Involvement of Peroxisome Proliferator-Activated Receptor-Alpha in Liver Tumor Production by Permethrin in the Female Mouse

: The nongenotoxic pyrethroid insecticide permethrin produced hepatocellular tumors in CD-1 mice but not in Wistar rats. Recently, based on findings of a Pathology Working Group involving an expert panel of pathologists, it was concluded that permethrin increased liver tumors at 2500 and 5000 ppm in female mice, but no treatment-related tumorigenic response occurred in male mice at dose levels examined in the 2-year bioassay. To evaluate a possible mode of action (MOA) for the permethrin female CD-1 mouse hepatocellular tumors, a number of investigative studies were conducted. In time-course studies in female CD-1 mice, permethrin increased relative liver weight and enhanced hepatocyte proliferation within 1 week. Treatment with permethrin resulted in marked increases in CYP4A enzyme activities and mRNA levels, but only slightly increased CYP2B markers, suggesting that permethrin primarily activates the peroxisome proliferator-activated receptor alpha (PPARα) and to a much lesser extent the constitutive androstane receptor. The effects of permethrin on relative liver weight, hepatocyte proliferation and CYP4A enzyme activities and mRNA levels were dose-dependent and were reversible within 5 weeks after cessation of treatment. The hepatic effects of permethrin observed in wild-type female mice were markedly reduced in PPARα knockout female mice. These results demonstrate that the MOA for hepatocellular tumor formation by permethrin in female mice involves activation of PPARα resulting in a mitogenic effect. The MOA for permethrin-induced mouse liver tumor formation due to PPARα activation is considered to be not plausible for humans. This conclusion is strongly supported by available epidemiological data for permethrin.