Xenoestrogens Alter Estrogen Receptor (ER) α Intracellular Levels

17 beta-estradiol (E2)-dependent estrogen receptor (ER) a intracellular concentration is a well recognized critical step in the pleiotropic effects elicited by E2 in several target tissues. Beside E2, a class of synthetic and plant-derived chemicals collectively named endocrine disruptors (EDs) or xenoestrogens bind to and modify both nuclear and extra-nuclear ER alpha activities. However, at the present no information is available on the ability of EDs to hamper ER alpha intracellular concentration. Here, the effects of bisphenol A (BPA) and naringenin (Nar), prototypes of synthetic and plant-derived ER alpha ligands, have been evaluated on ER alpha levels in MCF-7 cells. Both EDs mimic E2 in triggering ER alpha Ser118 phosphorylation and gene transcription. However, only E2 or BPA induce an increase of cell proliferation; whereas 24 hrs after Nar stimulation a dose-dependent decrease in cell number is reported. E2 or BPA treatment reduces ER alpha protein and mRNA levels after 24 hrs. Contrarily, Nar stimulation does not alter ER alpha content but reduces ER alpha mRNA levels like other ligands. Co-stimulation experiments indicate that 48 hrs of Nar treatment prevents the E2-induced ER alpha degradation and hijacks the physiological ability of E2:ER alpha complex to regulate gene transcription. Mechanistically, Nar induces ER alpha protein accumulation by preventing proteasomal receptor degradation via persistent activation of p38/MAPK pathway. As a whole these data demonstrate that ER alpha intracellular concentration is an important target through which EDs hamper the hormonal milieu of E2 target cells driving cells to different outcomes or mimicking E2 even in the absence of the hormone.