近日，environmental health perspectives杂志在线发表了中科院生态环境研究中心环境化学与生态毒理学国家重点实验室自由基化学与复合毒理研究组盛治国、朱本占的研究成果，他们在研究低剂量双酚A诱导精原细胞增殖新机制方面取得重要进展。
双酚A（2,2-(4,4-dihydroxydiphenol)propane, BPA）是制造聚碳酸脂、环氧树脂等的前体物，广泛用于杀菌剂、染料、饮料容器、餐具、婴儿奶瓶等的制造，是世界上产量最大的工业用品之一，并且每年以6-10%的速度增长。近年的流行病学研究表明，BPA及其代谢物广泛存在于一般人群体液中。由于BPA的化学结构与雌激素E2高度相似，因此，其对生殖内分泌系统的潜在干扰效应受到广泛关注。大量的体内外研究提示，环境相关剂量BPA可以通过快速激活膜G蛋白偶联受体介导的相关信号传导通路促使生殖细胞增殖。但是具体分子机制仍不清楚。
盛治国、朱本占研究发现，环境相关剂量BPA (10-10-10-8 M)主要经由PKG和EFGR-ERK信号通路诱导鼠精原细胞系GC-1细胞增殖。BPA可以快速地（15分钟）激活细胞增殖标志蛋白：转录因子cAMP效应区结合蛋白CREB和细胞周期调控蛋白Rb。值得注意的是，在本研究中，雌激素受体ER-α尽管参与了BPA对GC-1细胞的增殖过程，但并没有被BPA直接激活。进一步的研究表明，BPA是通过激活膜偶联的孤儿受体GPR30介导的EFGR-ERK-c-foc信号通路而激活ER-α，而ER-α的激活又正调控这个信号通路，最终刺激GC-1细胞增殖。
本研究首次表明，在环境相关低剂量下，BPA是通过膜偶联受体GPR30和核受体ER-α的相互作用而激活PKG和EGFR/ERK/c-fos信号通路，诱导鼠精原细胞GC-1增殖。本研究为环境相关低剂量BPA诱发生殖细胞癌的潜在可能性提供了新的证据和机制，也为其他类似的雌激素样化合物对生殖系统的内分泌干扰作用提供了新的理论基础。（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.
