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内分泌干扰物对核受体二聚化影响的研究进展

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黄付晏, 陈钦畅, 谭皓月, 郭婧, 于南洋, 史薇, 于红霞. 内分泌干扰物对核受体二聚化影响的研究进展[J]. 生态毒理学报, 2021, 16(4): 17-31. doi: 10.7524/AJE.1673-5897.20201105004
引用本文: 黄付晏, 陈钦畅, 谭皓月, 郭婧, 于南洋, 史薇, 于红霞. 内分泌干扰物对核受体二聚化影响的研究进展[J]. 生态毒理学报, 2021, 16(4): 17-31. doi: 10.7524/AJE.1673-5897.20201105004
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Huang Fuyan, Chen Qinchang, Tan Haoyue, Guo Jing, Yu Nanyang, Shi Wei, Yu Hongxia. Review on the Effects of Endocrine Disrupting Chemicals on Dimerization of Nuclear Receptors[J]. Asian Journal of Ecotoxicology, 2021, 16(4): 17-31. doi: 10.7524/AJE.1673-5897.20201105004
Citation: Huang Fuyan, Chen Qinchang, Tan Haoyue, Guo Jing, Yu Nanyang, Shi Wei, Yu Hongxia. Review on the Effects of Endocrine Disrupting Chemicals on Dimerization of Nuclear Receptors[J]. Asian Journal of Ecotoxicology, 2021, 16(4): 17-31. doi: 10.7524/AJE.1673-5897.20201105004
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内分泌干扰物对核受体二聚化影响的研究进展

  • 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, E-mail: 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

  • 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 ; 
  • Fund Project:

  • 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。
    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.
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  • Gronemeyer H, Gustafsson J A, Laudet V. Principles for modulation of the nuclear receptor superfamily[J]. Nature Reviews Drug Discovery, 2004, 3(11):950-964
    Gore A C, Chappell V A, Fenton S E, et al. EDC-2:The endocrine society's second scientific statement on endocrine-disrupting chemicals[J]. Endocrine Reviews, 2015, 36(6):E1-E150
    Gore A C, Chappell V A, Fenton S E, et al. Executive summary to EDC-2:The endocrine society's second scientific statement on endocrine-disrupting chemicals[J]. Endocrine Reviews, 2015, 36(6):593-602
    Chen L G, Zhang W P, Hua J H, et al. Dysregulation of intestinal health by environmental pollutants:Involvement of the estrogen receptor and aryl hydrocarbon receptor[J]. Environmental Science & Technology, 2018, 52(4):2323-2330
    Soto A M, Sonnenschein C. Environmental causes of cancer:Endocrine disruptors as carcinogens[J]. Nature Reviews Endocrinology, 2010, 6(7):363-370
    Melzer D, Osborne N J, Henley W E, et al. Urinary bisphenol A concentration and risk of future coronary artery disease in apparently healthy men and women[J]. Circulation, 2012, 125(12):1482-1490
    Legler J, Fletcher T, Govarts E, et al. Obesity, diabetes, and associated costs of exposure to endocrine-disrupting chemicals in the European Union[J]. The Journal of Clinical Endocrinology and Metabolism, 2015, 100(4):1278-1288
    Mustieles V, Pérez-Lobato R, Olea N, et al. Bisphenol A:Human exposure and neurobehavior[J]. Neurotoxicology, 2015, 49:174-184
    Trasande L, Zoeller R T, Hass U, et al. Burden of disease and costs of exposure to endocrine disrupting chemicals in the European Union:An updated analysis[J]. Andrology, 2016, 4(4):565-572
    Attina T M, Hauser R, Sathyanarayana S, et al. Exposure to endocrine-disrupting chemicals in the USA:A population-based disease burden and cost analysis[J]. The Lancet Diabetes & Endocrinology, 2016, 4(12):996-1003
    Chen Q C, Tan H Y, Yu H X, et al. Activation of steroid hormone receptors:Shed light on the in silico evaluation of endocrine disrupting chemicals[J]. Science of the Total Environment, 2018, 631-632:27-39
    Leduc A M, Trent J O, Wittliff J L, et al. Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions[J]. Proceedings of the National Academy of Sciences of the United States of America, 2003, 100(20):11273-11278
    Chakraborty S, Cole S, Rader N, et al. In silico design of peptidic inhibitors targeting estrogen receptor alpha dimer interface[J]. Molecular Diversity, 2012, 16(3):441-451
    Helsen C, Kerkhofs S, Clinckemalie L, et al. Structural basis for nuclear hormone receptor DNA binding[J]. Molecular and Cellular Endocrinology, 2012, 348(2):411-417
