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

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

Author information

1
Molecular Pathogenesis Group, National Toxicology Program Laboratory (NTPL), Division of the NTP (DNTP), Research Triangle Park, NC, 27709, USA.
2
Flow Cytometry Center, Signal Transduction Laboratory, Research Triangle Park, NC, 27709, USA.
3
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences (NIEHS), National Institutes of Health (NIH), Department of Health and Human Services (HHS), Research Triangle Park, NC, 27709, USA.
4
Molecular Pathogenesis Group, National Toxicology Program Laboratory (NTPL), Division of the NTP (DNTP), Research Triangle Park, NC, 27709, USA. Electronic address: dixon@niehs.nih.gov.

Abstract

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

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