title: Glucocorticoid-enhanced expression of dioxin target genes through regulation of the rat aryl hydrocarbon receptor.
abstract: The aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) are ligand-activated transcription factors and members of the basic helix-loop-helix Period-aryl hydrocarbon nuclear translocator-single minded 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, quantitative reverse transcription-PCR showed enhanced GR-mediated effects of dexamethasone on endogenous 2,3,7,8-tetrachlorodibenzo-[p]-dioxin target genes as well in rat H4IIe cells, but not in human HepG2 and human T47D cells. Surprisingly, AhR itself was upregulated 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 glucocorticoid response elements in the rat AhR promoter, but not in the human AhR promoter. This GR-mediated expression of dioxin target genes through upregulation 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 into the interactions of stress-related pathways, biological effects of dioxin-like compounds and may possibly have implications for risk assessment.
authors: BioDetection Systems B.V., Amsterdam, the Netherlands. edwin.sonneveld@bds.nl
authors: Edwin
authors: E
authors: Sonneveld
authors: Arjen
authors: A
authors: Jonas
authors: Onno C
authors: OC
authors: Meijer
authors: Abraham
authors: A
authors: Brouwer
authors: Bart
authors: B
authors: van der Burg
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D019363:Cytochrome P-450 CYP1A1 / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D051381:Rats; D018336:Receptors, Aryl Hydrocarbon / Q000502:physiology*; D015398:Signal Transduction; D013045:Species Specificity
chemical_list: D005938:Glucocorticoids; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D019363:Cytochrome P-450 CYP1A1