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Comparative Hepatic Effects of Perfluorooctanoic Acid and WY 14,643 in PPAR- Knockout and Wild-type Mice

¹ Environmental Carcinogenesis Division, US Environmental Protection Agency, Research Triangle Park, North Carolina, USA
² Reproductive Toxicology Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, North Carolina, USA
³ Human Exposure and Atmospheric Science Division, National Exposure Research Laboratory, Office of Research and Development, US Environmental Protection Agency, Research Triangle Park, North Carolina, USA

Correspondence: Dr. Douglas C. Wolf, Mail Drop B305-02, US Environmental Protection Agency, Research Triangle Park, NC 27711, USA; e-mail:wolf.doug{at}epa.gov.

Perfluorooctanoic acid (PFOA) is a chemical used in the production of fluoropolymers. Its persistence in the environment and presence in humans and wildlife has raised health concerns. Liver tumor induction by PFOA is thought to be mediated in rodents by PPAR-. A recent US EPA scientific advisory board questioned the contribution of PPAR- in PFOA-induced liver tumors. Liver response in CD-1, SV/129 wild-type (WT), and PPAR- knockout (KO) SV/129 mice was evaluated after seven daily treatments of PFOA-NH₄⁺ (1, 3, or 10 mg/kg, p.o.) or the prototype PPAR-agonist Wyeth 14,643 (WY, 50 mg/kg). Livers were examined by light and electron microscopy. Proliferation was quantified after PCNA immunostaining. PFOA treatment induced a dose-dependent increase in hepatocyte hypertrophy and labeling index (LI) similar to WY in WT mice. Ultrastructural alterations of peroxisome proliferation were similar between WY-treated and 10 mg/kg PFOA-treated WT mice. KO mice had a dose-dependent increase in hepatocyte vacuolation but increased LI only at 10 mg PFOA/kg. WY-treated KO mice were not different from KO control. These data suggest that PPAR- is required for WY- and PFOA-induced cellular alterations in WT mouse liver. Hepatic enlargement observed in KO mice may be due to an accumulation of cytoplasmic vacuoles that contain PFOA.

Key Words: cell proliferation • histopathology • immunohistochemistry • liver • mouse • PPAR • PFOA

This version was published on June 1, 2008

Toxicologic Pathology, Vol. 36, No. 4, 632-639 (2008)
DOI: 10.1177/0192623308318216


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