{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T07:31:56Z","timestamp":1787988716244,"version":"build-2784847793"},"reference-count":33,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T00:00:00Z","timestamp":1712793600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Natural Science Foundation of China","award":["52200229"],"award-info":[{"award-number":["52200229"]}]},{"name":"National Natural Science Foundation of China","award":["21976079"],"award-info":[{"award-number":["21976079"]}]},{"name":"National Natural Science Foundation of China","award":["2022YFC3902201"],"award-info":[{"award-number":["2022YFC3902201"]}]},{"name":"National Natural Science Foundation of China","award":["JCYJ20190809171201660"],"award-info":[{"award-number":["JCYJ20190809171201660"]}]},{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People\u2019s Republic of China","doi-asserted-by":"publisher","award":["52200229"],"award-info":[{"award-number":["52200229"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People\u2019s Republic of China","doi-asserted-by":"publisher","award":["21976079"],"award-info":[{"award-number":["21976079"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People\u2019s Republic of China","doi-asserted-by":"publisher","award":["2022YFC3902201"],"award-info":[{"award-number":["2022YFC3902201"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002855","name":"Ministry of Science and Technology of the People\u2019s Republic of China","doi-asserted-by":"publisher","award":["JCYJ20190809171201660"],"award-info":[{"award-number":["JCYJ20190809171201660"]}],"id":[{"id":"10.13039\/501100002855","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shenzhen Science and Technology Innovation Commission (STIC) Project","award":["52200229"],"award-info":[{"award-number":["52200229"]}]},{"name":"Shenzhen Science and Technology Innovation Commission (STIC) Project","award":["21976079"],"award-info":[{"award-number":["21976079"]}]},{"name":"Shenzhen Science and Technology Innovation Commission (STIC) Project","award":["2022YFC3902201"],"award-info":[{"award-number":["2022YFC3902201"]}]},{"name":"Shenzhen Science and Technology Innovation Commission (STIC) Project","award":["JCYJ20190809171201660"],"award-info":[{"award-number":["JCYJ20190809171201660"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats: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 TR\u03b1 and TR\u03b2. 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\u201325,000 nM. AutoDock CrankPep (ADCP) simulations suggest that the conformation of SRC and TR\u2013ligand complexes, particularly their interaction with Helix 12, rather than binding affinity, plays a pivotal role in ligand agonistic activity. 6,6\u2032-diOH-BDE-47 displayed antagonistic activity towards both TR\u03b1 and TR\u03b2, while the antagonism of 3,5-diOH-BDE-100 for TR\u03b1 and TR\u03b2 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\u2032,5-triiodo-L-thyronine (T3) surpassed that of OH\/diOH-PBDEs. 3,5-diOH-BDE-100 exhibited the highest binding energy, whereas 6,6\u2032-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.<\/jats:p>","DOI":"10.3390\/toxics12040281","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T07:09:28Z","timestamp":1712819368000},"page":"281","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Thyroid Hormone Receptor Agonistic and Antagonistic Activity of Newly Synthesized Dihydroxylated Polybrominated Diphenyl Ethers: An In Vitro and In Silico Coactivator Recruitment Study"],"prefix":"10.3390","volume":"12","author":[{"given":"Mengtao","family":"Zhang","sequence":"first","affiliation":[{"name":"State Environmental Protection Key Laboratory of Integrated Surface Water-Groundwater Pollution Control, School of Environmental Science and Engineering, Southern University of Science and Technology, Shenzhen 518055, China"},{"name":"China State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China"},{"name":"Institute of Environment and Ecology, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianghong","family":"Shi","sequence":"additional","affiliation":[{"name":"State Environmental Protection Key Laboratory of Integrated Surface Water-Groundwater Pollution Control, School of Environmental Science and Engineering, Southern University of Science and Technology, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bing","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Environment and Ecology, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Ge","sequence":"additional","affiliation":[{"name":"State Environmental Protection Key Laboratory of Integrated Surface Water-Groundwater Pollution Control, School of Environmental Science and Engineering, Southern University of Science and Technology, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-6212-539X","authenticated-orcid":false,"given":"Huanyu","family":"Tao","sequence":"additional","affiliation":[{"name":"State Environmental Protection Key Laboratory of Integrated Surface Water-Groundwater Pollution Control, School of Environmental Science and Engineering, Southern University of Science and