hypertrophy were evaluated using non-invasive tail-cuff method and echocardiography respectively.Results: Blood plasma analysis demonstrated that in-utero (IU) arsenic-exposed mice exhibited a significant increase in plasma glucose levels between weaning age and 4 months of age, which remained elevated after 8 months. Similarly, IU arsenic-exposed mice showed a consistent elevation in LDL and total cholesterol at weaning age, 4 months and 8 months of age. Mouse weight was not statistically different between groups, and no significant cardiovascular changes were seen. Further histological analysis of liver samples demonstrated the development of nonalcoholic fatty liver disease in IU arsenic-exposed mice, as evidenced by major morphological changes and an increase in steatosis concomitant with hepatocellular ballooning. Conclusions: Taken together, the results found in this study suggest that IU arsenic exposure is a possible contributor to metabolic syndrome onset in mice, having important implications in the evaluation of fetal exposures on the development of adult disease.

Although it is generally believed that the developing fetus is principally exposed to inorganic arsenic and the methylated metabolites from the maternal metabolism of arsenic, little is known about whether the developing embryo can autonomously metabolize arsenic. This study investigates inorganic arsenic methylation by murine embryonic organ cultures of the heart, lung, and liver. mRNA for AS3mt, the gene responsible for methylation of arsenic, was detected in all of embryonic tissue types studied. In addition, methylated arsenic metabolites were generated by all three tissue types. The fetal liver explants yielded the most methylated arsenic metabolites (~7% of total arsenic/ 48 hr incubation) while the heart, and lung preparations produced slightly greater than 2% methylated metabolites. With all tissues the methylation proceeded mostly to the dimethylated arsenic species. This has profound implications for understanding arsenic-induced fetal toxicity, particularly if the methylated metabolites are produced autonomously by embryonic tissues.