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

Abstract

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) α and/or ERβ 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 ERα and/or ERβ 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 ERα and ERβ to recruit TIF2 and SRC-1a in the presence of 17β-estradiol, genistein, diethylstilbestrol, 4-tert-octylphenol, 2',3',4',5'-tetrachlorobiphenyl-ol, and bisphenol A. We show that ligand-dependent differences exist in the ability of ERα and ERβ to bind coactivator proteins in vitro, despite the similarity in binding affinity of the various ligands for both ER subtypes. The enhanced ability of ERβ (over ERα) to recruit coactivators in the presence of xenoestrogens was consistent with a greater ability of ERβ to potentiate reporter gene activity in transiently transfected HeLa cells expressing SRC-1e and TIF2. We conclude that ligand-dependent differences in the ability of ERα and ERβ to recruit coactivator proteins may contribute to the complex tissue-dependent agonistic/antagonistic responses observed with certain xenoestrogens.