| Subchronic Exposure to TCDD, PeCDF, PCB126, and PCB153: Effect on Hepatic Gene Expression Chad M. Vezina,1 Nigel J. Walker,2 and James R. Olson3 1University of Wisconsin-Madison, School of Pharmacy, Madison, Wisconsin, USA; 2National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA; 3University at Buffalo, Department of Pharmacology and Toxicology, Buffalo, New York, USA Abstract
We employed DNA microarray to identify unique hepatic gene expression patterns associated with subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and other halogenated aromatic hydrocarbons (HAHs) . Female Harlan Sprague-Dawley rats were exposed for 13 weeks to toxicologically equivalent doses of four different HAHs based on the toxic equivalency factor of each chemical: TCDD (100 ng/kg/day) , 2,3,4,7,8-pentachlorodibenzofuran (PeCDF ; 200 ng/kg/day) , 3,3´,4,4´,5-pentachlorobiphenyl (PCB126 ; 1,000 ng/kg/day) , or 2,2´,4,4´,5,5´-hexachlorobiphenyl (PCB153 ; 1,000 µg/kg/day) . Global gene expression profiles for each exposure, which account for 8,799 gene probe sets contained on Affymetrix RGU34A GeneChips, were compared by principal components analysis. The aryl hydrocarbon receptor (AhR) ligands TCDD, PeCDF, and PCB126 produced very similar global gene expression profiles that were unique from the nonAhR ligand PCB153, underscoring the extensive impact of AhR activation and/or the resulting hepatic injury on global gene expression in female rat liver. Many genes were co-expressed during the 13-week TCDD, PeCDF, or PCB126 exposures, including classical AhR-regulated genes and some genes not previously characterized as being AhR regulated, such as carcinoembryonic-cell adhesion molecule 4 (C-CAM4) and adenylate cyclase-associated protein 2 (CAP2) . Real-time reverse-transcriptase polymerase chain reaction confirmed the increased expression of these genes in TCDD-, PeCDF-, and PCB126-exposed rats as well as the up- or down-regulation of several other novel dioxin-responsive genes. In summary, DNA microarray successfully identified dioxin-responsive genes expressed after exposure to AhR ligands (TCDD, PeCDF, PCB126) but not after exposure to the non-AhR ligand PCB153. Together, these findings may help to elucidate some of the fundamental features of dioxin toxicity and may further clarify the biologic role of the AhR signaling pathway. Key words: AhR, HAH, liver, microarray, PCB, TCDD. Environ Health Perspect 112:1636-1644 (2004) . doi:10.1289/txg.7253 available via http://dx.doi.org/ [Online 22 September 2004]
Address correspondence to J. Olson, University at Buffalo, Department of Pharmacology and Toxicology, 102 Farber Hall, 3435 Main Street, Buffalo, NY 14214 USA. Telephone: (716) 829-2319. Fax: (716) 829-2800. E-mail: jolson@buffalo.edu Tissues for this study were provided to us by the National Toxicology Program as part of a series of chronic 2-year rat bioassays examining the relative potencies for carcinogenicity of individual and mixtures of dioxin-like compounds. These studies were supported in part by National Institute of Environmental Health Sciences ES09440, the University at Buffalo, and the Environment and Society Institute, University at Buffalo. The authors declare they have no competing financial interests. Received 13 May 2004 ; accepted 22 September 2004.
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