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Article: Thyroid Hormone Receptor Agonistic and Antagonistic Activity of Newly Synthesized Dihydroxylated Polybrominated Diphenyl Ethers: An In Vitro and In Silico Coactivator Recruitment Study

TitleThyroid Hormone Receptor Agonistic and Antagonistic Activity of Newly Synthesized Dihydroxylated Polybrominated Diphenyl Ethers: An In Vitro and In Silico Coactivator Recruitment Study
Authors
Keywordsagonistic or antagonistic activities
coactivator recruitment assay
DiOH-PBDEs
thyroid hormone receptors
Issue Date11-Apr-2024
PublisherMDPI
Citation
Toxics, 2024, v. 12, n. 4 How to Cite?
Abstract

Dihydroxylated polybrominated diphenyl ethers (DiOH-PBDEs) could be the metabolites of PBDEs of some organisms or the natural products of certain marine bacteria and algae. OH-PBDEs may demonstrate binding affinity to thyroid hormone receptors (TRs) and can disrupt the functioning of the systems modulated by TRs. However, the thyroid hormone disruption mechanism of diOH-PBDEs remains elusive due to the absence of diOH-PBDEs standards. This investigation explores the potential disruptive effects of OH/diOH-PBDEs on thyroid hormones via competitive binding and coactivator recruitment with TRα and TRβ. At levels of 5000 nM and 25,000 nM, 6-OH-BDE-47 demonstrated significant recruitment of steroid receptor coactivator (SRC), whereas none of the diOH-PBDEs exhibited SRC recruitment within the range of 0.32–25,000 nM. AutoDock CrankPep (ADCP) simulations suggest that the conformation of SRC and TR–ligand complexes, particularly their interaction with Helix 12, rather than binding affinity, plays a pivotal role in ligand agonistic activity. 6,6′-diOH-BDE-47 displayed antagonistic activity towards both TRα and TRβ, while the antagonism of 3,5-diOH-BDE-100 for TRα and TRβ was concentration-dependent. 3,5-diOH-BDE-17 and 3,5-diOH-BDE-51 exhibited no discernible agonistic or antagonistic activities. Molecular docking analysis revealed that the binding energy of 3,3′,5-triiodo-L-thyronine (T3) surpassed that of OH/diOH-PBDEs. 3,5-diOH-BDE-100 exhibited the highest binding energy, whereas 6,6′-diOH-BDE-47 displayed the lowest. These findings suggest that the structural determinants influencing the agonistic and antagonistic activities of halogen phenols may be more intricate than previously proposed, involving factors beyond high-brominated PBDEs or hydroxyl group and bromine substitutions. It is likely that the agonistic or antagonistic propensities of OH/diOH-PBDEs are instigated by protein conformational changes rather than considerations of binding energy.


Persistent Identifierhttp://hdl.handle.net/10722/350885
ISSN
2023 Impact Factor: 3.9
2023 SCImago Journal Rankings: 0.815

 

DC FieldValueLanguage
dc.contributor.authorZhang, Mengtao-
dc.contributor.authorShi, Jianghong-
dc.contributor.authorLi, Bing-
dc.contributor.authorGe, Hui-
dc.contributor.authorTao, Huanyu-
dc.contributor.authorZhang, Jiawei-
dc.contributor.authorLi, Xiaoyan-
dc.contributor.authorCai, Zongwei-
dc.date.accessioned2024-11-06T00:30:26Z-
dc.date.available2024-11-06T00:30:26Z-
dc.date.issued2024-04-11-
dc.identifier.citationToxics, 2024, v. 12, n. 4-
dc.identifier.issn2305-6304-
dc.identifier.urihttp://hdl.handle.net/10722/350885-
dc.description.abstract<p>Dihydroxylated polybrominated diphenyl ethers (DiOH-PBDEs) could be the metabolites of PBDEs of some organisms or the natural products of certain marine bacteria and algae. OH-PBDEs may demonstrate binding affinity to thyroid hormone receptors (TRs) and can disrupt the functioning of the systems modulated by TRs. However, the thyroid hormone disruption mechanism of diOH-PBDEs remains elusive due to the absence of diOH-PBDEs standards. This investigation explores the potential disruptive effects of OH/diOH-PBDEs on thyroid hormones via competitive binding and coactivator recruitment with TRα and TRβ. At levels of 5000 nM and 25,000 nM, 6-OH-BDE-47 demonstrated significant recruitment of steroid receptor coactivator (SRC), whereas none of the diOH-PBDEs exhibited SRC recruitment within the range of 0.32–25,000 nM. AutoDock CrankPep (ADCP) simulations suggest that the conformation of SRC and TR–ligand complexes, particularly their interaction with Helix 12, rather than binding affinity, plays a pivotal role in ligand agonistic activity. 6,6′-diOH-BDE-47 displayed antagonistic activity towards both TRα and TRβ, while the antagonism of 3,5-diOH-BDE-100 for TRα and TRβ was concentration-dependent. 3,5-diOH-BDE-17 and 3,5-diOH-BDE-51 exhibited no discernible agonistic or antagonistic activities. Molecular docking analysis revealed that the binding energy of 3,3′,5-triiodo-L-thyronine (T3) surpassed that of OH/diOH-PBDEs. 3,5-diOH-BDE-100 exhibited the highest binding energy, whereas 6,6′-diOH-BDE-47 displayed the lowest. These findings suggest that the structural determinants influencing the agonistic and antagonistic activities of halogen phenols may be more intricate than previously proposed, involving factors beyond high-brominated PBDEs or hydroxyl group and bromine substitutions. It is likely that the agonistic or antagonistic propensities of OH/diOH-PBDEs are instigated by protein conformational changes rather than considerations of binding energy.</p>-
dc.languageeng-
dc.publisherMDPI-
dc.relation.ispartofToxics-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectagonistic or antagonistic activities-
dc.subjectcoactivator recruitment assay-
dc.subjectDiOH-PBDEs-
dc.subjectthyroid hormone receptors-
dc.titleThyroid Hormone Receptor Agonistic and Antagonistic Activity of Newly Synthesized Dihydroxylated Polybrominated Diphenyl Ethers: An In Vitro and In Silico Coactivator Recruitment Study -
dc.typeArticle-
dc.identifier.doi10.3390/toxics12040281-
dc.identifier.scopuseid_2-s2.0-85191728503-
dc.identifier.volume12-
dc.identifier.issue4-
dc.identifier.eissn2305-6304-
dc.identifier.issnl2305-6304-

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