摘要:Ba c k g r o u n d: Bisphenol A (BPA) is a well-known endocrine disruptor that imperfectly mimics the effects of physiologic estrogens via membrane-bound estrogen receptors (mERα, mERβ, and GPER/GPR30), thereby initiating non genomic signaling. Bisphenol S (BPS) is an alternative to BPA in plastic consumer products and thermal paper.oB j e c t i v e: To characterize the non genomic activities of BPS, we examined signaling pathways it evoked in GH3/B6/F10rat pituitary cells alone and together with the physiologic estrogen estradiol (E2). Extracellular signal-regulated kinase (ERK)– and c-Jun-N-terminal kinase (JNK)–specific phosphorylations were examined for their correlation to three functional responses: proliferation, caspase activation, and prolactin (PRL) release.Me t h o d s: We detected ERK and JNK phosphorylations by fixed-cell immuno assays, identified the predominant mER initiating the signaling with selective inhibitors, estimated cell numbers by crystal violet assays, measured caspase activity by cleavage of fluorescent caspase substrates, and measured PRL release by radio immunoassay.re s u l t s: BPS phospho activated ERK within 2.5 min in a non monotonic dose-dependent manner (10–15to 10–7M). When combined with 10–9M E2, the physiologic estrogen's ERK response was attenuated. BPS could not activate JNK, but it greatly enhanced E2-induced JNK activity. BPS induced cell proliferation at low concentrations (femtomolar to nanomolar), similar to E2.Combinations of both estrogens reduced cell numbers below those of the vehicle control and also activated caspases. Earlier activation of caspase 8 versus caspase 9 demonstrated that BPS initiates apoptosis via the extrinsic pathway, consistent with activation via a membrane receptor. BPS also inhibited rapid (≤ 1 min) E2-induced PRL release.co n c l u s i o n: BPS, once considered a safe substitute for BPA, disrupts membrane-initiated E2-induced cell signaling, leading to altered cell proliferation, cell death, and PRL release