The overall objective of the basic research proposed here is to understand mechanisms underlying differential sensitivity to the developmental toxicity of dioxins. We will address this objective by elucidating the differences in expression and functional characteristics of two distinct aryl hydrocarbon receptor (AHR1 and AHR2) and an AHR repressor during development using a fish models of dioxin sensitivity and resistance. In the previous grant period, we characterized a PHAH-resistant population of the estuarine teleost Fundulus heteroclitus and New Bedford Harbor, a Superfund site. We showed that these fish were approximately 15-fold less sensitive to TCDD and that this diminished sensitivity was heritable We also identified two distinct AHRs in this species, including a novel AHR form (AHR2) that has been identified in several other species of fish. The proposed research seeks to understand the role of these two AHRs, and related proteins, in differential PHAH sensitivity in this model of dioxin resistance Elucidating the molecular mechanisms underlying such innate or acquired resistance is important for understanding the response of animals to chronic PHAH exposure and identifying molecular markers of susceptibility associated with increased risk in populations and subpopulations of animals, including humans. The central hypothesis to be tested is that alterations in the expression and/or function of AHR1, AHR2, and/or AHRR underlie differential dioxin sensitivity. This hypothesis will be tested primarily in Fundulus, with parallel studies in zebrafish The studies will focus on developmental toxicity of TCDD, which is among the most sensitive effects of this compound in vertebrates.
The specific aims of the project are: 1. To measure the developmental expression of AHR1 and AHR2 in embryos and larvae of dioxin sensitive and dioxin resistant fundulus and zebrafish. 2. To determine the effect of TCDD treatment of AHR1 and AHR2 expression in Fundulus and zebrafish embryos. 3. To determine the ligand-binding specificity of Fundulus AHR1 and AHR2. 4. To determine if Fundulus and zebrafish express a homolog (ortholog) of the AHR repressor (AHRR) recently cloned from mice. 5. To determine the DNA- binding specificity of Fundulus AHR1 and AHR2. 6. To assess functional interactions among AHR1, AHR2, and AhRR.
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