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

Mutsuko MINATA; Kouji H. HARADA; Anna KÄRRMAN; Toshiaki HITOMI; Michi HIROSAWA; Mariko MURATA; Frank J. GONZALEZ; Akio KOIZUMI

doi:10.2486/indhealth.48.96

Original Articles

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

Mutsuko MINATA, Kouji H. HARADA, Anna KÄRRMAN, Toshiaki HITOMI, Michi HIROSAWA, Mariko MURATA, Frank J. GONZALEZ, Akio KOIZUMI

Author information

Mutsuko MINATA
Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine
Kouji H. HARADA
Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine
Anna KÄRRMAN
MTM Research Centre, Örebro University
Toshiaki HITOMI
Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine
Michi HIROSAWA
Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine
Mariko MURATA
Department of Environmental and Molecular Medicine, Mie University Graduate School of Medicine
Frank J. GONZALEZ
Laboratory of Metabolism, National Cancer Institute, National Institutes of Health
Akio KOIZUMI
Department of Health and Environmental Sciences, Kyoto University Graduate School of Medicine

Keywords: Peroxisome proliferator-activated receptor-α, Perfluorooctanoic acid, Hepatobiliary injury, Bile acid transporter, Histopathology

JOURNAL FREE ACCESS

2010 Volume 48 Issue 1 Pages 96-107

DOI https://doi.org/10.2486/indhealth.48.96

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Abstract

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.

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