Skip to main content
SpringerLink
Log in

In vitro and in silico assessment of the structure-dependent binding of bisphenol analogues to glucocorticoid receptor

  • Research Paper
  • Published:
Analytical and Bioanalytical Chemistry Aims and scope Submit manuscript

Abstract

Widespread use of bisphenol A (BPA) and other bisphenol analogues has attracted increasing attention for their potential adverse effects. As environmental endocrine-disrupting compounds (EDCs), bisphenols (BPs) may activate a variety of nuclear receptors, including glucocorticoid receptor (GR). In this work, the binding of 11 BPs to GR was investigated by fluorescence polarization (FP) assay in combination with molecular dynamics simulations. The human glucocorticoid receptor was prepared as a soluble recombinant protein. A fluorescein-labeled dexamethasone derivative (Dex-fl) was employed as tracer. Competitive displacement of Dex-fl from GR by BPs showed that the binding affinities of bisphenol analogues were largely dependent on their characteristic functional groups. In order to further understand the relationship between BPs structures and their GR-mediated activities, molecular docking was utilized to explore the binding modes at the atomic level. The results confirmed that structural variations of bisphenol analogues contributed to different interactions of BPs with GR, potentially causing distinct toxic effects. Comparison of the calculated binding energies vs. experimental binding affinities yielded a good correlation (R 2 = 0.8266), which might be helpful for the design of environmentally benign materials with reduced toxicities. In addition, the established FP assay based on GR exhibited the potential to offer an alternative to traditional methods for the detection of bisphenols.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Stossi F, Bolt Michael J, Ashcroft Felicity J, Lamerdin Jane E, Melnick Jonathan S, Powell Reid T, et al. Defining estrogenic mechanisms of bisphenol A analogs through high throughput microscopy-based contextual assays. J Biol Chem. 2014;21(6):743–53. doi:10.1016/j.chembiol.2014.03.013.

    Article  CAS  Google Scholar 

  2. Staples CA, Dome PB, Klecka GM, Oblock ST, Harris LR. A review of the environmental fate, effects, and exposures of bisphenol A. Chemosphere. 1998;36(10):2149–73. doi:10.1016/S0045-6535(97)10133-3.

    Article  CAS  Google Scholar 

  3. Vandenberg LN, Chahoud I, Heindel JJ, Padmanabhan V, Paumgartten FJ, Schoenfelder G. Urinary, circulating, and tissue biomonitoring studies indicate widespread exposure to bisphenol A. Environ Health Perspect. 2010;118(8):1055–70. doi:10.1289/ehp.0901716.

    Article  CAS  Google Scholar 

  4. Vandenberg LN, Hauser R, Marcus M, Olea N, Welshons WV. Human exposure to bisphenol A (BPA). Reprod Toxicol. 2007;24(2):139–77. doi:10.1016/j.reprotox.2007.07.010.

    Article  CAS  Google Scholar 

  5. Rubin BS. Bisphenol A: an endocrine disruptor with widespread exposure and multiple effects. J Steroid Biochem Mol Biol. 2011;127(1-2):27–34. doi:10.1016/j.jsbmb.2011.05.002.

    Article  CAS  Google Scholar 

  6. Vogel SA. The politics of plastics: the making and unmaking of bisphenol a “safety”. Am J Public Health. 2009;99 Suppl 3:S559–66. doi:10.2105/ajph.2008.159228.

    Article  Google Scholar 

  7. Jing P, Zhang X, Wu Z, Bao L, Xu Y, Liang C, et al. Electrochemical sensing of bisphenol A by graphene-1-butyl-3-methylimidazolium hexafluorophosphate modified electrode. Talanta. 2015;141:41–6. doi:10.1016/j.talanta.2015.03.042.

    Article  CAS  Google Scholar 

  8. Rochester JR, Bolden AL. Bisphenol S and F: a systematic review and comparison of the hormonal activity of bisphenol A substitutes. Environ Health Perspect. 2015;123(7):643–50. doi:10.1289/ehp.1408989.

    Google Scholar 

  9. Chen D, Kannan K, Tan H, Zheng Z, Feng Y-L, Wu Y, et al. Bisphenol analogues other than BPA: environmental occurrence, human exposure, and toxicity-a review. Environ Sci Technol. 2016;50(11):5438–53. doi:10.1021/acs.est.5b05387.

