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?

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32ES017568-03
Application #
8105327
Study Section
Special Emphasis Panel (ZRG1-F09-B (20))
Program Officer
Humble, Michael C
Project Start
2009-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$54,734
Indirect Cost
Name
Pennsylvania State University
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
003403953
City
University Park
State
PA
Country
United States
Zip Code
16802