The lipid lowering function of PPARa, an essential regulator of fatty acid metabolism and transport, occurs across all mammalian species examined to date. PPARa is also known to mediate liver cancer in rodents after prolonged exposure to PPARa agonists, and humans may be resistant to this effect. However, there are a number of important questions that need to be answered before it can be concluded that humans are resistant to the hepatocarcinogenic effects of PPARa agonists. Given the potential for human exposure to PPARa agonists in the form of hypolipidemic drugs and environmental chemicals, there remains a concern for human risk to PPARa-mediated liver cancer. More importantly, very little is known about the effects of these compounds in neonates, an age group that often exhibits greater susceptibility to toxic agents. The central hypothesis of this proposal is that neonatal/early postnatal mice are more susceptible than adult mice to PPARa-mediated hepatocarcinogenesis. A secondary hypothesis is that mice containing a human-PPARa transgene will be less susceptible to PPARa-mediated liver cancer than mice containing a mouse- PPARa gene. These hypotheses will be tested by examining the effect of a high affinity human PPARa agonist (GW7647) in wild-type, PPARa-null and humanized PPARa mice and comparing the mechanisms and responses between neonatal and adult mouse exposures. Results from these studies will address five timely, important questions: 1) Are neonates more sensitive to PPARa agonist-induced hepatocarcinogenesis? 2) Are there any differences in the sensitivity of key molecular mechanisms that mediate PPARa agonist-induced hepatocarcinogenesis observed during development, and is there a species difference in any of these key mechanisms? 3) Is there a species-specific component to developmental sensitivity to PPARa agonist-induced hepatocarcinogenesis? 4) Will the species-specific hepatocarcinogenic effect of a high affinity mouse PPARa agonist (Wy-14,643) be similar to that observed for a high affinity human PPARa agonist (GW7647)? 5) Will any PPARa-independent hepatocarcinogenic effects be observed with lifelong exposure to a high affinity human PPARa agonist?