    Article  CAS  Google Scholar 

  10. Usman A, Ahmad M. From BPA to its analogues: is it a safe journey? Chemosphere. 2016;158:131–42. doi:10.1016/j.chemosphere.2016.05.070.

    Article  CAS  Google Scholar 

  11. Matthews JB, Twomey K, Zacharewski TR. In vitro and in vivo interactions of bisphenol A and its metabolite, bisphenol A glucuronide, with estrogen receptors α and β. Chem Res Toxicol. 2001;14(2):149–57. doi:10.1021/tx0001833.

    Article  CAS  Google Scholar 

  12. Takayanagi S, Tokunaga T, Liu X, Okada H, Matsushima A, Shimohigashi Y. Endocrine disruptor bisphenol A strongly binds to human estrogen-related receptor γ (ERRγ) with high constitutive activity. Toxicol Lett. 2006;167(2):95–105. doi:10.1016/j.toxlet.2006.08.012.

    Article  CAS  Google Scholar 

  13. Riu A, Grimaldi M, le Maire A, Bey G, Phillips K, Boulahtouf A, et al. Peroxisome proliferator-activated receptor γ is a target for halogenated analogs of bisphenol A. Environ Health Perspect. 2011;119(9):1227–32. doi:10.1289/ehp.1003328.

    Article  CAS  Google Scholar 

  14. Sui Y, Ai N, Park S-H, Rios-Pilier J, Perkins JT, Welsh WJ, et al. Bisphenol A and its analogues activate human pregnane X receptor. Environ Health Perspect. 2012;120(3):399–405. doi:10.1289/ehp.1104426.

    Article  CAS  Google Scholar 

  15. Sargis RM, Johnson DN, Choudhury RA, Brady MJ. Environmental endocrine disruptors promote adipogenesis in the 3T3-L1 cell line through glucocorticoid receptor activation. Obesity (Silver Spring, Md). 2010;18(7):1283–8. doi:10.1038/oby.2009.419.

    Article  CAS  Google Scholar 

  16. Lee HJ, Chattopadhyay S, Gong E-Y, Ahn RS, Lee K. Antiandrogenic effects of bisphenol A and nonylphenol on the function of androgen receptor. Toxicol Sci. 2003;75(1):40–6. doi:10.1093/toxsci/kfg150.

    Article  CAS  Google Scholar 

  17. Zoeller RT, Bansal R, Parris C. Bisphenol-A, an environmental contaminant that acts as a thyroid hormone receptor antagonist in vitro, increases serum thyroxine, and alters RC3/neurogranin expression in the developing rat brain. Endocrinology. 2005;146(2):607–12. doi:10.1210/en.2004-1018.

    Article  CAS  Google Scholar 

  18. Liao C, Liu F, Moon HB, Yamashita N, Yun S, Kannan K. Bisphenol analogues in sediments from industrialized areas in the United States, Japan, and Korea: spatial and temporal distributions. Environ Sci Technol. 2012;46(21):11558–65. doi:10.1021/es303191g.

    Article  CAS  Google Scholar 

  19. Song S, Song M, Zeng L, Wang T, Liu R, Ruan T, et al. Occurrence and profiles of bisphenol analogues in municipal sewage sludge in China. Environ Pollut. 2014;186:14–9. doi:10.1016/j.envpol.2013.11.023.

    Article  CAS  Google Scholar 

  20. Yamazaki E, Yamashita N, Taniyasu S, Lam J, Lam PKS, Moon H-B, et al. Bisphenol A and other bisphenol analogues including BPS and BPF in surface water samples from Japan, China. Korea India Ecotox Environ Saf. 2015;122:565–72. doi:10.1016/j.ecoenv.2015.09.029.

    Article  CAS  Google Scholar 

  21. Zang X, Chang Q, Hou M, Wang C, Wang Z. Graphene grafted magnetic microspheres for solid phase extraction of bisphenol A and triclosan from water samples followed by gas chromatography-mass spectrometric analysis. Anal Methods. 2015;7(20):8793–800. doi:10.1039/c5ay01578b.

    Article  CAS  Google Scholar 

  22. Li Y, Jiao Y, Guo Y, Yang Y. Determination of bisphenol-A, 2,4-dichlorophenol, bisphenol-AF and tetrabromobisphenol-A in liquid foods and their packaging materials by vortex-assisted supramolecular solvent microextraction/high-performance liquid chromatography. Anal Methods. 2013;5(19):5037. doi:10.1039/c3ay40586a.

