Abstract
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 1.46x10−7M to 7.90x10−6M, 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 105 to 107 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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