    Louw A. GR dimerization and the impact of GR dimerization on GR protein stability and half-life[J]. Frontiers in Immunology, 2019, 10:1693
    Iwabuchi E, Miki Y, Ono K, et al. In situ detection of estrogen receptor dimers in breast carcinoma cells in archival materials using proximity ligation assay (PLA)[J]. The Journal of Steroid Biochemistry and Molecular Biology, 2017, 165(Pt B):159-169
    Chandra V, Wu D L, Li S, et al. The quaternary architecture of RARβ-RXRα heterodimer facilitates domain-domain signal transmission[J]. Nature Communications, 2017, 8(1):868
    Zheng W L, Lu Y, Tian S Y, et al. Structural insights into the heterodimeric complex of the nuclear receptors FXR and RXR[J]. Journal of Biological Chemistry, 2018, 293(32):12535-12541
    Wang Y M, Ong S S, Chai S C, et al. Role of CAR and PXR in xenobiotic sensing and metabolism[J]. Expert Opinion on Drug Metabolism & Toxicology, 2012, 8(7):803-817
    Ahmadian M, Suh J M, Hah N, et al. PPARγ signaling and metabolism:The good, the bad and the future[J]. Nature Medicine, 2013, 19(5):557-566
    Evans R M, Mangelsdorf D J. Nuclear receptors, RXR, and the big Bang[J]. Cell, 2014, 157(1):255-266
    Manolagas S C, O'Brien C A, Almeida M. The role of estrogen and androgen receptors in bone health and disease[J]. Nature Reviews Endocrinology, 2013, 9(12):699-712
    Zhou W, Slingerland J M. Links between oestrogen receptor activation and proteolysis:Relevance to hormone-regulated cancer therapy[J]. Nature Reviews Cancer, 2014, 14(1):26-38
    Otte K, Kranz H, Kober I, et al. Identification of farnesoid X receptor beta as a novel mammalian nuclear receptor sensing lanosterol[J]. Molecular and Cellular Biology, 2003, 23(3):864-872
    Huang W, Peng Y, Kiselar J, et al. Multidomain architecture of estrogen receptor reveals interfacial cross-talk between its DNA-binding and ligand-binding domains[J]. Nature Communications, 2018, 9(1):3520
    Schwabe J W, Chapman L, Finch J T, et al. The crystal structure of the estrogen receptor DNA-binding domain bound to DNA:How receptors discriminate between their response elements[J]. Cell, 1993, 75(3):567-578
    Tamrazi A, Carlson K E, Daniels J R, et al. Estrogen receptor dimerization:Ligand binding regulates dimer affinity and dimer dissociation rate[J]. Molecular Endocrinology, 2002, 16(12):2706-2719
    De Bosscher K, Desmet S J, Clarisse D, et al. Nuclear receptor crosstalk-defining the mechanisms for therapeutic innovation[J]. Nature Reviews Endocrinology, 2020, 16(7):363-377
    Forman B M, Umesono K, Chen J, et al. Unique response pathways are established by allosteric interactions among nuclear hormone receptors[J]. Cell, 1995, 81(4):541-550
    Kurokawa R, Yu V C, Näär A, et al. Differential orientations of the DNA-binding domain and carboxy-terminal dimerization interface regulate binding site selection by nuclear receptor heterodimers[J]. Genes & Development, 1993, 7(7B):1423-1435
    Leblanc B P, Stunnenberg H G. 9-cis retinoic acid signaling:Changing partners causes some excitement[J]. Genes & Development, 1995, 9(15):1811-1816
    Gampe R T, Montana V G, Lambert M H, et al. Asymmetry in the PPARgamma/RXRalpha crystal structure reveals the molecular basis of heterodimerization among nuclear receptors[J]. Molecular Cell, 2000, 5(3):545-555
    Eiler S, Gangloff M, Duclaud S, et al. Overexpression, purification, and crystal structure of native ER alpha LBD[J]. Protein Expression and Purification, 2001, 22(2):165-173
    Takacs M, Petoukhov M V, Atkinson R A, et al. The asymmetric binding of PGC-1α to the ERRα and ERRγ nuclear receptor homodimers involves a similar recognition mechanism[J]. PLoS One, 2013, 8(7):e67810
    Nadal M, Prekovic S, Gallastegui N, et al. Structure of the homodimeric androgen receptor ligand-binding domain[J]. Nature Communications, 2017, 8:14388
    Williams S P, Sigler P B. Atomic structure of progesterone complexed with its receptor[J]. Nature, 1998, 393(6683):392-396
