Polybrominated diphenyl ethers (PBDEs) have been shown to affect the estrogen receptor (ER) signaling pathway, and one of the proposed disruption mechanisms is direct binding of hydroxylated PBDE (OH-PBDE) to ER. In this paper, the binding affinity of 22 OH-PBDEs with different degrees of bromination to ER was assessed quantitatively using a surface plasmon resonance biosensor technique. Seven OH-PBDEs were found to bind directly with ER with KD ranging from 1.46x10(-7) M to 7.90x10(-6) M, and the affinity is in the order of 6-OH-BDE-047>/=4'-OH-BDE-049>4'-OH-BDE-017>6'-OH-BDE-099>/=5'-OH-BDE-099>2'-OH-BDE-007>3'-OH-BDE-028. In MVLN luciferase gene reporter assays, 10 low-brominated OH-PBDEs induced luciferase activity alone, but are 10(5) to 10(7) fold less potent than E2. Their estrogenic activity is in the order of 4'-OH-BDE-049>4'-OH-BDE-017>2'-OH-BDE-007>3'-OH-BDE-028>3-OH-BDE-047>/=3'-OH-BDE-007. The good correlation between estrogenic activity and ER binding affinity of the low-brominated OH-PBDEs strongly suggest that these compounds induce ER transcriptional activity by binding directly with ER. The other 12 high-brominated OH-PBDEs inhibited luciferase activity of E2 to various degrees, demonstrating their antagonistic activity. Molecular docking analysis of the ER/OH-PBDE complexes revealed two distinctive binding modes between low- and high-brominated OH-PBDEs which provided rationale for the difference in their ER activity.
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