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Archives of Toxicology

, Volume 92, Issue 4, pp 1471–1482 | Cite as

Anti-estrogenic activity of tris(2,3-dibromopropyl) isocyanurate through disruption of co-activator recruitment: experimental and computational studies

  • Huiming Cao
  • Xun Li
  • Wenjuan Zhang
  • Ling Wang
  • Yu Pan
  • Zhen Zhou
  • Minjie Chen
  • Aiqian Zhang
  • Yong Liang
  • Maoyong Song
Molecular Toxicology
  • 294 Downloads

Abstract

As a potential endocrine disruptor, tris(2,3-dibromopropyl) isocyanurate (TBC) has previously been demonstrated to reduce expression of estrogen-dependent vitellogenin (vtg) mRNA in adult zebrafish. However, the underlying toxicity pathways and molecular mechanisms involved in TBC-induced endocrine disruption remain elusive. In the current study, E-Screen and MVLN assays were employed to explore the potential anti-estrogenic effects of TBC via the estrogen receptor α (ERα)-mediated signaling pathway. Within a dose range between 1 × 10− 9 and 1 × 10− 7 M, TBC significantly inhibited 17β-estradiol (E2)-induced cell proliferation in a breast cancer cell line. The luciferase activity induced by E2 was also significantly inhibited by TBC in a dose-dependent manner. Moreover, neither TBC nor E2 affected proliferation of the ERα-negative breast cancer cell line MDA-MB-231. These experimental results confirmed that TBC has anti-estrogenic effects by affecting the ERα-mediated signaling pathway. By comparing TBC with known antagonists of ERα, we found that TBC has similar molecular structure as certain co-activator binding inhibitors. Therefore, using molecular docking and molecular dynamics simulations, TBC was further predicted to competitively occupy the surface site of ERα rather than the canonical E2-binding pocket of ERα, thus disrupt subsequent co-activator recruitment and transcription activation. Our findings elucidate the anti-estrogenic mechanism of TBC at the atomic level and highlight the biological importance of surface sites of nuclear receptors for a risk assessment of potential environmental pollutants.

Keywords

Tris(2,3-dibromopropyl) isocyanurate MVLN assays AF-2 site Molecular dynamics simulations 

Notes

Acknowledgements

This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB14030501), the National Nature Science Foundation of China (21277062, 21477049) and the Natural Science Foundation of Hubei Province (2017CFB368).

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

Supplementary material

204_2018_2159_MOESM1_ESM.doc (3.7 mb)
Supplementary material 1 (DOC 3788 KB)

