Differential effects of xenoestrogens on coactivator recruitment by estrogen receptor (ER) α and ERβ

It has been proposed that tissue-specific estrogenic and/or antiestrogenic actions of certain xenoestrogens may be associated with alterations in the tertiary structure of estrogen receptor (ER) alpha and/or ER beta following ligand binding; changes which are sensed by cellular factors (coactivators) required for normal gene expression. However, it is still unclear whether xenoestrogens affect the normal behavior of ER alpha and/or ER beta subsequent to receptor binding. In view of the wide range of structural forms now recognized to mimic the actions of the natural estrogens, we have assessed the ability of ER alpha and ER beta to recruit TIF2 and SRC-1a in the presence of 17 beta -estradiol, genistein, diethylstilbestrol, 4-tert-oc-tylphenol, 2',3',4',5' -tetrachlorobiphenyl-1, and bisphenol A. We show that ligand-dependent differences exist in the ability of ER alpha and ER beta to bind coactivator proteins in vitro, despite the similarity in binding affinity of the various ligands for both ER subtypes, The enhanced ability of ER beta (over ER alpha) to recruit coactivators in the presence of xenoestrogens was consistent with a greater ability of ERP to potentiate reporter gene activity in transiently transfected HeLa cells expressing SRC-1e and TIFS. We conclude that ligand-dependent differences in the ability of ER alpha and ER beta to recruit coactivator proteins may contribute to the complex tissue-dependent agonistic/antagonistic responses observed with certain xenoestrogens.