Technology, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiawei","family":"Zhang","sequence":"additional","affiliation":[{"name":"State Environmental Protection Key Laboratory of Integrated Surface Water-Groundwater Pollution Control, School of Environmental Science and Engineering, Southern University of Science and Technology, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Li","sequence":"additional","affiliation":[{"name":"Institute of Environment and Ecology, Shenzhen International Graduate School, Tsinghua University, Shenzhen 518055, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongwei","family":"Cai","sequence":"additional","affiliation":[{"name":"China State Key Laboratory of Environmental and Biological Analysis, Department of Chemistry, Hong Kong Baptist University, Hong Kong, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"6330","DOI":"10.1021\/acs.est.8b07032","article-title":"Global Historical Stocks and Emissions of PBDEs","volume":"53","author":"Abbasi","year":"2019","journal-title":"Environ. Sci. Technol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"166180","DOI":"10.1016\/j.scitotenv.2023.166180","article-title":"A review of polybrominated diphenyl ethers and novel brominated flame retardants in Chinese aquatic environment: Source, occurrence, distribution, and ecological risk assessment","volume":"904","author":"Wang","year":"2023","journal-title":"Sci. Total Environ."},{"key":"ref_3","unstructured":"UNEP (2024, March 18). Fourth Meeting of the Conference of the Parties to the Stockholm Convention. Available online: http:\/\/Chm.Pops.Int\/Programmes\/Newpops\/The9newpops\/Tabid\/672\/Language\/En-Us\/Default.Aspx."},{"key":"ref_4","unstructured":"UNEP (2024, March 18). Technical Review of the Implications of Recycling Commercial Penta and Octabromodiphenyl Ethers. Annexes. Stockholm Convention Document for 6th Pop Reviewing Committee Meeting (Unep\/Pops\/Poprc.6\/Inf\/6). Available online: http:\/\/Chm.Pops.Int\/Portals\/0\/Repository\/Poprc6\/Unep-Pops-Poprc.6-2.English.Pdf."},{"key":"ref_5","unstructured":"UNEP (2024, March 18). Eighth Meeting of the Conference of the Parties to the Stockholm Convention. Available online: http:\/\/Chm.Pops.Int\/Theconvention\/Conferenceoftheparties\/Meetings\/Cop8\/Tabid\/5309\/Default.Aspx."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.envres.2015.02.012","article-title":"Organohalogens and their hydroxylated metabolites in the blood of pigs from an open waste dumping site in south India: Association with hepatic cytochrome P450","volume":"138","author":"Mizukawa","year":"2015","journal-title":"Environ. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.envres.2015.10.023","article-title":"In vitro metabolism of BDE-47, BDE-99, and \u03b1-, \u03b2-, \u03b3-HBCD isomers by chicken liver microsomes","volume":"143","author":"Zheng","year":"2015","journal-title":"Environ. Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Agarwal, V., Blanton, J.M., Podell, S., Taton, A., Schorn, M.A., Busch, J., Lin, Z., Schmidt, E.W., Jensen, P.R., and Paul, V.J. (2017). Metagenomic discovery of polybrominated diphenyl ether biosynthesis by marine sponges. Nat. Chem. Biol., 13.","DOI":"10.1038\/nchembio.2330"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1126\/science.1106882","article-title":"Two Abundant Bioaccumulated Halogenated Compounds Are Natural Products","volume":"307","author":"Teuten","year":"2005","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1016\/j.envpol.2006.08.022","article-title":"Halogenated organic compounds in archived whale oil: A pre-industrial record","volume":"145","author":"Teuten","year":"2007","journal-title":"Environ. Pollut."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1980","DOI":"10.1021\/cb5004338","article-title":"Enzymatic Synthesis of Polybrominated Dioxins from the Marine Environment","volume":"9","author":"Agarwal","year":"2014","journal-title":"ACS Chem. Biol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Li, Y., Li, S.J., Huang, H., Chen, Y.Z., and Wang, X.T. (2022). A Review of Hydroxylated and Methoxylated Brominated Diphenyl Ethers in Marine Environments. Toxics, 10.","DOI":"10.3390\/toxics10120751"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"124878","DOI":"10.1016\/j.chemosphere.2019.124878","article-title":"Determination of newly synthesized dihydroxylated polybrominated diphenyl ethers in sea fish by gas chromatography-tandem mass spectrometry","volume":"240","author":"Zhang","year":"2020","journal-title":"Chemosphere"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"12429","DOI":"10.1021\/acs.est.6b02029","article-title":"Identification of Thyroid Hormone Disruptors among HO-PBDEs: In Vitro Investigations and Coregulator Involved Simulations","volume":"50","author":"Chen","year":"2016","journal-title":"Environ. Sci. Technol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1002\/mas.21640","article-title":"Emerging Environmental Pollutants Hydroxylated Polybrominated Diphenyl Ethers: From Analytical Methods to Toxicology Research","volume":"40","author":"Wei","year":"2021","journal-title":"Mass Spectrom. