Priming of Liver Disease by Arsenic Exposure

Inorganic arsenic is a natural drinking water contaminant and a known hepatotoxin. However, the exposure levels of arsenic required to cause overt liver damage may be higher than found in the US water supply. In preliminary studies, it was shown that chronic exposure to arsenic at exposure levels that caused no overt hepatoxicity, sensitized the liver to a subsequent inflammatory `hit' owing to injection of lipopolysaccharide (LPS). This new finding suggests that arsenic, even at exposure levels that are not hepatotoxic per se, may increase the risk of liver disease owing to a second hepatotoxic event. <P> Based on these Preliminary Studies, it is hypothesized that low-dose arsenic primes liver to a subsequent hepatotoxic insult. This hypothesis will be tested via the following specific aims. 1). To test the hypothesis that arsenic sensitizes to LPS-induced liver injury in the mouse. In the Preliminary Studies, it was shown chronic exposure of arsenic in drinking water enhances hepatic inflammation and damage caused by LPS. However, the drinking water concentration of arsenic used in this preliminary study is still higher than relevant to human exposure in the US. We will therefore test our hypothesis with lower, more relevant, water concentrations of arsenic. <P> Specific subaims are: a) To determine the minimal low dose arsenic exposure conditions to cause sensitization to LPS. b) To identify potential mechanisms by which arsenic preexposure enhances liver damage caused by LPS. 2). To test the hypothesis that low-dose arsenic exposure sensitizes liver to hepatotoxicity in mouse models of non alcoholic fatty liver disease (NAFLD). <P> A liver disease that is currently endemic to the US population is obesity-induced NAFLD. Here, using minimal exposure conditions determined in Specific Aim 1, the hypothesis that low dose arsenic exposure will enhance chronic liver damage in established models of NAFLD will be tested. <P> Specific subaims are: a) To determine the effect of arsenic on early, intermediate and late stages of fatty liver diseases. b) To determine whether arsenic enhances the formation of progenitor cells and/or preneoplastic lesions in experimental NAFLD. <P> Taken together, these results will also establish new models of arsenic priming of liver disease in which new hypotheses and/or treatment regimens may be tested. Should arsenic cause such a priming effect, the significance of this work to the US population is significant. Specifically, such results would suggest that the relative risk of hepatic damage caused by arsenic exposure may have to be modified to take into account other mitigating factors, such as type II diabetes and/or NAFLD. Exposure to arsenic in the drinking water is a major health concern. Our preliminary studies indicate that arsenic exposure, even below levels that are overtly hepatotoxic, may increase the stimulated inflammatory response in the liver, possibly increasing the risk of serious chronic liver diseases (e.g., non-alcoholic fatty liver diseases). <P> The project will develop a new model of arsenic exposure that will not investigate direct toxicity per se, but rather test the hypothesis that arsenic exacerbates the response in established liver toxicity models.