Anti-estrogenic activity of tris(2,3-dibromopropyl) isocyanurate through disruption of co-activator recruitment: experimental and computational studies
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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.
KeywordsTris(2,3-dibromopropyl) isocyanurate MVLN assays AF-2 site Molecular dynamics simulations
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).
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Conflict of interest
The authors declare that there are no conflicts of interest.
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