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ToxSci Advance Access published online on September 19, 2006
Toxicological Sciences, 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
Received September 13, 2006
Accepted September 18, 2006

Environmental Toxicology

Hepatic Gene Down-Regulation Following Acute and Subchronic Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Bladimir J. Ovando 1, Chad M. Vezina 2, Barb McGarrigle 1, and James R. Olson 1 *

1 Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, University at Buffalo, Buffalo, New York 14214 phone: (716) 829-3066
2 School of Pharmacy and Molecular and Environmental Toxicology Center, University of Wisconsin, Madison, Wisconsin 53705

* To whom correspondence should be addressed.
James R. Olson, E-mail: jolson{at}buffalo.edu


  Abstract

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 down-regulation in response to acute and subchronic TCDD exposure. We identified 61 probes which exhibited a down-regulation of 2-fold 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 down-regulation 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 6h, 24h and 72h 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 down-regulation of 7 of 11 genes. Together these results assist efforts to understand the multitude of effects imposed by TCDD and AhR ligands on gene expression.

Keywords: TCDD; PCB126; PCB153; AhR; Down-regulation.
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