Nonalcoholic steatohepatitis as a potential contributor to individual susceptibility to tetrachloroethylene-associated toxicity

Texas A&M University, College Station TX

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Abstract

? DESCRIPTION (provided by applicant): Inter-individual variability in susceptibility to environmental chemical-associated adverse health effects is a major challenge in public health assessment. Many factors, including life style factors which lead to chronic diseases, may contribute to individual susceptibility to such chemicals. However, little data exist on the contribution of common chronic diseases to individual susceptibility to environmental chemical-associated toxicity. One disease with potential impact on public health assessment of environmental chemicals is nonalcoholic steatohepatitis (NASH). NASH is a chronic disease that is increasing in prevalence in the developed nations. Being a systemic disease, NASH affects hepatic and extrahepatic physiology, including the ability of these organs to metabolize, detoxify, and eliminate xenobiotics. NASH likely has effect on the toxicokinetics and toxicodynamics of environmental chemicals, particularly those that produce reactive metabolites upon intracellular metabolic activation; however a systematic evaluation of toxicokinetic and toxicodynamic relationships for environmental chemicals in individuals with NASH has not yet been conducted. A case study to examine the effects of NASH on environmental chemical toxicokinetics and toxicodynamics is tetrachloroethylene (perchloroethylene; PERC). PERC is metabolically-activated by multiple enzymes, including those induced by NASH, and is associated with toxicity in multiple organs. The hypothesis to be tested is that individuals with NASH exposed to PERC will display altered PERC toxicokinetics, which will lead to increased concentrations of reactive PERC metabolites in target organs, and will ultimately result in increased susceptibility to PERC-associated toxicity. To test this hypothesis, an in vivo mouse model will be used. Mice with or without diet-induced NASH will be dosed with PERC in both acute and sub-acute studies. Concentration-time and concentration-response relationships will be established. PERC metabolite profiling, PERC-metabolizing enzyme expression profiling, and toxicodynamic effects of PERC will be evaluated in multiple organs, including the liver and kidney. The immediate goal is to determine the extent to which NASH contributes to individual susceptibility to PERC-associated toxicity. The long-term goal of this research is to characterize the contribution of other common chronic diseases, such as obesity, to the adverse health effects associated with exposure to other common environmental pollutants. These data will aid in public health assessments of environmental chemicals.