Phytoestrogens and Their Human Metabolites Show Distinct Agonistic and Antagonistic Properties on Estrogen Receptor a (ERa) and ERb in Human Cells

Phytoestrogens exert pleiotropic effects on cellular signaling and show some beneficial effects on estrogen-dependent diseases. However, due to activation/inhibition of the estrogen receptors ERa or ERb, these compounds may induce or inhibit estrogen action and, therefore, have the potential to disrupt estrogen signaling. We performed a comprehensive analysis and potency comparison of phytoestrogens and their human metabolites for ERbinding, induction/ suppression of ERa and ERb transactivation, and coactivator
recruitment in human cells. The soy-derived genistein, coumestrol, and equol displayed a preference for transactivation of ERb compared to ERa and were 10- to 100-fold less potent than diethylstilbestrol. In contrast, zearalenone was the most potent phytoestrogen tested and activated preferentially ERa. All other phytoestrogens tested, including resveratrol and humanmetabolites of daidzein and enterolactone, were weak ER agonists. Interestingly, the daidzein metabolites 3',4',7-isoflavone and 4',6,7-isoflavone were superagonists on ERa and ERb. All phytoestrogens tested showed reduced potencies to activate ERa and ERb compared to diethylstilbestrol on the estrogen-responsive C3 promoter compared to a consensus
estrogen response element indicating a degree of promoter dependency. Zearalenone and resveratrol were antagonistic on both ERa andERb at high doses. The phytoestrogens enhanced preferentially recruitment of GRIP1 to ERa similar to 17b-estradiol. In contrast, for ERb no distinct preference for one coactivator (GRIP1 or SRC- 1) was apparent and the overall coactivator association was less pronounced than for ERa. Due to their abundance and (anti)-estrogenic potencies, the soy-derived isoflavones, coumestrol, resveratrol, and zearalenone would appear to have the potential for effectively functioning as endocrine disruptors. Author's Abstract