近日,，environmental health perspectives雜志在線發(fā)表了中科院生態(tài)環(huán)境研究中心環(huán)境化學(xué)與生態(tài)毒理學(xué)國家重點實驗室自由基化學(xué)與復(fù)合毒理研究組盛治國、朱本占的研究成果,，他們在研究低劑量雙酚A誘導(dǎo)精原細(xì)胞增殖新機制方面取得重要進(jìn)展,。
雙酚A（2,2-(4,4-dihydroxydiphenol)propane, BPA）是制造聚碳酸脂、環(huán)氧樹脂等的前體物,，廣泛用于殺菌劑,、染料、飲料容器,、餐具,、嬰兒奶瓶等的制造,，是世界上產(chǎn)量最大的工業(yè)用品之一,，并且每年以6-10%的速度增長,。近年的流行病學(xué)研究表明，BPA及其代謝物廣泛存在于一般人群體液中,。由于BPA的化學(xué)結(jié)構(gòu)與雌激素E2高度相似,，因此，其對生殖內(nèi)分泌系統(tǒng)的潛在干擾效應(yīng)受到廣泛關(guān)注,。大量的體內(nèi)外研究提示,，環(huán)境相關(guān)劑量BPA可以通過快速激活膜G蛋白偶聯(lián)受體介導(dǎo)的相關(guān)信號傳導(dǎo)通路促使生殖細(xì)胞增殖。但是具體分子機制仍不清楚,。
盛治國,、朱本占研究發(fā)現(xiàn)，環(huán)境相關(guān)劑量BPA (10-10-10-8 M)主要經(jīng)由PKG和EFGR-ERK信號通路誘導(dǎo)鼠精原細(xì)胞系GC-1細(xì)胞增殖,。BPA可以快速地（15分鐘）激活細(xì)胞增殖標(biāo)志蛋白：轉(zhuǎn)錄因子cAMP效應(yīng)區(qū)結(jié)合蛋白CREB和細(xì)胞周期調(diào)控蛋白Rb,。值得注意的是，在本研究中,，雌激素受體ER-α盡管參與了BPA對GC-1細(xì)胞的增殖過程,，但并沒有被BPA直接激活。進(jìn)一步的研究表明,，BPA是通過激活膜偶聯(lián)的孤兒受體GPR30介導(dǎo)的EFGR-ERK-c-foc信號通路而激活ER-α,，而ER-α的激活又正調(diào)控這個信號通路，最終刺激GC-1細(xì)胞增殖,。
本研究首次表明,，在環(huán)境相關(guān)低劑量下，BPA是通過膜偶聯(lián)受體GPR30和核受體ER-α的相互作用而激活PKG和EGFR/ERK/c-fos信號通路,，誘導(dǎo)鼠精原細(xì)胞GC-1增殖,。本研究為環(huán)境相關(guān)低劑量BPA誘發(fā)生殖細(xì)胞癌的潛在可能性提供了新的證據(jù)和機制，也為其他類似的雌激素樣化合物對生殖系統(tǒng)的內(nèi)分泌干擾作用提供了新的理論基礎(chǔ),。（生物谷Bioon.com）
doi:10.1289/ehp.1103781
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Low Concentrations of Bisphenol A Induce Mouse Spermatogonial Cell Proliferation by G Protein–Coupled Receptor 30 and Estrogen Receptor-α
Zhi-Guo Sheng, Ben-Zhan Zhu
Bisphenol A (BPA) is one of the most prevalent chemicals in daily-use materials; therefore, human exposure to BPA is ubiquitous. The estrogenicity of BPA is generally mediated by nuclear estrogen receptors (ERs). However, low concentrations of BPA stimulate seminoma cell proliferation by an uncertain mechanism that does not involve activation of ERs. We investigated the possible promoting effects of low-concentration BPA and the possible mechanism(s) using the murine ER-β negative spermatogonial GC-1 cell line. Using the specific signaling inhibitor, BPA at test concentrations ranging from 10–10 to 10–8 M markedly induced proliferation of GC-1 cells by activating both cGMP-dependent protein kinase (PKG) and epidermal growth factor receptor (EGFR) extracellular regulated kinase (ERK) pathways. BPA stimulated a rapid (15-min) phosphorylation of the transcription factor cAMP response element binding protein (CREB) and the cell cycle regulator retinoblastoma protein (Rb). Interestingly, ER-α phosphorylation is involved in the proliferation, whereas BPA does not directly transactivate ER-α in gene reporter assays. Using specific agonists and gene silencing, we further observed that BPA mediates the proliferation and fos gene expression of GC-1 cells by G protein–coupled receptor 30 (GPR30) and ER-α. Our data suggest that low concentrations of BPA activate the PKG and EGFR/ERK/c-fos pathways through a cross-talk between GPR30 and ER-α, which in turn stimulates GC-1 cell proliferation. The present study provides a novel insight regarding the potential role of GPR30 and ER-α in mediating the proliferative effects of BPA in male germ cells.
