Fetal exposure to arsenic results in hyperglycemia, hypercholesterolemia, and nonalcoholic fatty liver disease in adult mice

Abstract

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.

Deficiencies in mitochondrial dynamics sensitize Caenorhabditis elegans to arsenite and other mitochondrial toxicants by reducing mitochondrial adaptability

“…Of the toxicants tested, arsenite may have the highest potential for human health relevance, as over 140 million people worldwide are chronically exposed to arsenite via consumption of contaminated drinking water (Chowdhury et al 2006; Ravenscroft et al 2009). Although chronic arsenite exposure is associated with cancer (Gilbert-Diamond et al 2013; Karagas et al 2004; Marshall et al 2007; Yu et al 2006), and other metabolism-related pathologies (Ditzel et al 2015; Sanchez-Soria et al 2014; Shi et al 2013), the precise mechanisms underlying pathogenesis are complex, and remain poorly understood. We also demonstrate that arsenite disrupts mitochondrial energy metabolism in fusion ( fzo-1 , eat-3 )-deficient nematodes, while increasing mitochondrial function in wild-type nematodes, and has minimal effect on mitochondrial function in fission ( drp-1 )-deficient nematodes.…”

Methylation of inorganic arsenic by murine fetal tissue explants

“…This was the first report revealing protracted developmental exposure to arsenic and cardiovascular disease in adulthood. Our group has also demonstrated that developmental exposure to 100 ppb As (III) led to adult incidence of non-alcoholic fatty liver disease (Sanchez-Soria et al, 2014). The mechanisms of arsenic-induced cardiovascular, lung, and liver diseases are not clear and the risks and biological effects associated with arsenic ingestion at lower levels commonly found in the U.S. remain ambiguous especially for in utero exposures.…”

“…These are critical developmental periods for heart, lung, and liver, potentially making the development of these organ systems susceptible to effects of arsenic. In this regard, our laboratory reported mice exposed to 100 ppb As(III) in drinking water in utero (ED 6-term) developed non-alcoholic fatty liver disease as adults (Sanchez-Soria et al, 2014). In addition, others have shown that in ApoE −/− mice, in utero drinking water exposure (ED 8-term) to 49 parts per million (ppm) arsenite resulted in an inflammatory state in the adult liver (States et al 2012) as well as increased atherosclerosis (Srivastava et al 2007).…”

Arsenic Exposure and the Western Diet: A Recipe for Metabolic Disorders?

“…In previous research Camenisch and colleagues studied metabolic disease risk in mice exposed prenatally to low-level arsenic. 9 In those experiments, offspring of female mice that drank water containing 100 ppb sodium arsenite during pregnancy developed nonalcoholic fatty liver disease and other signs of heightened risk for metabolic syndrome, a constellation of symptoms associated with diabetes and cardiovascular disease in humans.…”