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

Abstract

The biological effects of 17␤-estradiol (E 2 ) are mediated by the two estrogen receptor (ER) isoforms ER␣ and ER␤. 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 ER␤. 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.Eukaryotic cells respond and adapt to changes in their environment by altering their enzymatic activities. This can be accomplished in part by increasing or decreasing the transcription rate of genes encoding relevant proteins. A critical point for cells is to correctly decipher the environmental changes that occur. To meet this challenge, eukaryotic cells have developed receptor proteins with the ability to distinguish between different environmental cues. However, the intensive use of chemicals in today's modern society has introduced a plethora of manmade compounds into the environment that possess abilities to interfere with receptormediated signaling pathways, a phenomenon known as endocrine disruption.The two estrogen receptor isoforms, ER␣ and ER␤, regulate the cellular response to estrogens, which are involved in the regulation of a wide range of physiological functions, including cell growth and proliferation, regulation of the cardiovascular system, and maintaining of bone homeostasis. Besides the endogenous hormones, a broad range of natural and synthetic compounds induces ER activity. For example, dietary substances like isoflavonoids and coumestans activate the ERs and so do various types of environmental pollutants such as bisphenol A and polychlorinated hydroxybiphenyls.The ERs belong to the nuclear receptor (NR) superfamily and share a conserved structural arrangement with other members of the family. NRs carry a centrally located, highly conserved DNA binding domain that mediates both dimerization and specific DNA binding. The DNA binding domain

Persistent Induction of Cytochrome P4501A1 in Human Hepatoma Cells by 3-Methylcholanthrene: Evidence for Sustained Transcriptional Activation of the CYP1A1 Promoter

“…Our results showing very little parent compound in the media 12 h after MC treatment lends further credence to this idea and were consistent with the studies of Swedenborg et al (2008). Thus, our findings indicate that the induction of CYP1A1 by MC at 72 h and beyond was independent of the presence of the parent compound, as we reported previously in the in vivo rat model (Moorthy, 2000).…”

Endocrine disruptive chemicals: mechanisms of action and involvement in metabolic disorders

“…A later study demonstrated that the ability of 3-MC to activate ERa-dependent transcription requires biotransformation to metabolites with estrogenic activity. Interestingly, in cells where 3-MC was not metabolized, 3-MC acted as an antiestrogen in close analogy to dioxin (Swedenborg et al 2008). Similar findings have been obtained with other AhR ligands such as BaP (Arcaro et al 1999).…”

Receptors mediating toxicity and their involvement in endocrine disruption

“…HAHs and PAHs are potent ligands of the aryl hydrocarbon receptor (AhR), one of the main receptors mediating the response to xenobiotics. Even though HAHs and PAHs do not bind hormone receptors as such, some of them (e.g., B[a]P and 3-MC) are metabolized into compounds that are potent ER activators [11,12].…”