Academic journal article Environmental Health Perspectives

Subchronic Exposure to TCDD, PeCDF, PCB126, and PCB153: Effect on Hepatic Gene Expression

Academic journal article Environmental Health Perspectives

Subchronic Exposure to TCDD, PeCDF, PCB126, and PCB153: Effect on Hepatic Gene Expression

Article excerpt

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 [micro]g/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 cydase-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 downregulation 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]

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2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin, TCDD) is a persistent environmental contaminant, a human and rodent carcinogen, and the most potent ligand for the aryl hydrocarbon receptor gene (AhR) (Fingerhut et al. 1991; Gu et al. 2000; Kociba et al. 1978; McGregor et al. 1998). The AhR gene also displays affinity for structurally related xenobiotics, including polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and coplanar polychlorinated biphenyls (PCBs) (Denison et al. 2002). Ligand binding and activation of AhR induces nuclear localization and heterodimerization with the AhR nuclear transporter (ARNT) protein (Whitlock 1999). This activated heterodimer binds to cognate cis-acting sequences [dioxin response elements (DREs)], located in the 5'-regulatory region of target genes.

A specific subgroup of genes are activated by an AhR-dependent mechanism during dioxin exposure, including (but not limited to) cytochrome P450 (CYP)1A1 CYP1A1, CYP1A2, CYP1B1, aldehyde dehydrogenase (ADH), NADPH-quinoneoxidoteductase (NQO1), glutathione S-transferase (GST) Ya (GSTA1), and UDP-glucuronosyltransferase 1A1 (UGT1A1) (Manjunath and Dufresne 1988; Mimura and Fujii-Kuriyama 2003; Schrenk 1998; Sutter and Greenlee 1992). AhR-dependent transcription is required for dioxin toxicity (Bunger et al. 2003), but it is unclear how activation of AhR-dependent genes produces the multiplicity of toxic responses characteristic of dioxin exposure.

As an attempt to characterize AhR-dependent genes and signaling pathways responsible for subchronic dioxin toxicity, the present study evaluated differential hepatic gene expression in female Harlan Sprague-Dawley (SD) rats exposed subchronically (13 weeks) to toxicologically equivalent doses of the AhR ligands TCDD (100 ng/kg/day), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF; 200 ng/kg/day), 3,3',4,4',5-pentachlorobiphenyl (PCB 126; 1,000 ng/kg/day), or the non-AhR ligand 2,2', 4,4', 5,5'-hexachlorobiphenyl (PCB153; 1,000 [micro]g/kg/day). …

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