title: Modulation of ammonium perfluorooctanoate-induced hepatic damage by genetically different PPARα in mice.
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.
authors.affiliation: Department of Occupational and Environmental Health, Nagoya University Graduate School of Medicine, Showa-ku, Aichi, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Nakagawa
authors.forename: Doni Hikmat
authors.initials: DH
authors.lastname: Ramdhan
authors.forename: Naoki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Hisao
authors.initials: H
authors.lastname: Naito
authors.forename: Hazuki
authors.initials: H
authors.lastname: Tamada
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ito
authors.forename: Yufei
authors.initials: Y
authors.lastname: Li
authors.forename: Yumi
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Nozomi
authors.initials: N
authors.lastname: Yamagishi
authors.forename: Yukie
authors.initials: Y
authors.lastname: Yanagiba
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Aoyama
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Tamie
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000139:chemically induced / Q000473:pathology; D005260:Female; D005466:Fluorocarbons / Q000008:administration & dosage / Q000633:toxicity*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D014280:Triglycerides / Q000378:metabolism
chemical_list: D005466:Fluorocarbons; D047493:PPAR alpha; D014280:Triglycerides; C018959:hexadecafluoro-nonanoic acid