Nonalcoholic Fatty Liver Disease Is a Susceptibility Factor for Perchloroethylene-Induced Liver Effects in Mice.

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is the most prevalent pathological liver condition in developed countries. NAFLD results in severe alterations in liver function, including xenobiotic metabolism. Perchloroethylene (PERC) is a ubiquitous environmental pollutant, a known hepatotoxicant in rodents, and a probable human carcinogen. It is known that PERC disposition and metabolism are affected by NAFLD in mice; here, we examined how NAFLD changes PERC-associated liver effects. Male C57Bl6/J mice were fed a low-fat diet (LFD), high-fat diet (HFD), or methionine/folate/choline-deficient diet (MCD) to model a healthy liver, or mild and severe forms of NAFLD, respectively. After 8?weeks on diets, mice were orally administered PERC (300?mg/kg/day) or vehicle (5% aqueous Alkamuls-EL620) for 5 days. PERC-induced liver effects were exacerbated in both NAFLD groups. PERC exposure was associated with up-regulation of genes involved in xenobiotic, lipid, and glutathione metabolism, and down-regulation of the complement and coagulation cascades, regardless of the diet. Interestingly, HFD-fed mice, not MCD-fed mice, were generally more sensitive to PERC-induced liver effects. This was indicated by histopathology and transcriptional responses, where induction of genes associated with cell cycle and inflammation were prominent. Liver effects positively correlated with diet-specific differences in liver concentrations of PERC. We conclude that NAFLD alters the toxicodynamics of PERC and that NAFLD is a susceptibility factor that should be considered in future risk management decisions for PERC and other chlorinated solvents.

SUBMITTER: Cichocki JA 

PROVIDER: S-EPMC5837635 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature