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3-Methylcholanthrene Displays Dual Effects on Estrogen Receptor (ER) and ERβ Signaling in a Cell-Type Specific Fashion

Department for Biosciences and Nutrition, Karolinska Institutet at Novum, Huddinge, Sweden (E.S., J.R., M.H.-F., I.P., K.P.); Institut National de la Recherche Agronomique, Unité Mixte de Recherche 1089 Xénobiotiques, Toulouse, France (A.H., D.Z.); and Karo Bio AB, Novum, Huddinge, Sweden (S.R.)

The biological effects of 17β-estradiol (E₂) are mediated by the two estrogen receptor (ER) isoforms ER and ERβ. These receptors are ligand-inducible transcription factors that belong to the nuclear receptor superfamily. These receptors are also targets for a broad range of natural and synthetic compounds that induce ER activity, including dietary compounds, pharmaceuticals, and various types of environmental pollutants such as bisphenols and polychlorinated hydroxy-biphenyls. Here, we study the effect of the combustion byproduct 3-methylcholanthrene (3-MC) on ER and ERβ. 3-MC is a compound identified previously as an activator of the aryl hydrocarbon receptor (AhR). Activation of AhR is traditionally associated with an inhibition of the E₂ signaling network. In this study, we demonstrate that 3-MC is a cell-specific activator or inhibitor of E₂ signaling pathways. We show that 3-MC acts as a repressor in some cells, presumably via the AhR, whereas it is a potent activator of ER activity in other cells. It is interesting that we demonstrate that the estrogenic effects of 3-MC are dependent on the ability of cells to metabolize parental 3-MC to alternative compounds. In summary, our results suggest that exposure to AhR ligands like 3-MC can lead to either activation or repression of E₂ signaling, depending on the cellular context.

Address correspondence to: Katarina Pettersson, Karolinska Institute, Department for Biosciences and Nutrition, S-141 57 Huddinge, Sweden. E-mail: katarina.pettersson{at}biosci.ki.se

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