Peroxisome proliferator-activated receptor-α (PPARα) has been suggested to protect against chemically induced hepatobiliary injuries in rodents. This function could mask the potential toxicities of perfluorooctanoic acid (PFOA) that is an emerging environmental contaminant and a weak ligand of PPARα. However its function has not been clarified. In this study, PFOA was found to elicit hepatocyte and bile duct injuries in Pparα-null mice after 4 wk treatment with PFOA ammonium salt (0, 12.5, 25, 50 μmol/kg/d, gavage). In wild-type mice, PFOA caused major hepatocellular damage dose-dependently and minor cholangiopathy observed only at 25 and 50 μmol/kg. In treated Pparα-null mice, PFOA produced marked fat accumulation, severe cholangiopathy, hepatocellular damage and apoptotic cells especially in bile ducts. Oxidative stress was also increased 4-fold at 50 μmol/kg and TNF-α mRNA was upregulated more than 3-fold at 25 μmol/kg in Pparα-null mice. Biliary bile acid/phospholipid ratios were higher in Pparα-null mice than in wild-type mice. Results from these studies suggest that PPARα is protective against PFOA and have a critical role in drug induced hepatobiliary injury.
2010 by National Institute of Occupational Safety and Health