Peroxisome proliferator compounds (PPC), including commercially important drugs, plasticizers, herbicides, and solvents, are potent tumor promoters and hepatocarcinogens in rodents. These compounds appear to operate via a nongenotoxic mechanism, however, the precise molecular events leading to cancer are unknown. The lack of mechanistic data, coupled with the widespread exposure to PPC, has generated concern regarding the potential health effects in humans. Many, if not all of the effects of PPC are mediated through activation of a specific receptor, the peroxisome proliferator-activated receptor alpha (PPARalpha), that is highly expressed in rodent liver. The proposed studies will test the hypothesis that PPARalpha plays a critical role in tumor promotion.
The specific aims are to; (1) produce and characterize a mouse in which the PPARalpha is constitutively activated via an inducible promoter. (2) determine if PPARalpha activation is sufficient for PPC-induced short-term effects, including cell proliferation, peroxisome proliferation, inhibition of apoptosis, and enzyme induction; and (3) determine if PPARalpha activation is sufficient for the hepatocarcinogenic process, specifically for tumor promotion. These data will provide critical information for use in estimating the human health risk associated with PPC exposure.
