title: Bisphenol S disrupts estradiol-induced nongenomic signaling in a rat pituitary cell line: effects on cell functions.
abstract: BACKGROUND
  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 nongenomic signaling. Bisphenol S (BPS) is an alternative to BPA in plastic consumer products and thermal paper.
  
  
  OBJECTIVE
  To characterize the nongenomic activities of BPS, we examined signaling pathways it evoked in GH3/B6/F10 rat 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.
  
  
  METHODS
  We detected ERK and JNK phosphorylations by fixed-cell immunoassays, 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 radioimmunoassay.
  
  
  RESULTS
  BPS phosphoactivated ERK within 2.5 min in a nonmonotonic dose-dependent manner (10-15 to 10-7 M). When combined with 10-9 M 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch Galveston, Texas 77555-0645, USA.
authors: René
authors: R
authors: Viñas
authors: Cheryl S
authors: CS
authors: Watson
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D004958:Estradiol / Q000502:physiology*; D010636:Phenols / Q000633:toxicity*; D010766:Phosphorylation; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011388:Prolactin / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D011863:Radioimmunoassay; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013450:Sulfones / Q000633:toxicity*; D000098831:Bisphenol S Compounds
chemical_list: D004958:Estradiol; D010636:Phenols; D011388:Prolactin; D011494:Protein Kinases; D013450:Sulfones; C543008:bisphenol S; D000098831:Bisphenol S Compounds