Received for publication March 27, 2007.
Revised November 14, 2007.
Accepted for publication November 14, 2007.

3-methyl cholanthrene displays dual effects on ER and ER signaling in a cell-type specific fashion

Abstract

The biological effects of 17-estradiol (E₂) are mediated by the two estrogen receptor isoforms ER and ER. These receptors are ligand-inducible transcription factors that belong to the nuclear receptor superfamily. These receptors are also target 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 ER. 3-MC is a compound previously identified as an activator of the aryl hydrocarbon receptor (AhR). Activation of AhR is classically 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. Interestingly, 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.

Key words: Sex hormones, Regulation - transcriptional, Ah receptor, Toxicant-induced gene express