Ah Receptor Binding to its Cognate Response Element is Required for Dioxin-Mediated Toxicity

Abstract

The aryl hydrocarbon receptor (AHR) is a ligand-activated member of the bHLH-PAS family of transcription factors. Members of this family include HIF1α, EPAS, and SIM, which are involved in hypoxia and nervous system development. Another member of this family, aryl hydrocarbon nuclear translocator (ARNT), is the dimerization partner for the AHR. The AHR is often classified as a sensor of a wide range of xenobiotics, leading to induction of xenobiotic metabolism through enhanced expression of phase I/II enzymes. The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a prototypic ligand for the AHR and is often used to study the effects of prolonged AHR activation. Rodent exposure to TCDD results in a plethora of toxic effects, including wasting syndrome, tumor promotion, developmental defects, and liver toxicity (reviewed in Vanden Heuvel and Lucier, 1993). The key target genes that lead to these toxic end points are largely unknown. AHR activation can occur through a growing list of chemicals that appear to be structurally diverse and include many polycyclic aromatic hydrocarbons, tryptophan metabolites, and flavones (Denison and Nagy, 2003). Soluble receptors such as the AHR could possibility alter transcription of target genes through several distinct mechanisms. The work of Bunger and coworkers (Bunger et al., 2008) has examined whether TCDD-mediated liver toxicity can be mediated by the AHR in the absence of DNA binding.