Comparative hepatic effects of perfluorooctanoic acid and WY 14,643 in PPAR-alpha knockout and wild-type mice.

Abstract:

: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-alpha. A recent US EPA scientific advisory board questioned the contribution of PPAR-alpha in PFOA-induced liver tumors. Liver response in CD-1, SV/129 wild-type (WT), and PPAR-alpha 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 PPARalpha-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-alpha 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.

journal_name

Toxicol Pathol

journal_title

Toxicologic pathology

authors

Wolf DC,Moore T,Abbott BD,Rosen MB,Das KP,Zehr RD,Lindstrom AB,Strynar MJ,Lau C

doi

10.1177/0192623308318216

subject

Has Abstract

pub_date

2008-06-01 00:00:00

pages

632-9

issue

4

eissn

0192-6233

issn

1533-1601

pii

0192623308318216

journal_volume

36

pub_type

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