Bisphenol A induces human uterine leiomyoma cell proliferation through membrane-associated ERα36 via nongenomic signaling pathways

Mol Cell Endocrinol. 2019 Mar 15;484:59-68. doi: 10.1016/j.mce.2019.01.001. Epub 2019 Jan 4.


The role of ERα36 in regulating BPA's effects and its potential as a risk factor for human uterine fibroids were evaluated. BPA at low concentrations (10-6 μM - 10 μM) increased proliferation by facilitating progression of hormonally regulated, immortalized human uterine leiomyoma (ht-UtLM; fibroid) cells from G0-G1 into S phase of the cell cycle; whereas, higher concentrations (100 μM-200 μM) decreased growth. BPA upregulated ERα36 gene and protein expression, and induced increased SOS1 and Grb2 protein expression, both of which are mediators of the MAPKp44/42/ERK1/2 pathway. EGFR (pEGFR), Ras, and MAPKp44/42 were phosphorylated with concurrent Src activation in ht-UtLM cells within 10 min of BPA exposure. BPA enhanced colocalization of phosphorylated Src (pSrc) to ERα36 and coimmunoprecipitation of pSrc with pEGFR. Silencing ERα36 with siERα36 abolished the above effects. BPA induced proliferation in ht-UtLM cells through membrane-associated ERα36 with activation of Src, EGFR, Ras, and MAPK nongenomic signaling pathways.

Keywords: Bisphenol A; Estrogen receptor alpha36 (ERα36); Leiomyoma cells; Nongenomic signaling.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Benzhydryl Compounds / adverse effects*
  • Benzhydryl Compounds / pharmacology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Estrogen Receptor alpha / genetics*
  • Estrogen Receptor alpha / metabolism*
  • Female
  • GRB2 Adaptor Protein / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Leiomyoma / chemically induced
  • Leiomyoma / genetics
  • Leiomyoma / metabolism*
  • Phenols / adverse effects*
  • Phenols / pharmacology
  • Phosphorylation
  • SOS1 Protein / metabolism
  • Signal Transduction / drug effects
  • Up-Regulation


  • Benzhydryl Compounds
  • Estrogen Receptor alpha
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Phenols
  • SOS1 Protein
  • SOS1 protein, human
  • estrogen receptor alpha 36, human
  • bisphenol A