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

The two estrogen receptor isoforms ERα and ERβ 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 ERα to the promoters of such genes. Interestingly, in contrast to DES, the estrogenic effects exerted by 3-MC were exclusively observed in ERα, but not in ERβ-expressing cells, suggesting ER isoform selectivity of 3-MC-derived metabolites.

► The two prototypical AhR agonists 3-MC and TCDD induce distinct sets of genes in HepG2 cells. ► 3-MC regulates 3× more genes than TCDD, probably by forming active metabolites. ► 3-MC metabolites activate ER target genes by recruiting ERα to their promoters. ► 3-MC acts only via ERα, not via ERβ. ► Follistatin is a novel direct ER-target gene and is induced by 3-MC.