Estrogen receptor activation via activation function 2 predicts agonism ofxenoestrogens in normal and neoplastic cells of the uterine myometrium

The possible contribution of endocrine disrupters to human disease, particu larly those compounds that modulate the estrogen receptor (ER), has recentl y drawn considerable attention. The tissue specificity of effects mediated by the ER is well recognized, although the mechanism of this specificity is not understood sufficiently to predict the effects of a particular ligand in different target tissues. Although the divergence of ER-mediated effects in the breast, bone, and uterine endometrium has been described, a frequen tly overlooked site of estrogen action is the smooth muscle of the uterus. The uterine myometrium is the tissue of origin of an extremely common hormo ne-responsive tumor, uterine leiomyoma, a tumor with a significant impact o n women's health and a possible environmental influence. This report descri bes an in vitro/in vivo system for identifying the effects of ER ligands in the myometrium and elucidating their mechanism of action. Several natural and synthetic xenoestrogens were evaluated at the cellular and molecular le vel for their ability to mimic estrogen action in uterine myometrial tissue s. Diethylstilbestrol, coumestrol, genistein, naringenin, and endosulfan we re able to activate the AF2 function of the ER in vitro and demonstrated ag onist activity in estrogen-responsive myometrial cells, as determined by in duction of proliferation and increased message Levels of progesterone recep tor. Compounds that could not activate AF2 function (4-hydroxy-tamoxifen, L Y117018, and LY317783) did not act as estrogen agonists. For agonists, rank order of potency was predicted by receptor affinity; however, endosulfan d isplayed a surprising degree of activity, despite negligible receptor bindi ng. Additionally, diethylstilbestrol and tamoxifen demonstrated prototypica l agonist and antagonist effects, respectively, in the intact myometrium of sexually mature rats. The results presented here suggest that some exogeno us ER ligands may mimic the effects of endogenous estrogens on uterine leio myoma and may contribute to a complex hormonal milieu that impacts both nor mal and neoplastic myometrium.