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Comparative hepatic effects of perfluorooctanoic acid and WY 14,643 in PPARa-knocked out and wild-type mice.
Citation:
Wolf, D. C., T. Moore, B. D. Abbott, M. B. Rosen, K. Das, R. D. Zehr, A. B. Lindstrom, M. J. Strynar, AND C. S. Lau. Comparative hepatic effects of perfluorooctanoic acid and WY 14,643 in PPARa-knocked out and wild-type mice. TOXICOLOGICAL PATHOLOGY 36(4):632-639, (2008).
Impact/Purpose:
Perflurooctanoic acid (PFOA) is a persistent compound in the environment that has raised human health concerns in recent years. PFOA is a carcinogen in rats (including liver tumor) and a developmental toxicant in mice. The mechanisms associated with PFOA- induced toxicity are not fully understood, although this compound is a known peroxisome proliferator-activated receptor α (PPARα) agonist. However, a previous study illustrated that while liver hypertrophy induced by WY14,643 (WY), a prototypic PPARα agonist, was detected in wildtype but not in PPARα-null mice, the liver enlargement induced by PFOA was seen in both. These findings thus raised the question as whether the hepatic effects of PFOA were primarily driven by the PPARα molecular pathway. This paper describes our study to address this issue by comparing the histopathological changes induced by WY and PFOA in wildtype and PPARα-null mice. Our results demonstrate that both WY and PFOA (at low doses of 1 and 3 mg/kg) induced hepatic hypertrophy and ultrastructural alterations in the liver of wildtype mice, but not the PPARα-null mice. However, at a high dose of PFOA (10 mg/kg), liver hypertrophy and increased proliferation persisted in the PPARα-null mice, which were accompanied by an accumulation of large clear cytoplasmic vacuoles. The nature of hepatocyte vacuolation is not clear, but may be associated with accumulation of PFOA. The serum and liver levels of PFOA corresponding to each administered dose were assessed for cross-species (rat and mouse) comparison. Findings from this paper thus confirm the primary link of PFOA-induced hepatotoxicity with PPAR signaling pathway, and support the proposed mode-of-action for liver toxicity, an assumption made by OPPT in their risk assessment of PFOA toxicity.
Description:
Perfluorooctanoic acid (PFOA) is an environmentally persistent chemical commonly found in humans and wildlife. Induction of liver tumors by PFOA in rodents is thought to be mediated by PPARα activation, although hepatic hypertrophy persists in PPARα-null mice. This study evaluated hepatocyte proliferation, hypertrophy and inflammation in CD-1, SV/129 (WT) or PPARα knock-out (KO) mice after 7 daily treatments of PFOA-NH4+ (1, 3, or 10 mg/kg, p.o.) or the prototype PPARα-agonist Wyeth 14,643 (WY, 50 mg/kg). Tissues were examined by light and electron microscopy, and proliferation was quantified by PCNA labeling index (LI). PFOA produced hepatocyte hypertrophy and increased LI in WT mice dose-dependently; these changes were similar to those elicited by WY. Ultrastructural alterations (primarily peroxisome proliferation) were similar between WY- and PFOA-treated WT mice. WY-treated KO mice were not different from KO-controls. Dose-dependent increase in accumulation of large, clear cytoplasmic vacuoles was seen in PFOA-exposed KO mice, but no hepatic inflammation was indicated, while increased LI was detected only at the 10 mg/kg. These data suggest that PPARα is required for WY- and PFOA-induced alterations in WT mouse liver. Hepatic enlargement in PPAR KO mice may be, in part, due to an accumulation of cytoplasmic vacuoles that contain PFOA.
