Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643

Chronic administration of peroxisome proliferators to mice and rats resultsin hepatomegaly and ultimately carcinogenesis. The mechanism underlying thecarcinogenic effect of nongenotoxic peroxisome proliferators is not wellunderstood. To determine whether nongenotoxic carcinogenesis is receptormediated, we evaluated the effect of the prototypical peroxisomeproliferator Wy-14,643 on replicative DNA synthesis and carcinogenesis inthe PPAR alpha-null mouse line. Male mice (F4, Sv/129 ter) of bothgenotypes (+/+) and (-/-) were fed either a control diet or one containing0.1% Wy-14,643 for either 1 week, 5 weeks, or 11 months. Wild-type mice fedthe Wy-14,643 diet for 1 or 5 weeks showed increased hepatic labeling bybromodeoxyuridine (BrDU) compared to untreated controls. In contrast, therewas no increase in hepatic BrDU labeling index in (-/-) mice fed theWy-14,643 diet for the same time periods compared to controls. After 11months, 100% of the (+/+) mice fed the Wy-14,643 diet had multiplehepatocellular neoplasms, including adenomas and carcinomas, while the(-/-) mice fed the Wy-14,643 diet were unaffected. This work demonstratesthat the effects of Wy-14,643 on replicative DNA synthesis andhepatocarcinogenesis are mediated by PPAR alpha.