Dioxin sensitivity of an amphibian toxicity test model

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DESCRIPTION (provided by applicant): Non-mammalian vertebrates are frequently used as model systems to determine the toxic, teratogenic, and carcinogenic properties of environmental contaminants. However, potential differences in sensitivity or toxic mechanisms in phylogenetically distant animals can confound interpretations and cloud the relevance of such toxicological data to human health. A clear understanding of the similarities and differences in the molecular mechanisms underlying contaminant effects in different species can greatly contribute to the evaluation of their suitability as toxicological models. FETAX (Frog Embryo Teratogenesis Assay - Xenopus), a widely employed, standardized toxicity test, uses frog embryos to measure the developmental toxicity of chemicals, complex mixtures, and environmental samples. However, the ability of FETAX to assess toxicity of halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD), is suspect. HAH sensitivity of Xenopus laevis, the FETAX model species, has not been systematically characterized, but studies in other frog species suggest that as a group, frogs are among the most resistant vertebrates to TCDD toxicity. Thus, the risk associated with HAH contaminants in environmental samples could be inaccurately estimated by FETAX criteria. The toxic effects of HAHs are mediated by the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor. Inherent properties of the AHR signal transduction pathway, including AHR expression levels and the binding affinity of AHR for xenobiotic ligands, can underlie variations in the sensitivity of different animal groups to HAH toxicity and the potency with which these compounds elicit characteristic biochemical responses. The overall objective of this project is to determine the toxic potency and molecular mechanisms of TCDD toxicity during development of Xenopus laevis. Through in vivo exposure studies, molecular cloning of AHR sequences, and biochemical assays of heterologously expressed AHR proteins, the proposed project will test the central hypothesis that Xenopus, like other frogs, is relatively insensitive to TCDD toxicity, and that this insensitivity results from properties intrinsic to the AHR signal transduction pathway. These studies should contribute substantially to the mechanistic understanding of the developmental toxicity of HAHs and the suitability of FETAX for assessing the toxicity of HAH-containing environmental samples.