title: Hydroxylated polybrominated diphenyl ethers exhibit different activities on thyroid hormone receptors depending on their degree of bromination.
abstract: Polybrominated diphenyl ethers (PBDEs) have been shown to disrupt thyroid hormone (TH) functions in experimental animals, and one of the proposed disruption mechanisms is direct binding of hydroxylated PBDE (OH-PBDE) to TH receptors (TRs). However, previous data on TH receptor binding and TH activity of OH-PBDEs were very limited and sometimes inconsistent. In the present paper, we examined the binding potency of ten OH-PBDEs with different degrees of bromination to TR using a fluorescence competitive binding assay. The results showed that the ten OH-PBDEs bound to TR with potency that correlated to their bromination level. We further examined their effect on TR using a coactivator binding assay and GH3 cell proliferation assay. Different TR activities of OH-PBDEs were observed depending on their degree of bromination. Four low-brominated OH-PBDEs (2'-OH-BDE-28, 3'-OH-BDE-28, 5-OH-BDE-47, 6-OH-BDE-47) were found to be TR agonists, which recruited the coactivator peptide and enhanced GH3 cell proliferation. However, three high-brominated OH-PBDEs (3-OH-BDE-100, 3'-OH-BDE-154, 4-OH-BDE-188) were tested to be antagonists. Molecular docking was employed to simulate the interactions of OH-PBDEs with TR and identify the structural determinants for TR binding and activity. According to the docking results, low-brominated OH-PBDEs, which are weak binders but TR agonists, bind with TR at the inner side of its binding pocket, whereas high-brominated compounds, which are potent binders but TR antagonists, reside at the outer region. These results indicate that OH-PBDEs have different activities on TR (agonistic or antagonistic), possibly due to their different binding geometries with the receptor.
authors: State Key Laboratory of Environmental Chemistry and Eco-toxicology, Research Centre for Eco-environmental Sciences, Chinese Academy of Sciences, 18 Shuangqing Road, P.O. Box 2871, Beijing 100085, China. rxm200318@gmail.com
authors: Xiao-Min
authors: XM
authors: Ren
authors: Liang-Hong
authors: LH
authors: Guo
authors: Yu
authors: Y
authors: Gao
authors: Bin-Tian
authors: BT
authors: Zhang
authors: Bin
authors: B
authors: Wan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055768:Halogenated Diphenyl Ethers / Q000737:chemistry* / Q000378:metabolism*; D054879:Halogenation / Q000502:physiology*; D006801:Humans; D006900:Hydroxylation / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*
chemical_list: D055768:Halogenated Diphenyl Ethers; D011988:Receptors, Thyroid Hormone