Glucocorticoid-enhanced expression of dioxin target genes through regulation of the rat aryl hydrocarbon receptor.

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.

[1]  C. Tohyama,et al.  Modulation of oestrogen receptor signalling by association with the activated dioxin receptor , 2003, Nature.

[2]  K. Lai,et al.  Modulation of AhR-mediated CYP1A1 mRNA and EROD activities by 17beta-estradiol and dexamethasone in TCDD-induced H411E cells. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[3]  J. Mathis,et al.  Glucocorticoid regulation of the rat cytochrome P450c (P450IA1) gene: receptor binding within intron I. , 1989, Archives of biochemistry and biophysics.

[4]  E. Glover,et al.  2,3,7,8,-Tetrachlorodibenzo-p-dioxin: segregation of toxocity with the Ah locus. , 1980, Molecular pharmacology.

[5]  F. Oesch,et al.  Interspecies differences in cancer susceptibility and toxicity. , 1999, Drug metabolism reviews.

[6]  Neil J. McKenna,et al.  Combinatorial Control of Gene Expression by Nuclear Receptors and Coregulators , 2002, Cell.

[7]  R. Hines,et al.  Role of canonical glucocorticoid responsive elements in modulating expression of genes regulated by the arylhydrocarbon receptor. , 1999, Drug metabolism reviews.

[8]  R. Shukin,et al.  Determinants of DNA sequence specificity of the androgen, progesterone, and glucocorticoid receptors: evidence for differential steroid receptor response elements. , 1999, Molecular endocrinology.

[9]  M. Denison,et al.  Analysis of the antiestrogenic activity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in human ovarian carcinoma BG-1 cells. , 2002, Molecular pharmacology.

[10]  G. Chrousos,et al.  Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids. , 1996, Endocrine reviews.

[11]  O. Gotoh,et al.  Molecular cloning of the human AH receptor gene promoter. , 1994, Biochemical and biophysical research communications.

[12]  S. Safe,et al.  Modulation of gene expression and endocrine response pathways by 2,3,7,8-tetrachlorodibenzo-p-dioxin and related compounds. , 1995, Pharmacology & therapeutics.

[13]  J. Giesy,et al.  Species-specific recombinant cell lines as bioassay systems for the detection of 2,3,7,8-tetrachlorodibenzo-p-dioxin-like chemicals. , 1996, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[14]  C. Jefcoate,et al.  Aryl hydrocarbon receptor regulation of cytochrome P4501B1 in rat mammary fibroblasts: evidence for transcriptional repression by glucocorticoids. , 1998, Molecular pharmacology.

[15]  W. Fiers,et al.  Cross-talk between steroids and NF-κB: what language? , 1998 .

[16]  E. Glover,et al.  Analysis of the four alleles of the murine aryl hydrocarbon receptor. , 1994, Molecular pharmacology.

[17]  K. Monostory,et al.  The effect of synthetic glucocorticoid, dexamethasone on CYP1A1 inducibility in adult rat and human hepatocytes , 2005, FEBS letters.

[18]  T. Bovee,et al.  Bioassays for the detection of growth-promoting agents, veterinary drugs and environmental contaminants in food. , 1999, The Analyst.

[19]  C. Chacon,et al.  PPARα activation potentiates AhR-induced CYP1A1 expression , 2005 .

[20]  W. Fiers,et al.  Cross-talk between steroids and NF-kappa B: what language? , 1998, TIBS -Trends in Biochemical Sciences. Regular ed.

[21]  Garet P Lahvis,et al.  Ahr null alleles: distinctive or different? , 1998, Biochemical pharmacology.

[22]  B. Abbott.  Review of the interaction between TCDD and glucocorticoids in embryonic palate. , 1995, Toxicology.

[23]  B. van der Burg,et al.  Interference between Progesterone and Dioxin Signal Transduction Pathways , 1998, The Journal of Biological Chemistry.

[24]  A. D. Rodrigues,et al.  Regulation of the Ah gene battery via Ah receptor-dependent and independent processes in cultured adult rat hepatocytes. , 1995, Drug metabolism and disposition: the biological fate of chemicals.

[25]  S. Kennedy,et al.  The molecular basis for differential dioxin sensitivity in birds: role of the aryl hydrocarbon receptor. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Hogenesch,et al.  The PAS superfamily: sensors of environmental and developmental signals. , 2000, Annual review of pharmacology and toxicology.

[27]  Kazunori Hosoe,et al.  Screening of dioxin-like toxicity equivalents for various matrices with wildtype and recombinant rat hepatoma H4IIE cells. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[28]  M. Denison,et al.  Analysis of the murine AhR gene promoter , 2000, Journal of biochemical and molecular toxicology.

[29]  A. Kong,et al.  Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes. , 2002, Current drug metabolism.

[30]  J. Whitlock,et al.  The DNA recognition site for the dioxin-Ah receptor complex. Nucleotide sequence and functional analysis. , 1988, The Journal of biological chemistry.

