陈钦畅,
谭皓月,
郭婧,
于南洋,,
史薇,
于红霞
污染控制与资源化研究国家重点实验室, 南京大学环境学院, 南京 210023
作者简介: 黄付晏(1996-),女,硕士研究生,研究方向为计算毒理学,E-mail:hfuyan2332@163.com.
通讯作者: 于南洋,yuny@nju.edu.cn ;
基金项目: 国家重点研发计划（2018YFC1801604，2018YFC1801503）；国家自然科学基金面上项目（21577058）；江苏省优秀青年基金资助项目（BK20170077）；国家水体污染控制与治理科技重大专项（2017ZX07202-001，2017ZX07602-002）中图分类号: X171.5
Review on the Effects of Endocrine Disrupting Chemicals on Dimerization of Nuclear Receptors
Huang Fuyan,Chen Qinchang,
Tan Haoyue,
Guo Jing,
Yu Nanyang,,
Shi Wei,
Yu Hongxia
State Key Laboratory of Pollution Control and Resource Reuse, School of the Environment, Nanjing University, Nanjing 210023, China
Corresponding author: Yu Nanyang,yuny@nju.edu.cn ;
CLC number: X171.5
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摘要:环境内分泌干扰物（endocrine disrupting chemicals，EDCs）可模仿或拮抗天然激素与核受体结合，干扰核受体的同源或异源二聚，进而通过共调节因子的招募调控转录活性，最终引起内分泌干扰效应。目前研究主要针对EDCs与核受体的结合过程，忽视了其对核受体二聚化过程的影响，而该过程的阻断可直接导致转录失活。EDCs对于不同核受体二聚化的影响不同，只有激动剂EDCs能够促进雄激素受体（androgen receptor，AR）的同源二聚化，而雌激素受体（estrogen receptor，ER）在与具有激动或拮抗活性的EDCs结合后都可诱导ER二聚体的形成，但二聚化类型不同。通过检索ToxCast和Tox21数据库发现多达227种EDCs可以诱导ER二聚化，相比于ERα-ERα同源二聚体（6.09%～7.38%的活性率），EDCs更易诱导ERα-ERβ异源二聚体（11.25%～12.22%的活性率）和ERβ-ERβ同源二聚体（10.02%～11.69%的活性率）。EDCs也能够差异性诱导其他核受体如维生素D受体（vitamin D receptor，VDR）与维甲酸X受体（retinoid X receptor，RXR）形成的异源二聚体，不同类型的二聚体对于研究EDCs转录活性的生理学相关性具有重要意义。基于经济合作与发展组织（Organization for Economic Co-operation and Development，OECD）报告的参考化学品研究发现，相比于配受体结合活性，二聚活性与转录活性之间有着更好的相关关系。本文从EDCs介导的核受体二聚化转录机制、二聚化与转录活性间的关系以及二聚化研究方法三方面，总结EDCs对核受体二聚化的影响，以期为深入理解EDCs的分子作用机制，推进化合物的内分泌干扰风险评估提供参考。
关键词: 内分泌干扰物/
核受体/
同源二聚体/
异源二聚体/
转录机制/
荧光共振能量转移/
双分子荧光互补
Abstract:Many environmental chemicals can mediate nuclear receptor (NR), causing endocrine disrupting effects on human. Endocrine disrupting chemicals (EDCs) can bind NR as a ligand by imitating or antagonizing natural hormones to form NR-ligand complex. The complex as homodimer or heterodimer in the nucleus, ultimately regulating transcription activity through the recruitment of coregulators. At present, studies on EDCs mainly focus on the process of NR-ligand binding, while few concentrate on nuclear receptor dimerization. The dimerization of NR plays a decisive role in transcription activity, and blocking the dimerization process will cause transcription inactivation. The effects of EDCs on dimerization of nuclear receptors are different. Only the agonist can promote the homodimerization of androgen receptor (AR), while estrogen receptor (ER) can induce the formation of ER dimer after binding with agonists or antagonists, but the dimerization types are different. Searching ToxCast and Tox21 databases, it is found that up to 227 EDCs can induce dimerization of estrogen receptor (ER). Compared with ERα-ERα homodimer (6.09%～7.38% active rate), EDCs are more likely to induce ERα-ERβ heterodimer (11.25%～12.22% active rate) and ERβ-ERβ homodimer (10.02%～11.69% active rate). EDCs can also differentially induce the formation of heterodimer between other nuclear receptors such as vitamin D receptor (VDR) and retinoid X receptor (RXR). Different dimers are of great significance for studying the physiological correlation of transcription activity of EDCs. Based on the reference chemicals reported by OECD, it is found that there is a better correlation between dimerization activity and transcription activity than NR-ligand binding. In this paper, the effects of EDCs on NR dimerization are summarized from three aspects: the transcription mechanism of NR dimerization mediated by EDCs, the relationship between NR dimerization and transcription activity, and the research methods of NR dimerization, in order to provide reference for an in-depth understanding of the molecular mechanism and the promotion of risk assessment of EDCs.
Key words:endocrine disrupting chemicals/
nuclear receptor/
homodimer/
heterodimer/
transcription mechanism/
resonance energy transfer/
bimolecular fluorescence complementation.
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