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Perfluorooctanoic acid (PFOA) is a ligand for peroxisome proliferator-activated receptor (PPAR) α, which exhibits marked species differences in expression and function, especially between rodents and humans. We investigated the functional difference in PFOA response between mice and humans, using a humanized PPARα transgenic mouse line. Three genotyped mice, 129/Sv wild-type (mPPARα), Pparα-null mice and humanized PPARα (hPPARα) mice (8-week-old males) were divided into three groups: the first was treated with water daily for 2 weeks by gavage (control group), and the remaining two groups were treated with 0.1 and 0.3 mg/kg ammonium perflurooctanate (APFO), respectively, for 2 weeks by gavage. The APFO dosages used did not influence the plasma triglyceride or total cholesterol levels in any mouse line, but the high dose increased both hepatic lipid levels only in mPPARα mice. APFO increased mRNA and/or protein levels of PPARα target genes cytochrome P450 Cyp4a10, peroxisomal thiolase and bifunctional protein only in the liver of mPPARα mice, but not in Pparα-null or hPPARα mice. This chemical also increased expression of mitochondrial very long chain acyl-CoA dehydrogenase only in the liver of mPPARα mice. Taken together, human PPARα may be less responsive to PFOA than that of mice when a relatively low dose is applied. This information may be very valuable in considering whether PFOA influences the lipid metabolism in humans.

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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.