    Bledsoe R K, Madauss K P, Holt J A, et al. A ligand-mediated hydrogen bond network required for the activation of the mineralocorticoid receptor[J]. The Journal of Biological Chemistry, 2005, 280(35):31283-31293
    Claessens F, Joniau S, Helsen C. Comparing the rules of engagement of androgen and glucocorticoid receptors[J]. Cellular and Molecular Life Sciences, 2017, 74(12):2217-2228
    Savory J G, Préfontaine G G, Lamprecht C, et al. Glucocorticoid receptor homodimers and glucocorticoid-mineralocorticoid receptor heterodimers form in the cytoplasm through alternative dimerization interfaces[J]. Molecular and Cellular Biology, 2001, 21(3):781-793
    Deckers J, Bougarne N, Mylka V, et al. Co-activation of glucocorticoid receptor and peroxisome proliferator-activated receptor-γ in murine skin prevents worsening of atopic March[J]. The Journal of Investigative Dermatology, 2018, 138(6):1360-1370
    Panet-Raymond V, Gottlieb B, Beitel L K, et al. Interactions between androgen and estrogen receptors and the effects on their transactivational properties[J]. Molecular and Cellular Endocrinology, 2000, 167(1-2):139-150
    Miranda T B, Voss T C, Sung M H, et al. Reprogramming the chromatin landscape:Interplay of the estrogen and glucocorticoid receptors at the genomic level[J]. Cancer Research, 2013, 73(16):5130-5139
    Fan W W, Evans R. PPARs and ERRs:Molecular mediators of mitochondrial metabolism[J]. Current Opinion in Cell Biology, 2015, 33:49-54
    Pratt W B, Galigniana M D, Morishima Y, et al. Role of molecular chaperones in steroid receptor action[J]. Essays in Biochemistry, 2004, 40:41-58
    Dull A, Goncharova E, Hager G, et al. Development of an image analysis screen for estrogen receptor alpha (ERα) ligands through measurement of nuclear translocation dynamics[J]. The Journal of Steroid Biochemistry and Molecular Biology, 2010, 122(5):341-351
    Kil S H, Kalinec F. Expression and dexamethasone-induced nuclear translocation of glucocorticoid and mineralocorticoid receptors in Guinea pig cochlear cells[J]. Hearing Research, 2013, 299:63-78
    Nott S L, Huang Y F, Li X D, et al. Genomic responses from the estrogen-responsive element-dependent signaling pathway mediated by estrogen receptor alpha are required to elicit cellular alterations[J]. The Journal of Biological Chemistry, 2009, 284(22):15277-15288
    Tata J R. Signalling through nuclear receptors[J]. Nature Reviews Molecular Cell Biology, 2002, 3(9):702-710
    Mangelsdorf D J, Thummel C, Beato M, et al. The nuclear receptor superfamily:The second decade[J]. Cell, 1995, 83(6):835-839
    Gronemeyer H, Moras D. Nuclear receptors. How to finger DNA[J]. Nature, 1995, 375(6528):190-191
    Chen Q C, Wang X X, Tan H Y, et al. Molecular initiating events of bisphenols on androgen receptor-mediated pathways provide guidelines for in silico screening and design of substitute compounds[J]. Environmental Science & Technology Letters, 2019, 6(4):205-210
    Chen Q C, Wang X X, Shi W, et al. Identification of thyroid hormone disruptors among HO-PBDEs:In vitro investigations and coregulator involved simulations[J]. Environmental Science & Technology, 2016, 50(22):12429-12438
    Bhhatarai B, Wilson D M, Price P S, et al. Evaluation of OASIS QSAR models using ToxCastTM in vitro estrogen and androgen receptor binding data and application in an integrated endocrine screening approach[J]. Environmental Health Perspectives, 2016, 124(9):1453-1461
    Paul-Friedman K, Martin M, Crofton K M, et al. Limited chemical structural diversity found to modulate thyroid hormone receptor in the Tox21 chemical library[J]. Environmental Health Perspectives, 2019, 127(9):97009
    Coriano C G, Liu F B, Sievers C K, et al. A computational-based approach to identify estrogen receptor α/β heterodimer selective ligands[J]. Molecular Pharmacology, 2018, 93(3):197-207
    Powell E, Xu W. Intermolecular interactions identify ligand-selective activity of estrogen receptor alpha/beta dimers[J]. PNAS, 2008, 105(48):19012-19017
