Hormone Activity of Hydroxylated Polybrominated Diphenyl Ethers on Human Thyroid Receptor-β: 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. OBJECTIVES: We investigated the interactions between HO-PBDEs and TR beta to identify critical structural features and physico-chemical 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 TR beta 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 TR beta, 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 TR beta are important factors governing thyroid hormone activities. The HO- PBDEs with higher ability to accept electrons tend to have weak hydrogen bonding with TR beta and lower thyroid hormone activities.