Structure-dependent activities of hydroxylated polybrominated diphenyl ethers on human estrogen receptor

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• 作者：Xinxin Li ; Yu Gao ; Liang-Hong Guo ; ^{LHGuo@rcees.ac.cn} ; Guibin Jiang
• 关键词：OH-PBDEs ; Estrogen receptor ; Ligand binding assay ; Surface plasmon resonance ; MVLN cell transactivation assay ; Molecular docking
• 刊名：Toxicology
• 出版年：2013
• 出版时间：5 July, 2013
• 年：2013
• 卷：309
• 期：Complete
• 页码：15-22
• 全文大小：1618 K

文摘

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 K_D ranging from 1.46 x 10^?7 M to 7.90 x 10^?6 M, and the affinity is in the order of 6-OH-BDE-047 ¨R 4¡ä-OH-BDE-049 > 4¡ä-OH-BDE-017 > 6¡ä-OH-BDE-099 ¨R 5¡ä-OH-BDE-099 > 2¡ä-OH-BDE-007 > 3¡ä-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¡ä-OH-BDE-049 > 4¡ä-OH-BDE-017 > 2¡ä-OH-BDE-007 > 3¡ä-OH-BDE-028 > 3-OH-BDE-047 ¨R 3¡ä-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.