    Depoix C, Delmotte M H, Formstecher P, et al. Control of retinoic acid receptor heterodimerization by ligand-induced structural transitions. A novel mechanism of action for retinoid antagonists[J]. The Journal of Biological Chemistry, 2001, 276(12):9452-9459
    Putcha B D, Wright E, Brunzelle J S, et al. Structural basis for negative cooperativity within agonist-bound TR:RXR heterodimers[J]. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(16):6084-6087
    Collingwood T N, Butler A, Tone Y, et al. Thyroid hormone-mediated enhancement of heterodimer formation between thyroid hormone receptor beta and retinoid X receptor[J]. The Journal of Biological Chemistry, 1997, 272(20):13060-13065
    Delfosse V, Grimaldi M, Pons J L, et al. Structural and mechanistic insights into bisphenols action provide guidelines for risk assessment and discovery of bisphenol A substitutes[J]. PNAS, 2012, 109(37):14930-14935
    Osz J, Brélivet Y, Peluso-Iltis C, et al. Structural basis for a molecular allosteric control mechanism of cofactor binding to nuclear receptors[J]. Proceedings of the National Academy of Sciences of the United States of America, 2012, 109(10):E588-E594
    Judson R S, Houck K A, Watt E D, et al. On selecting a minimal set of in vitro assays to reliably determine estrogen agonist activity[J]. Regulatory Toxicology and Pharmacology:RTP, 2017, 91:39-49
    Gounarides J S, Chen A D, Shapiro M J. Nuclear magnetic resonance chromatography:Applications of pulse field gradient diffusion NMR to mixture analysis and ligand-receptor interactions[J]. Journal of Chromatography B:Biomedical Sciences and Applications, 1999, 725(1):79-90
    Benedetti R, Conte M, Carafa V, et al. Analysis of chromatin-nuclear receptor interactions by laser-chromatin immunoprecipitation[J]. Methods in Molecular Biology, 2014, 1204:25-34
    Li S M, Armstrong C M, Bertin N, et al. A map of the interactome network of the metazoan C. elegans[J]. Science, 2004, 303(5657):540-543
    Cui Y N, Zhang X, Yu M, et al. Techniques for detecting protein-protein interactions in living cells:Principles, limitations, and recent progress[J]. Science China Life Sciences, 2019, 62(5):619-632
    Medintz I L, Mattoussi H. Quantum dot-based resonance energy transfer and its growing application in biology[J]. Physical Chemistry Chemical Physics:PCCP, 2009, 11(1):17-45
    Feige J N, Gelman L, Tudor C, et al. Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator-activated receptor/retinoid X receptor heterodimers in the absence and presence of ligand[J]. The Journal of Biological Chemistry, 2005, 280(18):17880-17890
    Schaufele F, Carbonell X, Guerbadot M, et al. The structural basis of androgen receptor activation:Intramolecular and intermolecular amino-carboxy interactions[J]. Proceedings of the National Academy of Sciences of the United States of America, 2005, 102(28):9802-9807
    Yoshimura K, Muto Y, Shimizu M, et al. Phosphorylated retinoid X receptor alpha loses its heterodimeric activity with retinoic acid receptor beta[J]. Cancer Science, 2007, 98(12):1868-1874
    Shrestha D, Jenei A, Nagy P, et al. Understanding FRET as a research tool for cellular studies[J]. International Journal of Molecular Sciences, 2015, 16(4):6718-6756
    Hayes S, Malacrida B, Kiely M, et al. Studying protein-protein interactions:Progress, pitfalls and solutions[J]. Biochemical Society Transactions, 2016, 44(4):994-1004
    Pfleger K D, Eidne K A. Illuminating insights into protein-protein interactions using bioluminescence resonance energy transfer (BRET)[J]. Nature Methods, 2006, 3(3):165-174
    Mulero M, Perroy J, Federici C, et al. Analysis of RXR/THR and RXR/PPARG2 heterodimerization by bioluminescence resonance energy transfer (BRET)[J]. PLoS One, 2013, 8(12):e84569
    Grossmann C, Ruhs S, Langenbruch L, et al. Nuclear shuttling precedes dimerization in mineralocorticoid receptor signaling[J]. Chemistry & Biology, 2012, 19(6):742-751
    Giner X C, Cotnoir-White D, Mader S, et al. Selective ligand activity at Nur/retinoid X receptor complexes revealed by dimer-specific bioluminescence resonance energy transfer-based sensors[J]. FASEB Journal:Official Publication of the Federation of American Societies for Experimental Biology, 2015, 29(10):4256-4267
