TCDD is a widespread environmental contaminant and one of the most potent toxicants known. TCDD mediated toxicity involves a ligand-induced association of the cytoplasmic aryl hydrocarbon receptor (AhR) with its partner, the aryl hydrocarbon nuclear translocator protein (Arnt). This heterodimer then translocates to the nucleus where it acts as a transcription factor to alter gene expression. Recent reports, however, suggest an Arnt-independent induction of gene expression after exposure to TCDD. The research proposed in this application makes use of the differential display technique to isolate genes that are either induced or repressed after exposure to TCDD, independent of the Arnt protein. The identification of any such gene would suggest a novel pathway of action of TCDD regulated gene expression. This could lead to the identification of other proteins involved in a TCDD-mediated response, other possible dimerization partners of the AhR, or novel AhR binding sites. It is possible that alternative (Arnt-independent) pathways may be responsible for some of the more broad effects of TCDD such as symptoms of vitamin A deficiency, hyperthyroidism, hyperlipidemia, hypoinsulinemia, wasting syndrome, and thymic atrophy, among others. The discovery and characterization of novel mechanisms of TCDD-induced toxicity would greatly enhance our current understanding of the extremely varied toxic effects of TCDD.
