2021 Volume 16 Issue 4
Article Contents

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

Review on the Effects of Endocrine Disrupting Chemicals on Dimerization of Nuclear Receptors

  • Corresponding author: Yu Nanyang, yuny@nju.edu.cn
  • Received Date: 05/11/2020
    Accepted Date: 29/12/2020
    Fund Project:
  • 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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Soto A M, Sonnenschein C. Environmental causes of cancer:Endocrine disruptors as carcinogens[J]. Nature Reviews Endocrinology, 2010, 6(7):363-370

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Mustieles V, Pérez-Lobato R, Olea N, et al. Bisphenol A:Human exposure and neurobehavior[J]. Neurotoxicology, 2015, 49:174-184

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Louw A. GR dimerization and the impact of GR dimerization on GR protein stability and half-life[J]. Frontiers in Immunology, 2019, 10:1693

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Evans R M, Mangelsdorf D J. Nuclear receptors, RXR, and the big Bang[J]. Cell, 2014, 157(1):255-266

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Leblanc B P, Stunnenberg H G. 9-cis retinoic acid signaling:Changing partners causes some excitement[J]. Genes & Development, 1995, 9(15):1811-1816

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Nadal M, Prekovic S, Gallastegui N, et al. Structure of the homodimeric androgen receptor ligand-binding domain[J]. Nature Communications, 2017, 8:14388

    Google Scholar Pub Med

    Williams S P, Sigler P B. Atomic structure of progesterone complexed with its receptor[J]. Nature, 1998, 393(6683):392-396

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Fan W W, Evans R. PPARs and ERRs:Molecular mediators of mitochondrial metabolism[J]. Current Opinion in Cell Biology, 2015, 33:49-54

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Tata J R. Signalling through nuclear receptors[J]. Nature Reviews Molecular Cell Biology, 2002, 3(9):702-710

    Google Scholar Pub Med

    Mangelsdorf D J, Thummel C, Beato M, et al. The nuclear receptor superfamily:The second decade[J]. Cell, 1995, 83(6):835-839

    Google Scholar Pub Med

    Gronemeyer H, Moras D. Nuclear receptors. How to finger DNA[J]. Nature, 1995, 375(6528):190-191

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Powell E, Xu W. Intermolecular interactions identify ligand-selective activity of estrogen receptor alpha/beta dimers[J]. PNAS, 2008, 105(48):19012-19017

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Grossmann C, Ruhs S, Langenbruch L, et al. Nuclear shuttling precedes dimerization in mineralocorticoid receptor signaling[J]. Chemistry & Biology, 2012, 19(6):742-751

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Bedi S. Identification of novel ligands and structural requirements for heterodimerization of the liver X receptor alpha[D]. Dayton:Wright State University, 2017:206

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    Kodama Y, Hu C D. Bimolecular fluorescence complementation (BiFC):A 5-year update and future perspectives[J]. BioTechniques, 2012, 53(5):285-298

    Google Scholar Pub Med

    Karplus M, McCammon J A. Molecular dynamics simulations of biomolecules[J]. Nature Structural Biology, 2002, 9(9):646-652

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

    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

    Google Scholar Pub Med

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Review on the Effects of Endocrine Disrupting Chemicals on Dimerization of Nuclear Receptors

Fund Project:

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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