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

Zhang, Mengtao1,2,3; Shi, Jianghong1; Li, Bing3; Ge, Hui1; Tao, Huanyu1; Zhang, Jiawei1; Li, Xiaoyan3; Cai, Zongwei2

2024-04-01

10.3390/toxics12040281

TOXICS   影响因子和分区

2305-6304

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 alpha and TR beta. 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 TR alpha and TR beta, while the antagonism of 3,5-diOH-BDE-100 for TR alpha and TR beta 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.

DiOH-PBDEs thyroid hormone receptors coactivator recruitment assay agonistic or antagonistic activities

SCI

英语

第一 ; 通讯

Environmental Sciences & Ecology ; Toxicology

Environmental Sciences ; Toxicology

WOS:001210551600001

MDPI

Web of Science

1.Southern Univ Sci & Technol, Sch Environm Sci & Engn, State Environm Protect Key Lab Integrated Surface, Shenzhen 518055, Peoples R China
2.Hong Kong Baptist Univ, Dept Chem, China State Key Lab Environm & Biol Anal, Hong Kong, Peoples R China
3.Tsinghua Univ, Inst Environm & Ecol, Shenzhen Int Grad Sch, Shenzhen 518055, Peoples R China

Zhang, Mengtao,Shi, Jianghong,Li, Bing,et al. Thyroid Hormone Receptor Agonistic and Antagonistic Activity of Newly Synthesized Dihydroxylated Polybrominated Diphenyl Ethers: An In Vitro and In Silico Coactivator Recruitment Study[J]. TOXICS,2024,12(4).

Zhang, Mengtao.,Shi, Jianghong.,Li, Bing.,Ge, Hui.,Tao, Huanyu.,...&Cai, Zongwei.(2024).Thyroid Hormone Receptor Agonistic and Antagonistic Activity of Newly Synthesized Dihydroxylated Polybrominated Diphenyl Ethers: An In Vitro and In Silico Coactivator Recruitment Study.TOXICS,12(4).

Zhang, Mengtao,et al."Thyroid Hormone Receptor Agonistic and Antagonistic Activity of Newly Synthesized Dihydroxylated Polybrominated Diphenyl Ethers: An In Vitro and In Silico Coactivator Recruitment Study".TOXICS 12.4(2024).