TY - JOUR
T1 - Thyroid Hormone Receptor Agonistic and Antagonistic Activity of Newly Synthesized Dihydroxylated Polybrominated Diphenyl Ethers
T2 - An In Vitro and In Silico Coactivator Recruitment Study
AU - Zhang, Mengtao
AU - Shi, Jianghong
AU - Li, Bing
AU - Ge, Hui
AU - Tao, Huanyu
AU - Zhang, Jiawei
AU - Li, Xiaoyan
AU - Cai, Zongwei
N1 - This research was funded by the National Natural Science Foundation of China (grant numbers 52200229 and 21976079); Ministry of Science and Technology of the People\u2019s Republic of China (grant numbers 2022YFC3902201); and the Shenzhen Science and Technology Innovation Commission (STIC) Project (grant numbers JCYJ20190809171201660).
Publisher Copyright:
© 2024 by the authors.
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
KW - agonistic or antagonistic activities
KW - coactivator recruitment assay
KW - DiOH-PBDEs
KW - thyroid hormone receptors
UR - http://www.scopus.com/inward/record.url?scp=85191728503&partnerID=8YFLogxK
U2 - 10.3390/toxics12040281
DO - 10.3390/toxics12040281
M3 - Journal article
AN - SCOPUS:85191728503
SN - 2305-6304
VL - 12
JO - Toxics
JF - Toxics
IS - 4
M1 - 281
ER -
