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
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  • 183 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 
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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)

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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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