Molecular Pathogenesis Group, National Toxicology Program Laboratory (NTPL), Division of the NTP (DNTP), Research Triangle Park, NC, 27709, USA.
Flow Cytometry Center, Signal Transduction Laboratory, Research Triangle Park, NC, 27709, USA.
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 μM - 10 μM) increased proliferation by facilitating progression of hormonally regulated, immortalized human uterine leiomyoma (ht-UtLM; fibroid) cells from G-G 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 MAPK/ERK1/2 pathway. EGFR (pEGFR), Ras, and MAPK 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.
评估了 ERα36 在调节 BPA 作用及其作为人类子宫肌瘤风险因素的作用。低浓度（10μM-10μM）的 BPA 通过促进激素调节的永生化人子宫平滑肌瘤（ht-UtLM；纤维瘤）细胞从 G 期进入细胞周期的 S 期，从而促进增殖；而较高浓度（100μM-200μM）则会降低生长速度。BPA 上调 ERα36 基因和蛋白表达，并诱导 SOS1 和 Grb2 蛋白表达增加，这两者都是 MAPK/ERK1/2 通路的介导物。在 BPA 暴露后 10 分钟内，ht-UtLM 细胞中的 EGFR（pEGFR）、Ras 和 MAPK 被磷酸化，同时 Src 被激活。BPA 增强了磷酸化 Src（pSrc）与 ERα36 的共定位，并促进了 pSrc 与 pEGFR 的共免疫沉淀。用 siERα36 沉默 ERα36 则消除了上述作用。BPA 通过膜结合的 ERα36 诱导 ht-UtLM 细胞增殖，激活Src、EGFR、Ras 和 MAPK 非基因组信号通路。
