The molecular mechanisms used by environmental estrogens to exert their estrogenic actions are still greatly undetermined. It is generally accepted that xenoestrogens act through their binding to the estrogen receptors ERalpha and ERbeta which then translocate to the nucleus and act as transcription factors. Nonetheless, in most cases, their binding affinity and their transcriptional activity is much lower than that of 17beta-estradiol and therefore, low dose effects are hardly explained by this mechanism. In this work we use isolated islets of Langerhans cultured for 48h in the presence or absence of physiological concentrations of 17beta-estradiol (E2) or environmentally relevant doses of the xenoestrogen Bisphenol A (BPA).

We show that both ERalpha and ERbeta are present in pancreatic beta-cells as seen by RT-PCR and immunocytochemistry. BPA is as potent as E2 in up-regulating pancreatic insulin content at doses as low as 100pM. The dose-response curves for both have an inverted U-shape. E2 also increases insulin secretion in cultured islets, as well as insulin mRNA. The specific anti-estrogen ICI182,780 blocks the effect of BPA and E2 on insulin content suggesting that they are mediated by ERs. Pharmacological tools as well as ERalphaKO and ERbetaKO mice unequivocally demonstrate that the effects produced by E2 and BPA are mediated by ERalpha. Additionally, our results suggest the involvement of the c-Src and ERKs pathways. The up-regulation of pancreatic insulin content by ERalpha activation is important to explain the actions of E2 and environmental estrogens in endocrine pancreatic function and blood glucose homeostasis.