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Archives of Toxicology

, Volume 92, Issue 3, pp 1215–1223 | Cite as

Estrogenicity of halogenated bisphenol A: in vitro and in silico investigations

  • Jie Zhang
  • Tiezhu Li
  • Tuoyi Wang
  • Cuiping Yuan
  • Shuning Zhong
  • Tianzhu Guan
  • Zhuolin Li
  • Yongzhi Wang
  • Hansong Yu
  • Quan Luo
  • Yongjun Wang
  • Tiehua Zhang
In vitro systems

Abstract

The binding interactions of bisphenol A (BPA) and its halogenated derivatives (halogenated BPAs) to human estrogen receptor α ligand binding domain (hERα-LBD) was investigated using a combined in vitro and in silico approach. First, the recombinant hERα-LBD was prepared as a soluble protein in Escherichia coli BL21(DE3)pLysS. A native fluorescent phytoestrogen, coumestrol, was employed as tracer for the fluorescence polarization assay. The results of the in vitro binding assay showed that bisphenol compounds could bind to hERα-LBD as the affinity ligands. All the tested halogenated BPAs exhibited weaker receptor binding than BPA, which might be explained by the steric effect of substituents. Molecular docking studies elucidated that the halogenated BPAs adopted different conformations in the flexible hydrophobic ligand binding pocket (LBP), which is mainly dependent on their distinct halogenation patterns. The compounds with halogen substituents on the phenolic rings and on the bridging alkyl moiety acted as agonists and antagonists for hERα, respectively. Interestingly, all the compounds in the agonist conformation of hERα formed a hydrogen bond with His524, while the compounds in the antagonist conformation formed a hydrogen bond with Thr347. These docking results suggested a pivotal role of His524/Thr347 in maintaining the hERα structure in the biologically active agonist/antagonist conformation. Comparison of the calculated binding energies vs. experimental binding affinities yielded a good correlation, which might be applicable for the structure-based design of novel bisphenol compounds with reduced toxicities and for environmental risk assessment. In addition, based on hERα-LBD as a recognition element, the proposed fluorescence polarization assay may offer an alternative to chromatographic techniques for the multi-residue determination of bisphenol compounds.

Keywords

Halogenated bisphenol A Estrogen receptor α Fluorescence polarization Molecular modeling 

Notes

Acknowledgements

This work was supported by the National Key Research and Development Program of China (2017YFD0300303 and 2017YFD0300603), the National Natural Science Foundation of China (31601534), the Project funded by China Postdoctoral Science Foundation (2017M621213), and the Agricultural Science and Technology Innovation Program of Jilin Province (CXGC2017JQ006 and CXGC2017JQ010).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Ethical standards

The manuscript does not contain clinical studies or participant data.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2017

Authors and Affiliations

  • Jie Zhang
    • 1
  • Tiezhu Li
    • 1
  • Tuoyi Wang
    • 1
  • Cuiping Yuan
    • 1
  • Shuning Zhong
    • 2
  • Tianzhu Guan
    • 2
  • Zhuolin Li
    • 1
  • Yongzhi Wang
    • 1
  • Hansong Yu
    • 3
  • Quan Luo
    • 4
  • Yongjun Wang
    • 1
  • Tiehua Zhang
    • 2
  1. 1.Institute of Agricultural Resources and EnvironmentJilin Academy of Agricultural SciencesChangchunChina
  2. 2.College of Food Science and EngineeringJilin UniversityChangchunChina
  3. 3.College of Food Science and EngineeringJilin Agricultural UniversityChangchunChina
  4. 4.State Key Laboratory of Supramolecular Structure and Materials, College of ChemistryJilin UniversityChangchunChina

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