References

  1. Anandakrishnan R, Aguilar B, Onufriev AV (2012) H++ 3.0: automating pK prediction and the preparation of biomolecular structures for atomistic molecular modeling and simulations. Nucleic Acids Res 40(W1):W537-W541CrossRefPubMedCentralGoogle Scholar
  2. Belorusova AY, Eberhardt J, Potier N, Stote RH, Dejaegere A, Rochel N (2014) Structural insights into the molecular mechanism of vitamin D receptor activation by lithocholic acid involving a new mode of ligand recognition. J Med Chem 57(11):4710–4719CrossRefPubMedGoogle Scholar
  3. Bernardes A, Souza PC, Muniz JR, Ricci CG, Ayers SD, Parekh NM, Godoy AS, Trivella DB, Reinach P, Webb P (2013) Molecular mechanism of peroxisome proliferator-activated receptor α activation by WY14643: a new mode of ligand recognition and receptor stabilization. J Mol Biol 425(16):2878–2893CrossRefPubMedGoogle Scholar
  4. Cao H, Sun Y, Wang L, Zhao C, Fu J, Zhang A (2017a) Understanding the microscopic binding mechanism of hydroxylated and sulfated polybrominated diphenyl ethers with transthyretin by molecular docking, molecular dynamics simulations and binding free energy calculations. Mol BioSyst 13(4):736–749CrossRefPubMedGoogle Scholar
  5. Cao H, Wang F, Liang Y, Wang H, Zhang A, Song M (2017b) Experimental and computational insights on the recognition mechanism between the estrogen receptor α with bisphenol compounds. Arch Toxicol 91(12):3897–3912CrossRefPubMedGoogle Scholar
  6. Cuzzolin A, Sturlese M, Deganutti G, Salmaso V, Sabbadin D, Ciancetta A, Moro S (2016) Deciphering the complexity of ligand–protein recognition pathways using supervised molecular dynamics (SuMD) simulations. J Chem Inf Model 56(4):687–705CrossRefPubMedGoogle Scholar
  7. Darden T, York D, Pedersen L (1993) Particle mesh Ewald: An N⋅log (N) method for Ewald sums in large systems. J Chem Phys 98:10089–10092CrossRefGoogle Scholar
  8. Estébanezperpiñá E, Arnold LA, Nguyen P, Rodrigues ED, Mar E, Bateman R, Pallai P, Shokat KM, Baxter JD, Guy RK (2007) A surface on the androgen receptor that allosterically regulates coactivator binding. Proc Natl Acad Sci USA 104(41):16074–16079CrossRefGoogle Scholar
  9. Freyberger A, Schmuck G (2005) Screening for estrogenicity and anti-estrogenicity: a critical evaluation of an MVLN cell-based transactivation assay. Toxicol Lett 155(1):1–13CrossRefPubMedGoogle Scholar
  10. Hale RC, La Guardia MJ, Harvey E, Gaylor MO, Mainor TM (2006) Brominated flame retardant concentrations and trends in abiotic media. Chemosphere 64(2):181–186CrossRefPubMedGoogle Scholar
  11. Hamers T, Kamstra JH, Sonneveld E, Murk AJ, Kester MHA, Andersson PL, Legler J, Brouwer A (2006) In vitro profiling of the endocrine-disrupting potency of brominated flame retardants. Toxicol Sci 92(1):157–173CrossRefPubMedGoogle Scholar
  12. Han C, Fang S, Cao H, Lu Y, Ma Y, Wei D, Xie X, Liu X, Li X, Fei D (2013) Molecular interaction of PCB153 to human serum albumin: insights from spectroscopic and molecular modeling studies. J Hazard Mater 248:313–321CrossRefPubMedGoogle Scholar
  13. Hou T, Wang J, Li Y, Wang W (2010) Assessing the performance of the MM/PBSA and MM/GBSA methods. 1. The accuracy of binding free energy calculations based on molecular dynamics simulations. J Chem Inf Model 51(1):69–82CrossRefPubMedPubMedCentralGoogle Scholar
  14. Huang H, Du G, Zhang W, Hu J, Wu D, Song L, Xia Y, Wang X (2014) The in vitro estrogenic activities of triclosan and triclocarban. J Appl Toxicol 34(9):1060–1067CrossRefPubMedGoogle Scholar
