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COMPARATIVE HEPATIC EFFECTS OF PERFLUOROOCTANOIC ACID AND WY 14,643 IN PPARÁ KNOCKED OUT AND WILD-TYPE MICE
Citation:
WOLF, D. C., B. D. ABBOTT, AND C. S. LAU. COMPARATIVE HEPATIC EFFECTS OF PERFLUOROOCTANOIC ACID AND WY 14,643 IN PPARÁ KNOCKED OUT AND WILD-TYPE MICE. Presented at Current Concepts in Toxicology-Perfluorinalkyl Acids and Related Chemistries: Toxicokinetics and Mode-of-Action Workshop, Arlington, VA, February 14 - 16, 2007.
Description:
Perfluorooctanoic acid (PFOA) is a fluorinated organic chemical widely used in consumer and industrial products. Its persistence in the environment and presence in humans and wildlife have raised considerable concerns. PFOA induces liver tumors in rodents, which is thought to be mediated by PPARα activation. A recent USEPA Scientific Advisory Board evaluation of PFOA questioned the contribution of PPARα activation to PFOA-induced liver tumors due to hepatic hypertrophy and a lack of kinetic information in PFOA treated PPARα-null mice. The present study evaluated hepatocyte proliferation, hepatic inflammation, and tissue alterations related to hepatic hypertrophy in CD-1 and 129S1 wild type (WT) or PPARα knock-out (KO) 129S1 mice after 7 daily treatments of PFOA-NH4+ (1, 3, or 10 mg/kg, p.o.) or the prototype PPARα-agonist WY 14,643 (WY, 50 mg/kg). Tissues were examined by light and electron microscopy, and proliferation was quantified as labeling index (LI, % labeled) from PCNA immunostained liver. PFOA treatment induced a dose-dependent increase in hepatocyte hypertrophy and hepatocyte LI in WT mice. In these animals, liver alterations were similar between WY and 10 mg/kg PFOA. The ultrastructural alterations were essentially the same between WY- and 10 mg/kg PFOA-treated WT mice and primarily consisted of peroxisome proliferation. KO mice had a dose-dependent increase in hepatocyte vacuolation but increased LI only at the 10 mg/kg dose of PFOA. The WY treated KO mice were not different from control. In KO mice, only PFOA treatment produced ultrastructural changes which consisted of accumulation of large clear cytoplasmic vacuoles. PFOA treated KO mice did not have hepatic inflammation and enhanced proliferation was only present at the highest dose tested. These data suggest that PPARα is required for WY- and PFOA-induced cellular alterations in WT mouse liver. The hepatic enlargement present in PPARα KO mice may be, in part, due to a dose¬dependent accumulation of cytoplasmic vacuoles and the enhanced proliferation is likely secondary to direct cellular toxicity.