A toxicogenetic and toxicogenomic approach towards understanding the mechanism of dioxin toxicity

2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD, dioxin) is a ubiquitous environmental contaminant and a known human carcinogen. The biological and toxicological activity of this contaminant may stem from its ability to bind to and activate the cytosolic aryl hydrocarbon receptor (AhR), which serves as a transcription factor for numerous target genes. Cytochrome P450 (CYP) 1A1 and 1B1 are two such genetic targets for the ligand-bound AhR.; Individuals in the human population display dramatic variations in the expression of CYP1A1 and CYP1B1, which may stem from differences in the genetic sequences of these genes. It is hypothesized that inheritable genetic variations, or polymorphisms, in human CYP1A1 and 1B1 may influence gene expression, thereby modifying xenobiotic metabolism and individual susceptibility to certain carcinogens. The proposed studies will further characterize known polymorphisms in CYP1A1, while attempting to identify and characterize novel polymorphisms in CYP1B1.; While the metabolic activities of CYP1A1 and CYP1B1 may serve as important determinants for susceptibility to TCDD toxicity, the toxicological effects of TCDD are certainly not limited to these genes. It is hypothesized that TCDD modulates the expression of many genes, some of which have not yet been characterized. To this regard, DNA microarray technology will be employed to better understand the mechanisms by which TCDD promotes chronic toxicity. RNA will be isolated from female Sprague Dawley rats chronically exposed (14 or 53 weeks) to TCDD or related toxicants and hepatic gene expression will be evaluated with RGU34a Affymetrix GeneChips and 26K cDNA chips from The Institute of Genomic Research (TIGR).