The aryl hydrocarbon receptor ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene regulate distinct genetic networks.
The two estrogen receptor isoforms ERα and ERβ mediate biological effects of estrogens, but are also targets for endocrine disruptive chemicals (EDCs), compounds that interfere with hormonal signaling. 3-Methylcholanthrene (3-MC) and dioxin (TCDD) are EDCs and prototypical aryl hydrocarbon receptor (AhR) agonists, and can inhibit ER signaling. However, in contrast to TCDD, 3-MC gives rise to metabolites with estrogenic properties. We compared gene expression profiles in HepG2 cells after exposure to 3-MC, TCDD, and the synthetic estrogen diethylstilbestrol (DES). Interestingly, we observed little overlap between the genetic networks activated by 3-MC and TCDD, two compounds sometimes considered as interchangeable AhR ligands. Like DES, 3-MC induced a number of ER-regulated genes and lead to recruitment of ERα to the promoters of such genes. Interestingly, in contrast to DES, the estrogenic effects exerted by 3-MC were exclusively observed in ERα, but not in ERβ-expressing cells, suggesting ER isoform selectivity of 3-MC-derived metabolites.
Department of Biosciences and Nutrition, Karolinska Institutet, Hälsovägen 7, 141 83 Huddinge, Sweden.
Elin
E
Swedenborg
Maria
M
Kotka
Martin
M
Seifert
Jun
J
Kanno
Ingemar
I
Pongratz
Joëlle
J
Rüegg
D047369:Chromatin Immunoprecipitation; D052244:Endocrine Disruptors / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D005796:Genes; D056945:Hep G2 Cells; D006801:Humans; D008748:Methylcholanthrene / Q000494:pharmacology*; D020411:Oligonucleotide Array Sequence Analysis; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists*; D015533:Transcriptional Activation / Q000187:drug effects; D059467:Transcriptome
D052244:Endocrine Disruptors; D047628:Estrogen Receptor alpha; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D008748:Methylcholanthrene