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- Title
Hormone Activity of Hydroxylated Polybrominated Diphenyl Ethers on Human Thyroid Receptor-β: In Vitro and In Silico Investigations.
- Authors
Fei Li; Qing Xie; Xuehua Li; Na Li; Ping Chi; Jingwen Chen; Zijian Wang; Ce Hao
- Abstract
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. Objectives: We investigated the interactions between HO-PBDEs and TRβ 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 TRβ 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 TRβ, 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 TRβ are important factors governing thyroid hormone activities. The HO-PBDEs with higher ability to accept electrons tend to have weak hydrogen bonding with TRβ and lower thyroid hormone activities.
- Subjects
POLYBROMINATED diphenyl ethers; THYROID hormones; HORMONE receptors; RECEPTOR-ligand complexes; HYDROGEN bonding; ELECTRONS; DENSITY functionals; QSAR models; BIOCHEMISTRY
- Publication
Environmental Health Perspectives, 2010, Vol 118, Issue 5, p602
- ISSN
0091-6765
- Publication type
Article
- DOI
10.1289/ehp.0901457