基于AhR信号通路的抗雌激素效应及其机制研究进展
Research Advances of Anti-estrogenic Effect Based on AhR Signaling Pathway and Its Mechanism
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摘要: 芳香烃受体（AhR）是一种配体依赖型转录因子，在生物体内发挥着重要的生理功能，并能够介导某些外源物质的毒性作用。已有研究表明AhR通路在调控雌性生物体生殖方面发挥着重要作用，无论AhR缺失还是AhR被过度激活均会损害雌性个体的生殖健康。近期有报道表明当AhR通路被激活后，会通过多种途径干扰生物体内源雌激素受体（ER）通路，这提示了一种外源物质发挥抗雌激素效应的新模式。本文通过归纳整理国内外相关研究，首先从AhR信号通路被激活后将会抑制雌激素（E2）合成和促进E2代谢两方面阐述了AhR激动剂降低雌性个体内源E2水平的作用途径，接着又从活化的AhR通路直接抑制雌激素效应基因的转录、与ER通路竞争共调控因子和促进ER降解3个角度总结了AhR激动剂拮抗ER功能的分子机制，以期为相关物质的抗雌激素机制研究提供借鉴与参考。Abstract: Aryl hydrocarbon receptor (AhR) is a ligand-dependent transcription factor that plays important endogenous physiological roles in organisms. Furthermore, AhR is a well-known factor that mediates many toxic effects of specific exogenous substances. Previous studies have shown that the AhR pathway regulates female reproduction. Both potent AhR ligands exposed females and transgenic models lacking AhR showed poor reproductive health. Recently, it is reported that the activated AhR pathway interfered with the endogenous estrogen receptor (ER) pathway through a variety of approaches, which suggested us there were new mechanisms underlying the anti-estrogenic effects of exogenous substance. Based on relevant studies from domestic and abroad, in this paper, firstly the roles of AhR agonists in reducing endogenous estrogen (E2) levels in female were described from two aspects:inhibiting E2 synthesis and enhancing E2 metabolism. Then, the molecular mechanisms of AhR agonists antagonizing ER functions were summarized from three aspects:directly inhibiting the transcription of estrogen-regulated genes, competing cofactors involved in ER pathway and enhancing metabolisms of ER. This review will provide new thoughts for exploring anti-estrogenic mechanisms of similar substances.
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