PEROXISOME PROLIFERATOR CARCINOGENESIS--GENE MODULATION

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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.