PUBLICATION
Anti-estrogenic activity of tris(2,3-dibromopropyl) isocyanurate through disruption of co-activator recruitment: experimental and computational studies
- Authors
- Cao, H., Li, X., Zhang, W., Wang, L., Pan, Y., Zhou, Z., Chen, M., Zhang, A., Liang, Y., Song, M.
- ID
- ZDB-PUB-180123-10
- Date
- 2018
- Source
- Archives of toxicology 92(4): 1471-1482 (Journal)
- Registered Authors
- Chen, Minjie, Liang, Yong
- Keywords
- AF-2 site, MVLN assays, Molecular dynamics simulations, Tris(2,3-dibromopropyl) isocyanurate
- MeSH Terms
-
- Endocrine Disruptors/toxicity*
- Environmental Pollutants/toxicity*
- Estradiol/metabolism*
- Estrogen Antagonists/toxicity*
- Estrogen Receptor alpha/metabolism*
- Humans
- MCF-7 Cells
- Molecular Docking Simulation
- Triazines/toxicity*
- PubMed
- 29356860 Full text @ Arch. Toxicol.
Citation
Cao, H., Li, X., Zhang, W., Wang, L., Pan, Y., Zhou, Z., Chen, M., Zhang, A., Liang, Y., Song, M. (2018) Anti-estrogenic activity of tris(2,3-dibromopropyl) isocyanurate through disruption of co-activator recruitment: experimental and computational studies. Archives of toxicology. 92(4):1471-1482.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping