Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice

Perfluorooctanoic acid is a ligand for peroxisome proliferator-activated receptor (PPAR alpha). Ammonium perfluorooctanoate (APFO) at 0.1 and 0.3 mg/kg doses activated mouse PPARa, but not human PPAR alpha. This study aimed to clarify whether milligram-order APFO can activate human PPAR alpha, and the receptor is involved in APFO-induced chronic hepatic damage. Male Sv/129 wild-type mPPAR alpha), Ppar alpha-null, and humanized PPAR alpha (hPPAR alpha) mice (8 weeks old) were divided into three groups. The first was treated with water and the other two with 1.0 and 5.0 mg/kg APFO for 6 weeks, orally, respectively. Both doses activated mouse and human PPAR alpha to a similar or lower degree in the latter. APFO dose dependently increased hepatic triglyceride levels in Ppar alpha-null and hPPAR alpha mice, but conversely decreased those in mPPAR alpha ones. APFO-induced hepatic damage differed markedly among the three genotyped groups: single-cell necrosis was observed in all genotyped mice; inflammatory cells and macrovesicular steatosis only in Ppar alpha-null mice; and microvesicular steatosis and hydropic degenerations in hPPAR alpha and Ppar alpha-null mice. The molecular mechanism underlying these differences may be attributable to those of gene expressions involved in lipid homeostasis (PPAR alpha, beta- and x-oxidation enzymes, and diacylglycerol acyltransferases) and uncoupling protein 2. Thus, milligram-order APFO activated both mouse and human PPAR alpha in a different manner, which may reflect histopathologically different types of hepatic damage.