Peroxisome proliferators currently include a broad spectrum of synthetic and naturally occurring compounds, such as certain hypolipidemic drugs (e.g. clofibrate), leukotriene antagonists, phthalate ester plasticizers, herbicides, solvents, and the naturally occurring steroid, dehydroepiandrosterone. Despite their structural diversity, peroxisome proliferators induce qualitatively predictable immediate and delayed pleiotropic responses in rats and mice: the immediate responses consist of hepatomegaly, proliferation of peroxisomes in hepatocytes, and the induction of several hepatic enzymes, particularly those responsible for lipid metabolism, and the delayed responses include the development of hepatocellular carcinomas. Peroxisome proliferators, irrespective of their structural diversity, are found to be nonmutagenic (nongenotoxic) in that they do not directly damage DNA, thereby leading to out hypothesis that the development of liver tumors is attributable to sustained induction of peroxisome proliferation and ensuing metabolic perturbations resulting from a receptor-mediated mechanism. These agents activate peroxisome proliferator-activated receptor alpha (PPARalpha), a nuclear receptor, and sustained induction of PPARalpha-mediated peroxisome proliferation and other metabolic alterations are considered the basis for the development of liver tumors. This raises some intriguing questions about cell/tissue specificity and possible differences in species sensitivity of this response and its presumed implications. A major focus of our ongoing research is to generate fundamental information, which can provide insights into the molecular complexity of the unique pleiotropic responses, so that meaningful extrapolations can be made regarding species sensitivity and cell specificity of gene activation. We propose the following specific aims: 1) investigate the functional implications of the disruption of genes of peroxisomal beta-oxidation system and the relationship of beta-oxidation to PPARalpha-ligand metabolism; 2) generate """"""""humanized"""""""" mouse models of PPARalpha expression to evaluate peroxisome proliferator response in an attempt to understand the basis for species differences in response; 3) explore the role of H2O2- generating peroxisomal oxidases in carcinogenesis using the in vitro/in vivo molecular approaches and delineate the mechanism by which H2O2 initiates the cascade of events leading to neoplastic transformation; and 4) generate molecular portraits of liver with peroxisome proliferation induced by synthetic peroxisome proliferators, or occurring spontaneously in fatty acyl-CoA oxidase null mice to identify and characterize novel genes during the process of carcinogenesis.
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