  15. Jain AN (2007) Surflex-Dock 2.1: robust performance from ligand energetic modeling, ring flexibility, and knowledge-based search. J Comput Aided Mol Des 21(5):281–306CrossRefPubMedGoogle Scholar
  16. Jorgensen WL, Chandrasekhar J, Madura JD, Impey RW, Klein ML (1983) Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935CrossRefGoogle Scholar
  17. Legler J, Brouwer A (2003) Are brominated flame retardants endocrine disruptors? Environ Int 29(6):879–885CrossRefPubMedGoogle Scholar
  18. Li J, Liang Y, Zhang X et al (2011) Impaired gas bladder inflation in zebrafish exposed to a novel heterocyclic brominated flame retardant tris(2,3-dibromopropyl) isocyanurate. Environ Sci Technol 45(22):9750–9757CrossRefPubMedGoogle Scholar
  19. Li H, Leung K-S, Ballester PJ, Wong M-H (2014) istar: A web platform for large-scale protein-ligand docking. Plos One 9(1):e85678CrossRefPubMedPubMedCentralGoogle Scholar
  20. Li J, Zhang X, Bao J et al (2015) Toxicity of new emerging pollutant tris-(2,3-dibromopropyl) isocyanurate on BALB/c mice. J Appl Toxicol 35(4):375–382CrossRefPubMedGoogle Scholar
  21. Li X, Pan Y, Wang C, Chen M, Liu Y, Li J, Zhou Z, Xu J, Liang Y, Song M (2016) Effects of tris(2,3-dibromopropyl) isocyanurate on steroidogenesis in H295R cells. Environ Earth Sci 75(20):1339CrossRefGoogle Scholar
  22. Liu Q, Sun Y, Qu G, Long Y, Zhao X, Zhang A, Zhou Q, Hu L, Jiang G (2017) Structure-dependent hematological effects of per- and polyfluoroalkyl substances on activation of plasma kallikrein–kinin system cascade. Environ Sci Technol 51(17):10173–10183CrossRefPubMedGoogle Scholar
  23. Maier JA, Martinez C, Kasavajhala K, Wickstrom L, Hauser KE, Simmerling C (2015) ff14SB: improving the accuracy of protein side chain and backbone parameters from ff99SB. J Chem Theory Comput 11(8):3696–3713CrossRefPubMedPubMedCentralGoogle Scholar
  24. Miller IIIBR., McGee TD Jr, Swails JM, Homeyer N, Gohlke H, Roitberg AE (2012) MMPBSA. py: an efficient program for end-state free energy calculations. J Chem Theory Comput 8(9):3314–3321CrossRefPubMedGoogle Scholar
  25. Minerva MF, Bigsby RM (2008) Hydroxylated metabolites of the polybrominated diphenyl ether mixture DE-71 are weak estrogen receptor-α ligands. Environ Health Perspect 116(10):1315–1321CrossRefGoogle Scholar
  26. Morris GM, Huey R, Lindstrom W, Sanner MF, Belew RK, Goodsell DS, Olson AJ (2009) AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem 30(16):2785–2791CrossRefPubMedPubMedCentralGoogle Scholar
  27. Onufriev A, Bashford D, Case DA (2004) Exploring protein native states and large-scale conformational changes with a modified generalized born model. Proteins Struct Funct Bioinf 55(2):383–394CrossRefGoogle Scholar
  28. Parent AA, Gunther JR, Katzenellenbogen JA (2008) Blocking estrogen signaling after the hormone: pyrimidine-core inhibitors of estrogen receptor-coactivator binding. J Med Chem 51(20):6512–6530CrossRefPubMedPubMedCentralGoogle Scholar
  29. Pendse SN, Maertens A, Rosenberg M, Roy D, Fasani RA, Vantangoli MM, Madnick SJ, Boekelheide K, Fornace AJ, Odwin SA (2017) Information-dependent enrichment analysis reveals time-dependent transcriptional regulation of the estrogen pathway of toxicity. Arch Toxicol 91(4):1749–1762CrossRefPubMedGoogle Scholar
  30. Qu GB, Shi JB, Li ZN, Ruan T, Fu JJ, Wang P, Wang T, Jiang GB (2011) Detection of tris-(2, 3-dibromopropyl) isocyanurate as a neuronal toxicant in environmental samples using neuronal toxicity-directed analysis. Sci China Chem 54(10):1651–1658CrossRefGoogle Scholar
