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

Tomohiko Nakagawa, Doni Hikmat Ramdhan, Naoki Tanaka, Hisao Naito, Hazuki Tamada, Yuki Ito, Yufei Li, Yumi Hayashi, Nozomi Yamagishi, Yukie Yanagiba, Toshifumi Aoyama, Frank J. Gonzalez, Tamie Nakajima

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Abstract

Perfluorooctanoic acid is a ligand for peroxisome proliferator-activated receptor (PPARα). Ammonium perfluorooctanoate (APFO) at 0.1 and 0.3 mg/kg doses activated mouse PPARα, but not human PPARα. This study aimed to clarify whether milligram-order APFO can activate human PPARα, and the receptor is involved in APFO-induced chronic hepatic damage. Male Sv/129 wild-type (mPPARα), Pparα-null, and humanized PPARα (hPPARα) 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 PPARα to a similar or lower degree in the latter. APFO dose dependently increased hepatic triglyceride levels in Pparα-null and hPPARα mice, but conversely decreased those in mPPARα 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 Pparα-null mice; and microvesicular steatosis and hydropic degenerations in hPPARα and Pparα-null mice. The molecular mechanism underlying these differences may be attributable to those of gene expressions involved in lipid homeostasis (PPARα, β- and ω-oxidation enzymes, and diacylglycerol acyltransferases) and uncoupling protein 2. Thus, milligram-order APFO activated both mouse and human PPARα in a different manner, which may reflect histopathologically different types of hepatic damage.

Original languageEnglish
Pages (from-to)63-74
Number of pages12
JournalArchives of Toxicology
Volume86
Issue number1
DOIs
Publication statusPublished - 01-2012

All Science Journal Classification (ASJC) codes

  • Toxicology
  • Health, Toxicology and Mutagenesis

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    Nakagawa, T., Ramdhan, D. H., Tanaka, N., Naito, H., Tamada, H., Ito, Y., Li, Y., Hayashi, Y., Yamagishi, N., Yanagiba, Y., Aoyama, T., Gonzalez, F. J., & Nakajima, T. (2012). Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice. Archives of Toxicology, 86(1), 63-74. https://doi.org/10.1007/s00204-011-0704-3