Project Summary (2005-2012)

The overall objective of this basic research is to understand mechanisms underlying differential sensitivity to the developmental toxicity of dioxins.  Project researchers address this objective by elucidating the differences in expression and functional characteristics of two distinct aryl hydrocarbon receptors (AHR1 and AHR2) and an AHR repressor during development using a fish models of dioxin sensitivity and resistance. In the previous grant period, they characterized a PHAH-resistant population of the estuarine teleost Fundulus heteroclitus from New Bedford Harbor, a Superfund site. The researchers showed that these fish were approximately 15-fold less sensitive to TCDD and that this diminished sensitivity was heritable. They also identified two distinct AHRs in this species, including a novel AHR form (AHR2) that has since been identified in several other species of fish. This 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 being tested is that alterations in the expression and/or function of AHR1, AHR2, and/or AHRR underlie differential dioxin sensitivity. This hypothesis is being tested primarily in Fundulus, with parallel studies in zebrafish. The studies focus on developmental toxicity of TCDD, which is among the most sensitive effects of this compound in vertebrates. The specific goals 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 on 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.