In vitro and in vivo interactions of bisphenol A and its metabolite, bisphenol A glucuronide, with estrogen receptors alpha and beta

The estrogenic activities of bisphenol A (BPA) and its major metabolite BPA glucuronide (BPA-G) were assessed in a number of in vitro and in vivo assa ys. BPA competed with [H-3]-17 beta -estradiol (E2) for binding to mouse ut erine cytosol ER, a glutathione S-transferase (GST)-human ER D, E, and F do main fusion protein (GST-hER alpha def) and full-length recombinant hER bet a. The IC50 values for E2 were similar for all three receptor preparations, whereas BPA competed more effectively for binding to hER beta (0.96 muM) t han to either mouse uterine cytosol ER (26 muM) or GST-hERadef (36 CIM) In contrast, BPA-G did not competitively displace [H-3]E2 from any of the ER p reparations. In MCF-7 cells transiently transfected with Gal4-hER alpha def or Gal4-hER beta def, BPA induced reporter gene activity with comparable E C50 values (71 and 39 muM, respectively). No significant induction of repor ter gene activity was seen for BPA-G. Cotreatment studies showed that conce ntrations of (10 muM) BPA and BPA-G did not antagonize EB-induced luciferas e mediated through either Gal4-hER alpha def or Gal4-hER beta def. In vivo, the uterotropic effect of gavage or subcutaneous (sc) administration of 0. 002-800 mg of BPA/kg of body weight/day for three consecutive days was exam ined in immature rats. Dose-related estrogenic effects on the rat uterus we re observed at oral doses of 200 and 800 mg/kg and at sc doses of 10, 100, and 800 mg/kg. These results demonstrate that BPA competes more effectively for binding to ER beta, but induces ER alpha- and ER beta -mediated gene e xpression with comparable efficacy. In contrast, BPA-G did not exhibit any in vitro estrogenic activity. In addition, there was a clear route dependen cy on the ability of BPA to induce estrogenic responses in vivo.