[31]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[32]  N. Sakuragi,et al.  The effect of the arylhydrocarbon receptor on the human steroidogenic acute regulatory gene promoter activity , 2001, The Journal of Steroid Biochemistry and Molecular Biology.

[33]  J. Michaud,et al.  Regulatory Interaction between Arylhydrocarbon Receptor and SIM1, Two Basic Helix-Loop-Helix PAS Proteins Involved in the Control of Food Intake* , 2004, Journal of Biological Chemistry.

[34]  Abraham Brouwer,et al.  Development of androgen- and estrogen-responsive bioassays, members of a panel of human cell line-based highly selective steroid-responsive bioassays. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[35]  A. Miller,et al.  Biochemical and genetic analysis of variant mouse hepatoma cells defective in the induction of benzo(a)pyrene-metabolizing enzyme activity. , 1983, The Journal of biological chemistry.

[36]  C. Tohyama,et al.  Differential susceptibilities of Holtzman and Sprague-Dawley rats to fetal death and placental dysfunction induced by 2,3,7,8-teterachlorodibenzo-p-dioxin (TCDD) despite the identical primary structure of the aryl hydrocarbon receptor. , 2006, Toxicology and applied pharmacology.

[37]  P. Harper,et al.  Regulating the regulator: factors that control levels and activity of the aryl hydrocarbon receptor. , 2006, Biochemical pharmacology.

[38]  McArdle,et al.  2 , 3 , 7 , 8-Tetrachlorodibenzo-p-dioxin : Segregation of Toxicity with the Ah Locus , 2022 .

[39]  J. Gustafsson,et al.  Estrogen receptor and aryl hydrocarbon receptor signaling pathways , 2006, Nuclear receptor signaling.

[40]  M. Gallo,et al.  Ah Receptor and NF-κB Interactions, a Potential Mechanism for Dioxin Toxicity* , 1999, The Journal of Biological Chemistry.

[41]  R. Prough,et al.  Regulation of NAD(P)H:quininone oxidoreductase by glucocorticoids. , 2004, Toxicology and applied pharmacology.

[42]  C. Tohyama,et al.  Cross-talk between 2,3,7,8-tetrachlorodibenzo-p-dioxin and testosterone signal transduction pathways in LNCaP prostate cancer cells. , 1999, Biochemical and biophysical research communications.

[43]  H. Swanson,et al.  DNA Binding Specificities and Pairing Rules of the Ah Receptor, ARNT, and SIM Proteins (*) , 1995, The Journal of Biological Chemistry.

[44]  O. Hankinson.  The aryl hydrocarbon receptor complex. , 1995, Annual review of pharmacology and toxicology.

[45]  R. Pollenz,et al.  The aryl hydrocarbon receptor and aryl hydrocarbon receptor nuclear translocator protein show distinct subcellular localizations in Hepa 1c1c7 cells by immunofluorescence microscopy. , 1994, Molecular pharmacology.

[46]  H. van Loveren,et al.  Immunotoxic effects of TCDD and toxic equivalency factors. , 1997, Teratogenesis, carcinogenesis, and mutagenesis (Print).

[47]  S. Safe,et al.  Inhibition of estrogen-induced progesterone receptor in MCF-7 human breast cancer cells by aryl hydrocarbon (Ah) receptor agonists , 1994, Molecular and Cellular Endocrinology.

[48]  M. Gallo,et al.  Ah receptor and NF-kappaB interactions, a potential mechanism for dioxin toxicity. , 1999, The Journal of biological chemistry.

[49]  C. Chacon,et al.  PPARalpha activation potentiates AhR-induced CYP1A1 expression. , 2005, Toxicology.

[50]  Debra C DuBois,et al.  Corticosteroid-regulated genes in rat kidney: mining time series array data. , 2005, American journal of physiology. Endocrinology and metabolism.

[51]  M. Denison,et al.  Development and modification of a recombinant cell bioassay to directly detect halogenated and polycyclic aromatic hydrocarbons in serum. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[52]  F. Wiebel,et al.  Dexamethasone-mediated potentiation of P450IA1 induction in H4IIEC3/T hepatoma cells is dependent on a time-consuming process and associated with induction of the Ah receptor. , 1990, Chemico-biological interactions.

[53]  R. Prough,et al.  Glucocorticoid regulation of polycyclic aromatic hydrocarbon induction of cytochrome P450IA1, glutathione S-transferases, and NAD(P)H:quinone oxidoreductase in cultured fetal rat hepatocytes. , 1990, Molecular pharmacology.

[54]  I. Kharat,et al.  Antiestrogenic Effects of 2,3,7,8-Tetrachlorodibenzo-p-dioxin Are Mediated by Direct Transcriptional Interference with the Liganded Estrogen Receptor , 1996, The Journal of Biological Chemistry.