ROLE PARTITIONING BY ARYL HYDROCARBON RECEPTORS (AHR) IN CELL REGULATION AND TOX

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall objective is to elucidate mechanisms underlying gene dysregulation and cell toxicity by environmental contaminants. Halogenated aromatic hydrocarbons (HAH) and polycyclic aromatic hydrocarbons (PAH) are widespread in the environment, highly toxic at low concentrations, and are linked to numerous health effects in humans and wildlife. Aryl hydrocarbon receptors (AHR) are ligand-activated transcription factors that regulate genes encoding biotransformation enzymes in response to HAH and PAH exposure. Moreover, numerous genes not associated with metabolism, including those necessary for normal cell physiology, are also regulated by AHR in the presence and absence of exogenous ligands. Thus, the hijacking of AHR from its physiological functions may play a major role in cell toxicity. Unlike mammals, which possess a single AHR, bony and cartilaginous fishes possess two or more divergent paralogs of the AHR. These proteins differ in their structure, function, and developmental and tissue specific expression, however their roles in cell regulation are not known. Investigating these AHRs may reveal novel regulatory functions and provide insight to the mechanisms underlying cell toxicity by AHR ligands. Understanding partitioning of functions among multiple AHR paralogs can reveal physiological roles of the single mammalian AHR, and provide an effective paradigm to separately test hypotheses about subsets of mammalian AHR gene targets. We will test the following hypotheses centered on role partitioning by AHR paralogs in cartilaginous and bony fishes: 1) Novel AHR structures differ in their ability to bind ligands and activate transcription, 2) multiple AHR paralogs in the same organism have distinct transcriptional targets germane to cell regulation, and 3) exposure to HAHs disrupts cell cycle regulation by an AHR-dependent mechanism.