PPAR, hormones, and xenobiotics

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Trichloroethylene (TCE), perchloroethylene (PCE) and related chemicals constitute an important class of environmental pollutants termed peroxisome proliferator chemicals (PPCs). Occupational and environmental exposure to PPCs is associated with a range of adverse health effects including liver, kidney and central nervous system toxicity, hematopoietic malignancies and reproductive toxicities. Rodent model systems have established that several of these toxicities, including the hepatocarcinogenic effects, are mediated by a nuclear receptor protein termed PPARalpha, peroxisome proliferator-activated receptor-alpha. Studies during the past project period demonstrated that PPAR transcriptional activity can be inhibited through cross-talk with hormone/cytokine-activated STAT signaling pathways, however the impact of this cross talk on the toxic and carcinogenic effects of PPCs, and the underlying mechanism of carcinogenicity of this class of xenochemicals are not known. The specific goals of this proposal are: 1) to investigate the mechanisms that govern the inhibitory cross-talk between cytokines/hormones and PPCs and to establish the impact of this cross-talk on cellular responses to, and the toxicological outcome of, PPC exposure; 2) to elucidate the impact of this cross-talk on cellular responses to, and the toxicological outcome of, PPC exposure; 2) to elucidate the mechanisms that underlie the suppression of apoptosis by PPCs, which is likely to be a key factor in the imbalance between cell proliferation and cell death that leads to PPC-induced tumor promotion and carcinogenesis; and 3) to use computational and experimental methods to identify PPC and other environmental activators of PPARgamma, which is highly expressed in multiple human tissues and may correspond to an important target in humans for some of the deleterious effects associated with PPC exposure. Together, these studies will provide fundamental new knowledge on the underlying mechanisms of PPAR-dependent toxicities and their modulation by endogenous hormones and cytokines, and may help explain how differences in hormone patterns between species, individuals and during development affect how TCE, PCE and other PPCs produce adverse health effects. The more complete understanding of the basic mechanisms of PPC and PPAR action that will derive from these studies will aid in the assessment of human risk of low-level exposure to an important class of environmental contaminants that is of special interest to Superfund clean-up efforts.