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化学进展 2019, Vol. 31 Issue (1): 167-179 DOI: 10.7536/PC180414 前一篇   后一篇

• 综述 •

膜受体介导双酚A低剂量内分泌干扰效应的分子机制

朱本占1,2,**(), 沈忱1,2, 盛治国1,2,**()   

  1. 1. 中国科学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 北京 100085
    2. 中国科学院大学 北京 100049
  • 收稿日期:2018-04-08 修回日期:2018-07-03 出版日期:2019-01-15 发布日期:2018-12-07
  • 通讯作者: 朱本占, 盛治国
  • 基金资助:
    中科院战略性先导科技专项(XDB01020300); 国家自然科学基金项目资助(21377158); 国家自然科学基金项目资助(21577149); 国家自然科学基金项目资助(21477139); 国家自然科学基金项目资助(21237005); 国家自然科学基金项目资助(21621064); 国家自然科学基金项目资助(21321004)

Mechanism of the Endocrine-Disruptive Effects of Low-Dose Bisphenol A via Transmembrane Receptor

Benzhan Zhu1,2,**(), Chen Shen1,2, Zhiguo Sheng1,2,**()   

  1. 1. State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China
    2. University of Chinese Academy of Sciences, Beijing 100049, China
  • Received:2018-04-08 Revised:2018-07-03 Online:2019-01-15 Published:2018-12-07
  • Contact: Benzhan Zhu, Zhiguo Sheng
  • About author:
    ** Corresponding author e-mail: (Benzhan Zhu);
    (Zhiguo Sheng)
  • Supported by:
    The work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB01020300); The National Natural Science Foundation of China(21377158); The National Natural Science Foundation of China(21577149); The National Natural Science Foundation of China(21477139); The National Natural Science Foundation of China(21237005); The National Natural Science Foundation of China(21621064); The National Natural Science Foundation of China(21321004)

双酚A(Bisphenol A, BPA)为苯酚系衍生物,作为生产聚碳酸酯塑料和环氧树脂的中间体被广泛应用于多种产品制造中,为全球产量最大的工业品之一。BPA的大量应用使普通人群暴露BPA的几率显著增加。BPA结构与雌激素相似,为一典型雌激素样内分泌干扰物,可以对机体产生多种毒性效应。高剂量BPA主要通过拮抗雌激素受体而发挥其内分泌干扰效应;环境相关低剂量BPA由于不能与雌激素竞争结合雌激素受体,主要通过膜受体介导的信号通路以非基因组方式诱导细胞生物学功能改变。但是,具体何种膜受体介导BPA的低剂量效应以及相关分子机制目前还不清楚。基于此,我们课题组近年来在这些方面做了一系列工作。我们发现,膜G蛋白偶联受体30和整合素αvβ3及其介导的信号传导通路分别介导了环境相关低剂量BPA对雄性生殖细胞的增殖诱导和甲状腺素基因转录的干扰。对环境相关低剂量BPA作用机制的深入理解不仅有助于更客观真实评价和预测环境暴露BPA对人体健康的可能潜在影响以及采取有针对性的预防和干预措施。同时,也将为评价其他类似结构雌激素样环境内分泌干扰物的健康效应提供理论基础及技术支持。本文将结合我们近年来的研究工作,综述目前环境低剂量BPA暴露对人体健康影响的分子机制研究进展、存在的问题以及将来研究的一些思考。

Bisphenol A (BPA) is a phenol derivative and widely used in the manufacture of polycarbonate plastics and epoxy resins. It is one of the largest industrial products in the world. The extensive use of BPA makes it more easily exposed to the general population. BPA is believed to be a typical estrogen-like endocrine disruptor that can induce multiple toxic effects on the human body. High-dose BPA exerts its endocrine-disrupting effects mainly by antagonizing estrogen receptors (ERs); environmentally-relevant low-dose BPA cannot compete with estrogen for binding to ERs, and induces biological effects in a non-genomic manner mainly through the membrane receptor-mediated signaling pathways. However, it is still unclear which membrane receptor mediates the low-dose effect of BPA and the related molecular mechanisms. Based on this, our laboratory has done a series of work in these areas in recent years. We have found that membrane G protein-coupled receptor 30 and integrin αvβ3 and their mediated signaling pathways mediate the effects of environmentally-relevant low-dose BPA on the induction of male germ cells proliferation and the transcription of thyroid hormone genes, respectively. An in-depth understanding of the molecular mechanism of environmentally-relevant low-dose BPA will contribute to a more objective and realistic evaluation and prediction of the potential effects of environmental exposure on human health and then perform targeted prevention and interventions. Likewise, it will also provide a theoretical basis and technical support for evaluating the health effects of endocrine disruptors in other similar structural estrogen-like environments. This article combines our research work in recent years, reviews the current progress in the molecular mechanism of environmental low-dose BPA exposure on human health, existing problems, and some future research.

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图1 低剂量BPA对GC-1细胞的增殖诱导效应[45]
Fig.1 Proliferative effects of low-dose BPA on GC-1 cells[45] (Reproduced with permission from Environmental Health Perspectives)
图2 沉默GPR30(A)和Ers-1基因(B)可以抑制BPA对细胞的增殖诱导[45]
Fig.2 Silencing of Gpr30 (A) or Ers-1(B) inhibits BPA-induced cell proliferation[45] (Reproduced with permission from Environmental Health Perspectives)
图3 低剂量BPA转录激活GPR30启动子区AP-1位点(A, B),通过GPR30/PKG/ER-α/EFGR-ERK通路募集C-FOS到AP-1位点(C)[71]
Fig.3 Low-dose BPA transactivates the AP-1 site of the Gpr30-5’-flanking region (A, B) and recruit C-FOS to AP-1 site via GPR30/PKG/ER-α/EFGR-ERK pathways in the GC-1 cells (C)[70]
图4 低剂量BPA通过GPR30和ER-α相互作用正反馈激活PKG和EGFR-ERK-C-FOS通路诱导鼠精原细胞增殖
Fig.4 Low-dose BPA makes the GPR30 interact with the ER-α to activate PKG and EGFR-ERK-C-FOS pathways via a positive feedback loop to induce mouse germ cell proliferation
图5 过表达β3(A)或c-Src(B)拮抗BPA对TR的转录抑制[100]
Fig.5 Overexpression of either β3 (A) or c-Src (B) alleviates BPA-mediated suppression of TR transcription[99]
图6 低剂量BPA以非基因组调控的方式干扰TH介导的αvβ3-c-Src-MAPK通路导致转录抑制因子N-CoR/SMRT募集到TR-β1,从而抑制TR调控的基因转录[99]
Fig.6 Low-dose BPA disrupted TH-regulated integrin αvβ3-c-Src-MAPK-TR-β1 pathway in a non-genomic manner to recruit the N-CoR or SMRT to TR, resulting in the transcription suppression of TR[100]
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