    Cotnoir-White D, El Ezzy M, Boulay P L, et al. Monitoring ligand-dependent assembly of receptor ternary complexes in live cells by BRETFect[J]. Proceedings of the National Academy of Sciences of the United States of America, 2018, 115(11):E2653-E2662
    Dragulescu-Andrasi A, Chan C T, De A, et al. Bioluminescence resonance energy transfer (BRET) imaging of protein-protein interactions within deep tissues of living subjects[J]. Proceedings of the National Academy of Sciences of the United States of America, 2011, 108(29):12060-12065
    European Society of Endocrinology. Measurement of estrogen receptor alpha homodimerization caused by xenoestrogens using bimolecular fluorescence complementation[R]. Florence, Italy:European Society of Endocrinology, 2012
    Xu D, Zhan Y, Qi Y F, et al. Androgen receptor splice variants dimerize to transactivate target genes[J]. Cancer Research, 2015, 75(17):3663-3671
    Bedi S. Identification of novel ligands and structural requirements for heterodimerization of the liver X receptor alpha[D]. Dayton:Wright State University, 2017:206
    Chinchilla D, Zipfel C, Robatzek S, et al. A flagellin-induced complex of the receptor FLS2 and BAK1 initiates plant defence[J]. Nature, 2007, 448(7152):497-500
    Kodama Y, Hu C D. Bimolecular fluorescence complementation (BiFC):A 5-year update and future perspectives[J]. BioTechniques, 2012, 53(5):285-298
    Karplus M, McCammon J A. Molecular dynamics simulations of biomolecules[J]. Nature Structural Biology, 2002, 9(9):646-652
    Li Y, Perera L, Coons L A, et al. Differential in vitro biological action, coregulator interactions, and molecular dynamic analysis of bisphenol A (BPA), BPAF, and BPS ligand-ERα complexes[J]. Environmental Health Perspectives, 2018, 126(1):017012
    Zhuang S L, Bao L L, Linhananta A, et al. Molecular modeling revealed that ligand dissociation from thyroid hormone receptors is affected by receptor heterodimerization[J]. Journal of Molecular Graphics and Modelling, 2013, 44:155-160
    Sonoda M T, Martínez L, Webb P, et al. Ligand dissociation from estrogen receptor is mediated by receptor dimerization:Evidence from molecular dynamics simulations[J]. Molecular Endocrinology, 2008, 22(7):1565-1578
    Chakraborty S, Willett H, Biswas P K. Insight into estrogen receptor beta-beta and alpha-beta homo- and heterodimerization:A combined molecular dynamics and sequence analysis study[J]. Biophysical Chemistry, 2012, 170:42-50
    Fratev F. Activation helix orientation of the estrogen receptor is mediated by receptor dimerization:Evidence from molecular dynamics simulations[J]. Physical Chemistry Chemical Physics:PCCP, 2015, 17(20):13403-13420
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  • 收稿日期:  2020-11-05
黄付晏, 陈钦畅, 谭皓月, 郭婧, 于南洋, 史薇, 于红霞. 内分泌干扰物对核受体二聚化影响的研究进展[J]. 生态毒理学报, 2021, 16(4): 17-31. doi: 10.7524/AJE.1673-5897.20201105004
引用本文: 黄付晏, 陈钦畅, 谭皓月, 郭婧, 于南洋, 史薇, 于红霞. 内分泌干扰物对核受体二聚化影响的研究进展[J]. 生态毒理学报, 2021, 16(4): 17-31. doi: 10.7524/AJE.1673-5897.20201105004
shu
Huang Fuyan, Chen Qinchang, Tan Haoyue, Guo Jing, Yu Nanyang, Shi Wei, Yu Hongxia. Review on the Effects of Endocrine Disrupting Chemicals on Dimerization of Nuclear Receptors[J]. Asian Journal of Ecotoxicology, 2021, 16(4): 17-31. doi: 10.7524/AJE.1673-5897.20201105004
Citation: Huang Fuyan, Chen Qinchang, Tan Haoyue, Guo Jing, Yu Nanyang, Shi Wei, Yu Hongxia. Review on the Effects of Endocrine Disrupting Chemicals on Dimerization of Nuclear Receptors[J]. Asian Journal of Ecotoxicology, 2021, 16(4): 17-31. doi: 10.7524/AJE.1673-5897.20201105004
shu

内分泌干扰物对核受体二聚化影响的研究进展

    通讯作者: 于南洋, E-mail: yuny@nju.edu.cn ; 
    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
  • 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
  • 收稿日期:  2020-11-05
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）

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。

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