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.

National Institute of Health (NIH)
National Institute of Environmental Health Sciences (NIEHS)
Research Project (R01)
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Alcohol and Toxicology Subcommittee 4 (ALTX)
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Heindel, Jerrold
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University of Colorado Denver
Schools of Pharmacy
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Sengupta, Sumitra; Bisson, William H; Mathew, Lijoy K et al. (2012) Alternate glucocorticoid receptor ligand binding structures influence outcomes in an in vivo tissue regeneration model. Comp Biochem Physiol C Toxicol Pharmacol 156:121-9
Mathew, Lijoy K; Simonich, Michel T; Tanguay, Robert L (2009) AHR-dependent misregulation of Wnt signaling disrupts tissue regeneration. Biochem Pharmacol 77:498-507
Mathew, Lijoy K; Sengupta, Sumitra; Franzosa, Jill A et al. (2009) Comparative expression profiling reveals an essential role for raldh2 in epimorphic regeneration. J Biol Chem 284:33642-53
Mathew, Lijoy K; Sengupta, Sumitra S; Ladu, Jane et al. (2008) Crosstalk between AHR and Wnt signaling through R-Spondin1 impairs tissue regeneration in zebrafish. FASEB J 22:3087-96
Mathew, Lijoy K; Sengupta, Sumitra; Kawakami, Atsushi et al. (2007) Unraveling tissue regeneration pathways using chemical genetics. J Biol Chem 282:35202-10
Andreasen, Eric A; Mathew, Lijoy K; Lohr, Christiane V et al. (2007) Aryl hydrocarbon receptor activation impairs extracellular matrix remodeling during zebra fish fin regeneration. Toxicol Sci 95:215-26
Mathew, Lijoy K; Andreasen, Eric A; Tanguay, Robert L (2006) Aryl hydrocarbon receptor activation inhibits regenerative growth. Mol Pharmacol 69:257-65
Prasch, Amy L; Tanguay, Robert L; Mehta, Vatsal et al. (2006) Identification of zebrafish ARNT1 homologs: 2,3,7,8-tetrachlorodibenzo-p-dioxin toxicity in the developing zebrafish requires ARNT1. Mol Pharmacol 69:776-87
Andreasen, Eric A; Mathew, Lijoy K; Tanguay, Robert L (2006) Regenerative growth is impacted by TCDD: gene expression analysis reveals extracellular matrix modulation. Toxicol Sci 92:254-69
Zodrow, Jeanmarie M; Stegeman, John J; Tanguay, Robert L (2004) Histological analysis of acute toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in zebrafish. Aquat Toxicol 66:25-38

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