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ToxSci Advance Access published online on August 9, 2007
Toxicological Sciences, doi:10.1093/toxsci/kfm176
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© The Author 2007. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Glucocorticoid Enhanced Expression of Dioxin Target Genes through Regulation of the Rat Aryl Hydrocarbon Receptor

Edwin Sonneveld*,{dagger}, Arjen Jonas*, Onno C. Meijer{ddagger}, Abraham Brouwer* and Bart van der Burg*

* BioDetection Systems B.V., Amsterdam, the Netherlands {ddagger} Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research and Leiden University Medical Center, the Netherlands

{dagger} To whom correspondence should be addressed at BioDetection Systems B.V., Kruislaan 406, 1098 SM Amsterdam, the Netherlands. tel: +31204350750; fax: +31204350757. E-mail: edwin.sonneveld{at}bds.nl

Received May 2, 2007; revision received June 22, 2007; accepted July 3, 2007


  Abstract

The aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) are ligand-activated transcription factors and members of the bHLH-PAS and nuclear hormone receptor superfamilies, respectively. Besides their individual role as activators of specific gene transcription, also interplay between both transcription factors can be an important mechanism of regulation. In this study, we report that GR can strongly activate AhR-mediated transcription and consequent gene expression in rat H4IIe cells. Reporter gene assays showed an enhanced effect of dexamethasone on the dioxin response mediated by GR in rat H4IIe cells and mouse Hepa 1c1c7 cells, but not in human HepG2 cells and human T47D cells. These deviations between the rodent and human cell lines were confirmed by CYP1A1 enzyme activities. In addition, QRT-PCR showed enhanced GR-mediated effects of dexamethasone on endogenous TCDD target genes as well in rat H4IIe cells, but not in human HepG2 and human T47D cells. Surprisingly, AhR itself was up-regulated by combined dioxin/glucocorticoid exposure in rat H4IIe cells but not in the human cells which could be explained by the presence of two putative GREs in the rat AhR promoter, but not in the human AhR promoter. This GR-mediated expression of dioxin target genes through up-regulation of the AhR in rat but not in human cells opens the possibility that dioxin responses in rodent-based models for toxicity differ from humans and provides new insight in the interactions of stress related pathways, biological effects of dioxin-like compounds and may possibly have implications for risk assessment.

Key Words: aryl hydrocarbon receptor; CALUX®; dioxin; glucocorticoid receptor; glucocorticoids.


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