3-Methylcholanthrene displays dual effects on estrogen receptor (ER) alpha and ER beta signaling in a cell-type specific fashion.
The biological effects of 17beta-estradiol (E(2)) are mediated by the two estrogen receptor (ER) isoforms ERalpha and ERbeta. 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 ERalpha and ERbeta. 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 E(2) signaling network. In this study, we demonstrate that 3-MC is a cell-specific activator or inhibitor of E(2) 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 E(2) signaling, depending on the cellular context.
Swedenborg
Elin
E
Karolinska Institute, Department for Biosciences and Nutrition, S-141 57 Huddinge, Sweden.
Rüegg
Joëlle
J
Hillenweck
Anne
A
Rehnmark
Stefan
S
Faulds
Malin Hedengran
MH
Zalko
Daniel
D
Pongratz
Ingemar
I
Pettersson
Katarina
K
D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004958:Estradiol / Q000378:metabolism / Q000502:physiology; D004965:Estrogen Antagonists / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000096:biosynthesis* / Q000235:genetics; D047629:Estrogen Receptor beta / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008748:Methylcholanthrene / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D004965:Estrogen Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004958:Estradiol; D008748:Methylcholanthrene