Role Partitioning by Aryl Hydrocarbon Receptors (AHR) in Cell Regulation and Toxicity (2006 - Present)

Investigator:  Rebeka Merson, Rhode Island College
Mentor:  Cyrus Vaziri, Boston University School of Medicine 

Abstract:  The overall objective is to uncover the mechanisms underlying gene dysregulation and cell toxicity by environmental contaminants. Halogenated aromatic hydrocarbons (HAH) and some polycyclic aromatic hydrocarbons (PAH) alter gene expression and cause toxicity by activating aryl hydrocarbon receptors (AHR). These receptors act as transcription factors to regulate the expression of genes encoding biotransformation enzymes and some genes necessary for normal cell physiology. Species sensitivities to the toxic effects of HAHs and PAHs are related to the structure and function of the AHR proteins. Unlike mammals, which have one AHR, fishes possess two or more AHR genes. The specific aims of the proposed research are centered on role partitioning by AHR paralogs: 1) Novel AHR structures present in sharks and skates will be evaluated for their ability to bind ligands and activate transcription, and 2) we will test the hypothesis that multiple AHR proteins in zebrafish have distinct target genes involved in cell regulation by determining the occupancy of promoters by AHR paralogs and cell cycle response to TCDD in zebrafish cells. Results will aid in defining molecular mechanisms of cell toxicity caused by environmental AHR ligands, and reveal the susceptibility of fishes to the toxic effects of HAHs and PAHs. Identification of gene targets of the multiple AHRs in fishes will provide insight on the multiple roles of the single mammalian AHR, and provide an effective paradigm to separately test hypotheses about subsets of mammalian AHR gene targets.