Polychlorinated dioxins, benzofurans and biphenyls are stable, lipophilic compounds that bioaccumulate in the food chain and produce toxicity through the arylhydrocarbon receptor (AhR) mediated mechanism. The molecular mechanism(s) of toxicity of these is not understood. This proposal is designed to establish the Zebrafish [ZF] (Danio rerio) fin regeneration as a model to examine TCDD effects on gene expression, neovascularization, and regeneration. Zebrafish can completely regenerate their caudal fins after partial amputation and the preliminary results indicate that exposure of the amputated fish to TCDD completely inhibits regeneration. The investigator proposes to use this model to: 1) establish the ZF model for the study of the effects of TCDD on vascular development; 2) determine if the TCDD induced block results from competition between the AhR and hypoxia-induced pathways; 3) utilize ZF mutants to identify genes involved in TCDD toxicity; and 4) identify genes differentially expressed in regenerating fins of TCDD-treated fish using differential display techniques. The fin generation model is a unique model for in vivo hypothesis testing. Completion of this work should result in a powerful model system that will allow a better understanding of the molecular mechanism underlying TCDD toxicity. The information obtained can be applied to higher vertebrates. This work will also contribute to the exciting field of tissue regeneration, which could benefit human health.
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