  31. Reistad T, Fonnum F, Mariussen E (2006) Neurotoxicity of the pentabrominated diphenyl ether mixture, DE-71, and hexabromocyclododecane (HBCD) in rat cerebellar granule cells in vitro. Arch Toxicol 80(11):785–796CrossRefPubMedGoogle Scholar
  32. Ren XM, Zhang YF, Guo LH, Qin ZF, Lv QY, Zhang LY (2015) Structure-activity relations in binding of perfluoroalkyl compounds to human thyroid hormone T3 receptor. Arch Toxicol 89(2):233–242CrossRefPubMedGoogle Scholar
  33. Roe DR, Cheatham TE III (2013) Ptraj and cpptraj: software for processing and analysis of molecular dynamics trajectory data. J Chem Theory Comput 9(7):3084–3095CrossRefPubMedGoogle Scholar
  34. Romkes M, Piskorska-Pliszczynska J, Safe S (1987) Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic and uterine estrogen receptor levels in rats. Toxicol Appl Pharmacol 87(2):306–314CrossRefPubMedGoogle Scholar
  35. Ruan T, Wang Y, Wang C, Wang P, Fu J, Yin Y, Qu G, Wang T, Jiang G (2009) Identification and evaluation of a novel heterocyclic brominated flame retardant tris(2,3-dibromopropyl) isocyanurate in environmental matrices near a manufacturing plant in southern China. Environ Sci Technol 43(9):3080–3086CrossRefPubMedGoogle Scholar
  36. Ryckaert J-P, Ciccotti G, Berendsen HJ (1977) Numerical integration of the cartesian equations of motion of a system with constraints: molecular dynamics of n-alkanes. J Comput Phys 23(3):327–341CrossRefGoogle Scholar
  37. Scheepstra M, Leysen S, Almen GCV, Miller JR, Piesvaux J, Kutilek V, Eenennaam HV, Zhang H, Barr K, Nagpal S (2015) Identification of an allosteric binding site for RORγt inhibition. Nat Commun 6(5):8833CrossRefPubMedPubMedCentralGoogle Scholar
  38. Schultz DJ, Wickramasinghe NS, Ivanova MM, Isaacs SM, Dougherty SM, Imbertfernandez Y, Cunningham AR, Chen C, Klinge CM (2010) Anacardic acid inhibits estrogen receptor alpha-DNA binding and reduces target gene transcription and breast cancer cell proliferation. Mol Cancer Ther 9(3):594–605CrossRefPubMedPubMedCentralGoogle Scholar
  39. Shao J, Tanner SW, Thompson N, CheathamTE (2007) Clustering molecular dynamics trajectories: 1. characterizing the performance of different clustering algorithms. J Chem Theory Comput 3(6):2312–2334CrossRefPubMedGoogle Scholar
  40. Sheng N, Li J, Liu H, Zhang A, Dai J (2016) Interaction of perfluoroalkyl acids with human liver fatty acid-binding protein. Arch Toxicol 90(1):217–227CrossRefPubMedGoogle Scholar
  41. Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL (1998) The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 95(7):927–937CrossRefPubMedGoogle Scholar
  42. Song M, Liang D, Liang Y, Chen M, Wang F, Wang H, Jiang G (2014) Assessing developmental toxicity and estrogenic activity of halogenated bisphenol A on zebrafish (Danio rerio). Chemosphere 112(1):275–281CrossRefPubMedGoogle Scholar
  43. Soto AM, Sonnenschein C, Chung KL, Fernandez MF, Olea N, Serrano FO (1995) The E-SCREEN assay as a tool to identify estrogens: an update on estrogenic environmental pollutants. Enviro Health Perspect 103(Suppl 7):113–122CrossRefGoogle Scholar
  44. Souza PC, Puhl AC, Martínez L, Aparício R, Nascimento AS, Figueira AC, Nguyen P, Webb P, Skaf MS, Polikarpov I (2014) Identification of a new hormone-binding site on the surface of thyroid hormone receptor. Mol Endocrinol 28(4):534–545CrossRefPubMedPubMedCentralGoogle Scholar
  45. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem 31(2):455–461PubMedPubMedCentralGoogle Scholar
  46. Wang J, Wolf RM, Caldwell JW, Kollman PA, Case DA (2004) Development and testing of a general amber force field. J Comput Chem 25(9):1157–1174CrossRefPubMedGoogle Scholar
