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.