Role of Peroxisome Proliferator-activated Receptor-alpha in Hepatobiliary Injury Induced by Ammonium Perfluorooctanoate in Mouse Liver

• Peroxisome proliferator-activated receptor-alpha (PPAR alpha) 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 PPAR alpha. However its function has not been clarified. In this study, PFOA was found to elicit hepatocyte and bile duct injuries in Ppar alpha-null mice after 4 wk treatment with PFOA ammonium salt (0, 12.5, 25, 50 mu mol/kg/d, gavage). In wild-type mice, PFOA caused major hepatocellular damage dose-dependently and minor cholangiopathy observed only at 25 and 50 mu mol/kg. In treated Ppar alpha-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 mu mol/kg and TNF-alpha mRNA was upregulated more than 3-fold at 25 mu mol/kg in Ppar alpha-null mice. Biliary bile acid/phospholipid ratios were higher in Ppar alpha-null mice than in wild-type mice. Results from these studies suggest that PPAR alpha is protective against PFOA and have a critical role in drug induced hepatobiliary injury.

Subject headings

NATURVETENSKAP  -- Geovetenskap och miljövetenskap -- Miljövetenskap (hsv//swe)

NATURAL SCIENCES  -- Earth and Related Environmental Sciences -- Environmental Sciences (hsv//eng)

Keyword

Peroxisome proliferator-activated receptor-alpha

Perfluorooctanoic acid

Hepatobiliary injury

Bile acid transporter

Histopathology

Environmental chemistry

Miljökemi

Environmental Chemistry

Miljökemi

Publication and Content Type

ref (subject category)

art (subject category)