  47. Wang Y, Chirgadze NY, Briggs SL, Khan S, Jensen EV, Burris TP (2006) A second binding site for hydroxytamoxifen within the coactivator-binding groove of estrogen receptor β. Proc Natl Acad Sci USA 103(26):9908–9911CrossRefPubMedPubMedCentralGoogle Scholar
  48. Wang C, Wang T, Liu W, Ruan T, Zhou Q, Liu J, Zhang A, Zhao B, Jiang G (2012) The in vitro estrogenic activities of polyfluorinated iodine alkanes. Enviro Health Perspect 120(1):119–125CrossRefGoogle Scholar
  49. Wang T, Han S, Ruan T, Wang Y, Feng J, Jiang G (2013) Spatial distribution and inter-year variation of hexabromocyclododecane (HBCD) and tris-(2,3-dibromopropyl) isocyanurate (TBC) in farm soils at a peri-urban region. Chemosphere 90(2):182–187CrossRefPubMedGoogle Scholar
  50. Wang L, Zhao Q, Zhao Y, Lou Y, Zheng M, Yu Y, Zhang M (2016) Determination of heterocyclic brominated flame retardants tris-(2, 3-dibromopropyl) isocyanurate and hexabromocyclododecane in sediment from Jiaozhou Bay wetland. Mar Pollut Bull 2016 113(1):509–512CrossRefPubMedGoogle Scholar
  51. Wärnmark A, Treuter E, Gustafsson JA, Hubbard RE, Brzozowski AM, Pike AC (2002) Interaction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alpha. J Biol Chem 277(24):21862–21868CrossRefPubMedGoogle Scholar
  52. Weiser J, Shenkin PS, Still WC (1999) Approximate atomic surfaces from linear combinations of pairwise overlaps (LCPO). J Comput Chem 20(2):217–230CrossRefGoogle Scholar
  53. Xu J, Li Q (2003) Review of the in vivo functions of the p160 steroid receptor coactivator family. Mol Endocrinol 17(9):1681–1692CrossRefPubMedGoogle Scholar
  54. Yang Y, Lv QY, Guo LH, Wan B, Ren XM, Shi YL, Cai YQ (2017) Identification of protein tyrosine phosphatase SHP-2 as a new target of perfluoroalkyl acids in HepG2 cells. Arch Toxicol 91(4):1697–1707CrossRefPubMedGoogle Scholar
  55. Ye L, Hu Z, Wang H, Zhu H, Dong Z, Jiang W, Zhao H, Li N, Mi W, Wang W, Hu X (2015) Tris-(2,3-Dibromopropyl) isocyanurate, a new emerging pollutant, impairs cognition and provokes depression-like behaviors in adult rats. Plos One 10(10):e0140281CrossRefPubMedPubMedCentralGoogle Scholar
  56. Zhang X, Li J, Chen MJ, Wu L, Zhang C, Zhang J, Zhou QF, Liang Y (2011) Toxicity of the brominated flame retardant tris-(2,3-dibromopropyl) isocyanurate in zebrafish (Danio rerio). Chin Sci Bull 56(15):1548–1555CrossRefGoogle Scholar
  57. Zhu N, Li A, Wang T, Wang P, Qu G, Ruan T, Fu J, Yuan B, Zeng L (2012) Tris(2,3-dibromopropyl) isocyanurate, hexabromocyclododecanes, and polybrominated diphenyl ethers in mollusks from Chinese Bohai Sea. Environ Sci Technol 46(13):7174–7181CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Huiming Cao
    • 1
  • Xun Li
    • 2
    • 3
  • Wenjuan Zhang
    • 1
  • Ling Wang
    • 1
  • Yu Pan
    • 1
  • Zhen Zhou
    • 4
  • Minjie Chen
    • 2
  • Aiqian Zhang
    • 5
  • Yong Liang
    • 1
    • 2
  • Maoyong Song
    • 5
  1. 1.Institute of Environment and HealthJianghan UniversityWuhanPeople’s Republic of China
  2. 2.School of MedicineJianghan UniversityWuhanPeople’s Republic of China
  3. 3.Key Laboratory of Plant Germplasm Enhancement and Specialty Agriculture, Wuhan Botanical GardenChinese Academy of SciencesWuhanPeople’s Republic of China
  4. 4.Key Laboratory of Optoelectronic Chemical Materials and Devices of the Ministry of EducationJianghan UniversityWuhanPeople’s Republic of China
  5. 5.State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental SciencesChinese Academy of SciencesBeijingPeople’s Republic of China

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