The long-term objective of this research proposal is to elucidate the biological responses to tetrachlorodibenzo-p-dioxin (TCDD; dioxin). Specifically, this proposal address the hypothesis that TCDD modifies gene expression patterns by interfering with the normal control mechanisms that regulate the steady state levels of tissue-specific transcription factors. The diverse biological manifestations of TCDD exposure, however unrelated, are always characterized by drastic changes in gene expression. Thus, depending on the particular tissue, TCDD may cause unscheduled cell proliferation (tumor promotion), hyperexpression of keratin genes (chloracne), inhibition of chondrogenic mesenchyme differentiation and unscheduled keratinization (cleft palate), or programmed death of immature thymocytes (thymic atrophy). TCDD is the prototype congener of the halogenated hydrocarbons, a group of toxic environmental pollutants known to be potent immunosuppresssors, teratogens, and tumor promoters. TCDD is a ligand for a xenobiotic receptor, the aromatic hydrocarbon (Ah) receptor, and its is believed that this receptor plays an essential role in the toxic effects of TCDD. Other Ah receptor ligands, such as benzo[a]pyrene, are metabolized by a ligand-inducible cytochrome P450 enzyme into reactive intermediates that are mutagenic and genotoxic. TCDD induced the same cytochrome P450 enzyme, but it is not a metabolizable substrate nor does it cause direct alterations in DNA, and therefore it is not a genotoxic tumor initiator. TCDD, however, is one of the most potent tumor promoters ever tested in rodents, and the molecular basis of this activity is still unknown. Other biological effects of TCDD, including induction of craniofacial abnormalities, chloracne, thymic atrophy, and porphyria, are even less well characterized at the molecular level. The proposed research is based on the observation from our laboratory that TCDD induces expression of a transcription factor, AP-1, that has an essential role in differentiation, cell proliferation, and tumor promotion. The goal of the proposed experiments is to study the effect of TCDD exposure on the oxidative stress pathways operative on the expression of AP-1 and to analyze the expression of genes controlled by the factor. Major objectives of this work are, (1) to determine the mechanisms by which TCDD induces AP-1 and, (2) to ascertain whether the biological effects of TCDD are dependent on AP-1 induction. An understanding of the mechanisms by which TCDD affects the control of gene expression in model systems will provide important information to elucidate not only the molecular basis of dioxin-induced disease, but also of the effects of other non-genotoxic environmental pollutants. This understanding may help formulate an adequate rationale to deal with health problems arising from an ever-increasing exposure to environmental agents.
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