The aryl hydrocarbon receptor ligands 2,3,7,8-tetrachlorodibenzo-p-dioxin and 3-methylcholanthrene regulate distinct genetic networks

The two estrogen receptor isoforms ER alpha and ER beta 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 ER alpha to the promoters of such genes. Interestingly, in contrast to DES, the estrogenic effects exerted by 3-MC were exclusively observed in ER alpha, but not in ER beta-expressing cells, suggesting ER isoform selectivity of 3-MC-derived metabolites. (C) 2012 Elsevier Ireland Ltd. All rights reserved.