Ammonium perfluorooctanoate (
APFO), a processing aid used in the production of
fluoropolymers, produces
hepatomegaly and hepatocellular
hypertrophy in rodents. In mice,
APFO-induced
hepatomegaly is associated with increased activation of the xenosensor
nuclear receptors, PPARα and CAR/PXR. Although non-genotoxic, chronic dietary treatment of Sprague-Dawley (S-D) rats with
APFO produced an increase in benign tumours of the liver, acinar pancreas, and testicular Leydig cells. Most of the criteria for establishing a PPARα-mediated mode of action for the observed hepatocellular tumours have been previously established with the exception of the demonstration of increased hepatocellular proliferation. The present study evaluates the potential roles for
APFO-induced activation of PPARα and CAR/PXR with respect to liver tumour production in the S-D rat and when compared to the specific PPARα agonist, 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic
acid (
Wy 14,643). Male S-D rats were fed
APFO (300 ppm in diet) or
Wy 14,643 (50 ppm in diet) for either 1, 7, or 28 days. Effects of treatment with
APFO included: decreased
body weight;
hepatomegaly, hepatocellular
hypertrophy, hepatocellular
hyperplasia (microscopically and by
BrdU labelling index), and hepatocellular
glycogen loss; increased activation of PPARα (peroxisomal β-oxidation and microsomal CYP4A1
protein); decreased plasma
triglycerides,
cholesterol, and
glucose; increased activation of CAR (
CYP2B1/2
protein) and CAR/PXR (CYP3A1
protein). Responses to treatment with
Wy 14,643 were consistent with increased activation of PPARα, specifically: increased CYP4A1 and peroxisomal β-oxidation; increased hepatocellular
hypertrophy and cell proliferation; decreased apoptosis; and hypolipidaemia. With the exception of decreased apoptosis, the effects observed with
Wy 14,643 were noted with
APFO, and
APFO was less potent. These data clearly demonstrate an early hepatocellular proliferative response to
APFO treatment and suggest that the
hepatomegaly and tumours observed after chronic dietary exposure of S-D rats to
APFO likely are due to a proliferative response to combined activation of PPARα and CAR/PXR. This mode of action is unlikely to pose a human hepatocarcinogenic hazard.