Peroxisome proliferators (PPs) are a class of agents that are ubiquitous in the environment and are categorized as high-volume production chemicals. Many of these agents are very potent rodent liver carcinogens but it is not clear whether they are carcinogenic to humans. The mechanism of action of PPs is non-genotoxic and involves increases in peroxisomal activity and cell proliferation in liver. While PPs have been studied extensively, uncertainty remains regarding the exact mechanism and the basis for species differences. Two key players in the mode of action of these agents are nuclear receptor PPAR-alpha in parenchymal cells, known to be required for liver cancer in rodents, and TNF-alpha, a mitogenic cytokine in Kupffer cells that induces cell proliferation. The goal of this research is to develop a better understanding of the molecular pathways by which PPAR-alpha and TNF-alpha are involved in rodent tumorigenesis. We hypothesize that PPs cause increased oxidant production in Kupffer cells, which signal activation of TNF-alpha and other mitogenic cytokines that require PPAR-alpha for rapid hepatic cell proliferation. The findings of this research will help in assessing human risk to these and perhaps other non-genotoxic carcinogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31ES013342-03
Application #
7095066
Study Section
Special Emphasis Panel (ZRG1-ONC-O (29))
Program Officer
Humble, Michael C
Project Start
2004-07-01
Project End
2007-01-07
Budget Start
2006-07-01
Budget End
2007-01-07
Support Year
3
Fiscal Year
2006
Total Cost
$25,545
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Public Health & Prev Medicine
Type
Schools of Public Health
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599