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  Identification of Thyroid Hormone Disruptors among HO-PBDEs: In Vitro Investigations and Coregulator Involved Simulations

Chen, Q., Wang, X., Shi, W., Yu, H., Zhang, X., & Giesy, J. P. (2016). Identification of Thyroid Hormone Disruptors among HO-PBDEs: In Vitro Investigations and Coregulator Involved Simulations. Environmental Science & Technology, 50(22), 12429-12438. doi:10.1021/acs.est.6b02029.

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 Creators:
Chen, Qinchang1, Author
Wang, X.2, Author              
Shi, Wei1, Author
Yu, Hongxia1, Author
Zhang, Xiaowei1, Author
Giesy, John P.1, Author
Affiliations:
1external, ou_persistent22              
2Multiphase Chemistry, Max Planck Institute for Chemistry, Max Planck Society, ou_1826290              

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 Abstract: Some hydroxylated polybrominated diphenyl ethers (HO-PBDEs), that have been widely detected in the environment and tissues of humans and wildlife, bind to thyroid hormone (TH) receptor (TR) and can disrupt functioning of systems modulated by the TR However, mechanisms of TH disrupting effects are still equivocal. Here, disruption of functions of TH modulated pathways by HO-PBDEs was evaluated by assays of competitive binding, coactivator recruitment, and proliferation of GH3 cells. In silico simulations considering effects of coregulators were carried out to investigate molecular mechanisms and to predict potencies for disrupting functions of the TH. Some HO-PBDEs were able to bind to TR with moderate affinities but were not agonists. In GH3 proliferation assays, 13 out of 16 HO-PBDEs were antagonists for the TH. In silico simulations of molecular dynamics revealed that coregulators were essential for identification of TH disruptors. Among HO-PBDEs, binding of passive antagonists induced repositioning of H12, blocking AF-2 (transactivation function 2) and preventing recruitment of the coactivator. Binding of active antagonists exposed the coregulator binding site, which tended to bind to the corepressor rather than the coactivator. By considering both passive and active antagonisms, anti-TH potencies of HO-PBDEs could be predicted from free energy of binding.

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Language(s): eng - English
 Dates: 2016
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000388155000042
DOI: 10.1021/acs.est.6b02029
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Title: Environmental Science & Technology
Source Genre: Journal
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Publ. Info: Easton, PA : American Chemical Society
Pages: - Volume / Issue: 50 (22) Sequence Number: - Start / End Page: 12429 - 12438 Identifier: ISSN: 0013-936X
CoNE: https://pure.mpg.de/cone/journals/resource/954921342157