    Article  CAS  Google Scholar 

  23. Khedr A. Optimized extraction method for LC-MS determination of bisphenol A, melamine and di(2-ethylhexyl) phthalate in selected soft drinks, syringes, and milk powder. J Chromatogr B. 2013;930:98–103. doi:10.1016/j.jchromb.2013.04.040.

    Article  CAS  Google Scholar 

  24. Inoue K, Murayama S, Takeba K, Yoshimura Y, Nakazawa H. Contamination of xenoestrogens bisphenol A and F in honey: safety assessment and analytical method of these compounds in honey. J Food Compos Anal. 2003;16(4):497–506. doi:10.1016/S0889-1575(03)00018-8.

    Article  CAS  Google Scholar 

  25. D’Antuono A, Dall’Orto VC, Balbo AL, Sobral S, Rezzano I. Determination of bisphenol A in food-simulating liquids using LCED with a chemically modified electrode. J Agr Food Chem. 2001;49(3):1098–101. doi:10.1021/jf000660n.

    Article  Google Scholar 

  26. Marchesini GR, Meulenberg E, Haasnoot W, Irth H. Biosensor immunoassays for the detection of bisphenol A. Anal Chim Acta. 2005;528(1):37–45. doi:10.1016/j.aca.2004.06.066.

    Article  CAS  Google Scholar 

  27. Moreno MJ, D’Arienzo P, Manclus JJ, Montoya A. Development of monoclonal antibody-based immunoassays for the analysis of bisphenol A in canned vegetables. J Environ Sci Heal B. 2011;46(6):509–17. doi:10.1080/03601234.2011.583871.

    CAS  Google Scholar 

  28. Zhang J, Zhao S-Q, Zhang K, Zhou J-Q. Cd-doped ZnO quantum dots-based immunoassay for the quantitative determination of bisphenol A. Chemosphere. 2014;95:105–10. doi:10.1016/j.chemosphere.2013.08.039.

    Article  CAS  Google Scholar 

  29. Kuruto-Niwa R, Tateoka Y, Usuki Y, Nozawa R. Measurement of bisphenol A concentrations in human colostrum. Chemosphere. 2007;66(6):1160–4. doi:10.1016/j.chemosphere.2006.06.073.

    Article  CAS  Google Scholar 

  30. Bledsoe RK, Montana VG, Stanley TB, Delves CJ, Apolito CJ, McKee DD, et al. Crystal structure of the glucocorticoid receptor ligand binding domain reveals a novel mode of receptor dimerization and coactivator recognition. Cell. 2002;110(1):93–105. doi:10.1016/s0092-8674(02)00817-6.

    Article  CAS  Google Scholar 

  31. Roelofs MJ, van den Berg M, Bovee TF, Piersma AH, van Duursen MB. Structural bisphenol analogues differentially target steroidogenesis in murine MA-10 Leydig cells as well as the glucocorticoid receptor. Toxicol. 2015;329:10–20. doi:10.1016/j.tox.2015.01.003.

    Article  CAS  Google Scholar 

  32. Prasanth GK, Divya LM, Sadasivan C. Bisphenol-A can bind to human glucocorticoid receptor as an agonist: an in silico study. J Appl Toxicol. 2010;30(8):769–74. doi:10.1002/jat.1570.

    Article  CAS  Google Scholar 

  33. Kroe RR, Baker MA, Brown MP, Farrow NA, Gautschi E, Hopkins JL, et al. Agonist versus antagonist induce distinct thermodynamic modes of co-factor binding to the glucocorticoid receptor. Biophys Chem. 2007;128(2-3):156–64. doi:10.1016/j.bpc.2007.03.013.

    Article  CAS  Google Scholar 

  34. Simmons CA, Bledsoe RK, Guex N, Pearce KH. Expression, purification, and characterization of multiple, multifunctional human glucocorticoid receptor proteins. Protein Express Purif. 2008;62(1):29–35. doi:10.1016/j.pep.2008.07.008.

    Article  CAS  Google Scholar 

  35. Roehrl MH, Wang JY, Wagner G. A general framework for development and data analysis of competitive high-throughput screens for small-molecule inhibitors of protein-protein interactions by fluorescence polarization. Biochemistry. 2004;43(51):16056–66. doi:10.1021/bi048233g.

    Article  CAS  Google Scholar 

  36. Scherrer LC, Dalman FC, Massa E, Meshinchi S, Pratt WB. Structural and functional reconstitution of the glucocorticoid receptor-hsp90 complex. J Biol Chem. 1990;265(35):21397–400.

    CAS  Google Scholar 

  37. Pratt WB, Toft DO. Steroid receptor interactions with heat shock protein and immunophilin chaperones. Endocr Rev. 1997;18(3):306–60. doi:10.1210/edrv.18.3.0303.

    CAS  Google Scholar 

  38. Kwon Y-U, Kodadek T. Quantitative comparison of the relative cell permeability of cyclic and linear peptides. Chem Biol. 2007;14(6):671–7. doi:10.1016/j.chembiol.2007.05.006.

    Article  CAS  Google Scholar 

  39. Yu P, Liu B, Kodadek T. A convenient, high-throughput assay for measuring the relative cell permeability of synthetic compounds. Nat Protoc. 2007;2(1):23–30.

    Article  CAS  Google Scholar 

  40. Kaya T, Mohr SC, Waxman DJ, Vajda S. Computational screening of phthalate monoesters for binding to PPARγ. Chem Res Toxicol. 2006;19(8):999–1009. doi:10.1021/tx050301s.

    Article  CAS  Google Scholar 

  41. Zhang J, Xing X, Sun Y, Li Z, Xue P, Wang T, et al. Characterization of the binding between phthalate esters and mouse PPARα for the development of a fluorescence polarization-based competitive binding assay. Anal Methods. 2016;8(4):880–5. doi:10.1039/c5ay03053f.

    Article  CAS  Google Scholar 

  42. Lind U, Greenidge P, Gillner M, Koehler KF, Wright A, Carlstedt-Duke J. Functional probing of the human glucocorticoid receptor steroid-interacting surface by site-directed mutagenesis. Gln-642 plays an important role in steroid recognition and binding. J Biol Chem. 2000;275(25):19041–9. doi:10.1074/jbc.M000228200.

    Article  CAS  Google Scholar 

  43. Kauppi B, Jakob C, Farnegardh M, Yang J, Ahola H, Alarcon M, et al. The three-dimensional structures of antagonistic and agonistic forms of the glucocorticoid receptor ligand-binding domain: RU-486 induces a transconformation that leads to active antagonism. J Biol Chem. 2003;278(25):22748–54. doi:10.1074/jbc.M212711200.

    Article  CAS  Google Scholar 

  44. Wang H, Aslanian R, Madison VS. Induced-fit docking of mometasone furoate and further evidence for glucocorticoid receptor 17α pocket flexibility. J Mol Graph Model. 2008;27(4):512–21. doi:10.1016/j.jmgm.2008.09.002.

    Article  CAS  Google Scholar 

  45. Onnis V, Kinsella GK, Carta G, Fayne D, Lloyd DG. Rational structure-based drug design and optimization in the ligand-binding domain of the glucocorticoid receptor-α. Future Med Chem. 2009;1(2):345–59. doi:10.4155/fmc.09.21.

    Article  CAS  Google Scholar 

  46. Veleiro AS, Alvarez LD, Eduardo SL, Burton G. Structure of the glucocorticoid receptor, a flexible protein that can adapt to different ligands. ChemMedChem. 2010;5(5):649–59. doi:10.1002/cmdc.201000014.

    Article  CAS  Google Scholar 

  47. Zhuang S, Zhang C, Liu W. Atomic insights into distinct hormonal activities of bisphenol A analogues toward PPARγ and ERα receptors. Chem Res Toxicol. 2014;27(10):1769–79. doi:10.1021/tx500232b.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This work was financially supported by the National Natural Science Foundation of China (31601534).

Author information

Authors and Affiliations

  1. College of Food Science and Engineering, Jilin Agricultural University, No. 2888 Xincheng Street, Changchun, Jilin, 130118, China

    Jie Zhang, Hansong Yu & Tiezhu Li

  2. College of Food Science and Engineering, Jilin University, Changchun, Jilin, 130062, China

    Tiehua Zhang & Tianzhu Guan

Authors
  1. Jie Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tiehua Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tianzhu Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hansong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tiezhu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Hansong Yu or Tiezhu Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

ESM 1

(PDF 353 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, J., Zhang, T., Guan, T. et al. In vitro and in silico assessment of the structure-dependent binding of bisphenol analogues to glucocorticoid receptor. Anal Bioanal Chem 409, 2239–2246 (2017). https://doi.org/10.1007/s00216-016-0168-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00216-016-0168-7

Keywords

Search

Navigation