Hormone activity of hydroxylated polybrominated diphenyl ethers on human thyroid receptor-beta: in vitro and in silico investigations.
BACKGROUND
Hydroxylated polybrominated diphenyl ethers (HO-PBDEs) may disrupt thyroid hormone status because of their structural similarity to thyroid hormone. However, the molecular mechanisms of interactions with thyroid hormone receptors (TRs) are not fully understood.


OBJECTIVE
We investigated the interactions between HO-PBDEs and TRbeta to identify critical structural features and physicochemical properties of HO-PBDEs related to their hormone activity, and to develop quantitative structure-activity relationship (QSAR) models for the thyroid hormone activity of HO-PBDEs.


METHODS
We used the recombinant two-hybrid yeast assay to determine the hormone activities to TRbeta and molecular docking to model the ligand-receptor interaction in the binding site. Based on the mechanism of action, molecular structural descriptors were computed, selected, and employed to characterize the interactions, and finally a QSAR model was constructed. The applicability domain (AD) of the model was assessed by Williams plot.


RESULTS
The 18 HO-PBDEs tested exhibited significantly higher thyroid hormone activities than did PBDEs (p < 0.05). Hydrogen bonding was the characteristic interaction between HO-PBDE molecules and TRbeta, and aromaticity had a negative effect on the thyroid hormone activity of HO-PBDEs. The developed QSAR model had good robustness, predictive ability, and mechanism interpretability.


CONCLUSIONS
Hydrogen bonding and electrostatic interactions between HO-PBDEs and TRbeta are important factors governing thyroid hormone activities.
Li
Fei
F
Key Laboratory of Industrial Ecology and Environmental Engineering, School of Environmental Science and Technology, Dalian University of Technology, Dalian, China.
Xie
Qing
Q
Li
Xuehua
X
Li
Na
N
Chi
Ping
P
Chen
Jingwen
J
Wang
Zijian
Z
Hao
Ce
C
D001665:Binding Sites; D001667:Binding, Competitive; D052244:Endocrine Disruptors / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D004785:Environmental Pollutants / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity; D005411:Flame Retardants / Q000378:metabolism / Q000633:toxicity; D055768:Halogenated Diphenyl Ethers / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D006860:Hydrogen Bonding; D006900:Hydroxylation; D066298:In Vitro Techniques; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D011994:Recombinant Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D055672:Static Electricity; D037042:Thyroid Hormone Receptors beta / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D020798:Two-Hybrid System Techniques
D052244:Endocrine Disruptors; D004785:Environmental Pollutants; D005411:Flame Retardants; D055768:Halogenated Diphenyl Ethers; D011994:Recombinant Proteins; D037042:Thyroid Hormone Receptors beta