The widespread human exposure to peroxisome proliferator (PP) xenobiotics such as cholesterol-lowering drugs, plasticizers, and herbicides is a health concern because many PP are rodent hepatocarcinogens. Controversy exists regarding the degree of health risk because the limited studies to date indicate that human hepatocytes are less susceptible to the phenomenon of peroxisomal organelle proliferation. However, the mechanism of carcinogenesis is unknown and may independent of peroxisomal proliferation. The broad, long-term objective of this proposal is to improve the estimation of human risk associated with PP exposure by defining a subset of he molecular events leading to PP induced rodent livers tumors. The PP are not genotixic, and recent work indicates that most, if not all, of their effects are mediated through a specific PP-activated receptor, the PPAR (alpha). Structurally homologous PPARs are present in many mammalian species, including humans. This proposal is designed to test the hypothesis that PP induce cancer through specific changes in hepatic gene expression modulated via an activated PPAR (alpha). The research design involves using an nRNA differential display technique to analyze gene expression differences between normal hepatic m RNA and hepatocellular tumor mRNA in rodents. A sequential process will identify PP-modulated changes in MRNA expression that are regulated via the PPAR (alpha). The results of this work will provide a defined framework for comparing human and rodent gene expression that can be used to predict the relevance of PP- induced rodent tumors for human hazard characterization.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32ES005715-02
Application #
2608505
Study Section
Chemical Pathology Study Section (CPA)
Project Start
1997-12-01
Project End
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
2
Fiscal Year
1998
Total Cost
Indirect Cost
Name
The Hamner Institutes
Department
Type
DUNS #
040052250
City
Research Triangle Park
State
NC
Country
United States
Zip Code
27709