Comparative Hepatic Effects of Perfluorooctanoic Acid and WY 14,643 in PPAR-α 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-α. A recent US EPA scientific advisory board questioned the contribution of PPAR-α in PFOA-induced liver tumors. Liver response in CD-1, SV/129 wild-type (WT), and PPAR-α knockout (KO) SV/129 mice was evaluated after seven daily treatments of PFOA-NH 4 + (1, 3, or 10 mg/kg, p.o.) or the prototype PPARα-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-α 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.

Effects of perfluorooctanoic acid (PFOA) exposure to pregnant mice on reproduction

“…Since PFOA is an agonist of peroxisome proliferator-activated receptor (PPAR)-alpha, the PFOAinduced liver enlargement is attributed to the effect on PPAR-alpha (Chevalier et al, 2000;Wolf et al, 2008).…”

Immunotoxic and hepatotoxic effects of perfluoro-n-decanoic acid (PFDA) on female Harlan Sprague–Dawley rats and B6C3F1/N mice when administered by oral gavage for 28 days

“…Published reports indicated that PFOA induced increases in hepatocyte hypertrophy, ultrastructural alterations of peroxisome proliferation (Wolf, Moore, et al 2008), and gene expression changes related to PPARa activation ) in SV/129 mice. However, PFOA and PFOS also induced gene expression changes that were independent of PPARa for xenobiotic and fatty acid metabolism, inflammation, and cell cycle regulation in PPARa null mice (Rosen et al , 2010.…”

“…It has been proposed that carbon chain length correlates positively with activity and adverse effects of PFAS compounds (Goecke-Flora and Reo 1996; Kudo et al 2006;Wolf, Moore, et al 2008;Buck et al 2011), which suggests that the 10-carbon PFDA should induce a higher degree of immune suppression as compared to shorter-chain compounds. However, variability in potency and mode of action have been observed between PFOA and PFOS, both 8-carbon compounds and the most commonly studied PFAS.…”

Gene Profiling in the Livers of Wild-type and PPARα-Null Mice Exposed to Perfluorooctanoic Acid

“…Both Wy14,643 and PFOA increased hepatic cell proliferation in wild-type mice (see Wolf et al, 2008), and among the genes up-regulated by either compound were Ccnd1 (Cyclin D1) and cJun (Figure 7). Ccnd1 is a cyclin gene involved in progression of cells through the G 1 phase of the cell cycle, whereas cJun, a component of AP-1, has been shown to positively influence hepatocyte proliferation during liver regeneration (Stepniak et al, 2006) and is a potential upstream regulator of Ccnd1 (Wisdom et al, 1999).…”