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"143036","DOI":"10.1016\/j.scitotenv.2020.143036","article-title":"Toxicity and accumulation of 6-OH-BDE-47 and newly synthesized 6,6\u2032-diOH-BDE-47 in early life-stages of Zebrafish (Danio rerio)","volume":"763","author":"Zhang","year":"2021","journal-title":"Sci. Total Environ."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1007\/s00427-002-0279-3","article-title":"Phenylthiourea disrupts thyroid function in developing zebrafish","volume":"212","author":"Elsalini","year":"2003","journal-title":"Dev. Genes Evolut."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.taap.2012.04.017","article-title":"Hydroxylated PBDEs induce developmental arrest in Zebrafish","volume":"262","author":"Usenko","year":"2012","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1210","DOI":"10.1289\/ehp.0900753","article-title":"Nuclear Hormone Receptor Activity of Polybrominated Diphenyl Ethers and Their Hydroxylated and Methoxylated Metabolites in Transactivation Assays Using Chinese Hamster Ovary Cells","volume":"117","author":"Kojima","year":"2009","journal-title":"Environ. Health Perspect."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.taap.2013.01.026","article-title":"Hydroxylated polybrominated diphenyl ethers exhibit different activities on thyroid hormone receptors depending on their degree of bromination","volume":"268","author":"Ren","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1248\/jhs.54.607","article-title":"Affinity for Thyroid Hormone and Estrogen Receptors of Hydroxylated Polybrominated Diphenyl Ethers","volume":"54","author":"Kitamura","year":"2008","journal-title":"J. Health Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5161","DOI":"10.1021\/acs.jctc.9b00557","article-title":"Docking Flexible Cyclic Peptides with AutoDock CrankPep","volume":"15","author":"Zhang","year":"2019","journal-title":"J. Chem. Theory Comput."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"5121","DOI":"10.1093\/bioinformatics\/btz459","article-title":"AutoDock CrankPep: Combining folding and docking to predict protein\u2013peptide complexes","volume":"35","author":"Zhang","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1002\/pro.3235","article-title":"UCSF ChimeraX: Meeting modern challenges in visualization and analysis","volume":"27","author":"Goddard","year":"2018","journal-title":"Protein Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1002\/pro.3943","article-title":"UCSF ChimeraX: Structure visualization for researchers, educators, and developers","volume":"30","author":"Pettersen","year":"2021","journal-title":"Protein Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.pharmthera.2017.02.012","article-title":"New insights into thyroid hormone action","volume":"173","author":"Mendoza","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1016\/j.bmc.2007.10.040","article-title":"Characterization of thyroid hormone receptor \u03b1(TR\u03b1)-specific analogs with varying inner- and outer-ring substituents","volume":"16","author":"Ocasio","year":"2008","journal-title":"Bioorg. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.chemosphere.2011.12.080","article-title":"Tetrabromobisphenol-A disrupts thyroid hormone receptor alpha function in vitro: Use of fluorescence polarization to assay corepressor and coactivator peptide binding","volume":"87","author":"Major","year":"2012","journal-title":"Chemosphere"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1093\/toxsci\/kfp086","article-title":"Interference of Endocrine Disrupters with Thyroid Hormone Receptor\u2013Dependent Transactivation","volume":"110","author":"Hofmann","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3158","DOI":"10.1021\/acs.jcim.3c00602","article-title":"Predicting Protein\u2013Peptide Interactions: Benchmarking Deep Learning Techniques and a Comparison with Focused Docking","volume":"63","author":"Shanker","year":"2023","journal-title":"J. Chem. Inf. Model."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0960-0760(98)00029-6","article-title":"X-ray Crystallographic and Functional Studies of Thyroid Hormone Receptor","volume":"65","author":"Ribeiro","year":"1998","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1016\/j.chemosphere.2017.06.056","article-title":"New insight into the distribution pattern, levels, and risk diagnosis of FRs in indoor and outdoor air at low- and high-altitude zones of Pakistan: Implications for sources and exposure","volume":"184","author":"Khan","year":"2017","journal-title":"Chemosphere"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1021\/acs.jcim.6b00742","article-title":"Protein Loop Structure Prediction Using Conformational Space Annealing","volume":"57","author":"Heo","year":"2017","journal-title":"J. Chem. Inf. Model."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/12\/4\/281\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:26:23Z","timestamp":1760106383000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/12\/4\/281"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,11]]},"references-count":33,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["toxics12040281"],"URL":"https:\/\/doi.org\/10.3390\/toxics12040281","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,11]]}}}