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ToxSci Advance Access originally published online on September 19, 2006
Toxicological Sciences 2006 94(2):428-438; doi:10.1093/toxsci/kfl111
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Hepatic Gene Downregulation following Acute and Subchronic Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Bladimir J. Ovando*, Chad M. Vezina{dagger}, Barbara P. McGarrigle* and James R. Olson*,1

* Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14214 {dagger} School of Pharmacy and Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53705

Received September 8, 2006; accepted September 13, 2006

Chronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) has been shown to lead to the development of hepatotoxicity and carcinogenicity in the liver of female rats. In this study, we investigated hepatic gene downregulation in response to acute and subchronic TCDD exposure. We identified 61 probes which exhibited a downregulation of twofold or greater following subchronic (13 weeks) exposure to TCDD. Comparative analysis of the hepatic expression of these 61 probes was conducted with rats subchronically exposed to PeCDF, PCB126, PCB153, and a mixture of PCB126 and PCB153. PCB153 produced little or no alteration in these probes, while the binary mixture mimicked most closely the downregulation observed with TCDD. To discern if the repression of genes within this probe set occur as a primary response to TCDD exposure, we analyzed the early responsiveness of 11 genes at 6, 24, and 72 h following a single exposure to TCDD. We observed early repression of the 11 genes within this early time course, indicating that the repression of this subset of genes occurs as a primary response to TCDD exposure and not as a secondary response to 13 weeks of subchronic treatment. In addition, the gender, species, and AhR dependence of these responses were also investigated. Gender- and species-dependent repression was observed within this subset of genes. Furthermore, utilizing AhR knockout mice, we were able to determine the AhR-dependent downregulation of seven of 11 genes. Together these results assist efforts to understand the multitude of effects imposed by TCDD and AhR ligands on gene expression.

Key Words: TCDD; PCB126; PCB153; AhR; downregulation.


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