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

• Published in: Toxics (Basel) 2024-04, Vol.12 (4), p.281
• Main Authors: Zhang, Mengtao, Shi, Jianghong, Li, Bing, Ge, Hui, Tao, Huanyu, Zhang, Jiawei, Li, Xiaoyan, Cai, Zongwei
• Format: Article
• Language: English
• Subjects: Affinity; agonistic or antagonistic activities; Algae; Binding energy; Bromination; Bromine; Chemical properties; coactivator recruitment assay; DiOH-PBDEs; Ethers; Health aspects; Hormone receptors; Hormones; Hydroxyl groups; Ligands; Metabolites; Molecular docking; Natural products; Phenols; Physiological aspects; Polybrominated diphenyl ethers; Receptors; Recruitment; Simulation; Src protein; Structure; Thermodynamics; Thyroid; Thyroid gland; Thyroid hormone receptors; Thyroid hormones; Toxicity; Triiodothyronine
• ISSN: 2305-6304; 2305-6304
• DOI: 10.3390/toxics12040281

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.