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Progress in Chemistry 2019, Vol. 31 Issue (1): 167-179 DOI: 10.7536/PC180414 Previous Articles   Next Articles

• Review •

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: Revised: Online: Published:
  • 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)
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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.

Key words: bisphenol A, low-dose effect, G protein-coupled receptor 30, integrin αvβ3, toxic effect
Fig.1 Proliferative effects of low-dose BPA on GC-1 cells[45] (Reproduced with permission from Environmental Health Perspectives)
Fig.2 Silencing of Gpr30 (A) or Ers-1(B) inhibits BPA-induced cell proliferation[45] (Reproduced with permission from Environmental Health Perspectives)
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]
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
Fig.5 Overexpression of either β3 (A) or c-Src (B) alleviates BPA-mediated suppression of TR transcription[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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