有机磷酸酯结合并抑制细胞中与雌激素相关的受体γ,Environmental Science & Technology Letters

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有机磷酸酯结合并抑制细胞中与雌激素相关的受体γ
Environmental Science & Technology Letters ( IF 8.9 ) Pub Date : 2018-01-30 00:00:00 , DOI: 10.1021/acs.estlett.7b00558
Lin-Ying Cao _{1,

2} , Xiao-Min Ren ₁ , Chuan-Hai Li _{1,

2} , Liang-Hong Guo _{1,

2}

Affiliation

据报道，有机磷酸酯（OPEs）会诱导内分泌干扰作用，并且已经研究了几种众所周知的核受体作为其作用方式的OPE的细胞靶标。在这里，我们首次证明了孤儿核受体雌激素相关受体γ（ERRγ）是OPE的另一个可能靶标。使用我们建立的荧光竞争结合测定法，我们测量了具有不同取代基团（包括芳环，氯化烷基链和烷基链）的9个OPE的结合亲和力。所述的OPE七个被发现结合ERRγ，与三米-cresyl磷酸盐（TCRP）显示出最高的结合亲和力（ķ _d，0.34μM）。通过使用ERRγ介导的萤光素酶报告基因检测，我们发现7种OPE对ERRγ表现出抑制作用。OPE的结合亲和力和抑制作用均与它们的取代基的疏水性呈正相关，其顺序如下：芳环>氯化烷基链>烷基链。在分子对接的基础上，提出了OPEs抑制作用的机制是激活功能2螺旋从受体中的活性位置被配体触发的位移。ERRγ途径可能为OPEs的内分泌干扰作用提供新的机制。

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Organophosphate Esters Bind to and Inhibit Estrogen-Related Receptor γ in Cells

Organophosphate esters (OPEs) have been reported to induce endocrine disruption effects, and several well-known nuclear receptors have been investigated as cellular targets of OPEs in their mode of action. Here, we demonstrated for the first time that an orphan nuclear receptor estrogen-related receptor γ (ERRγ) is another possible target of OPEs. Using the fluorescence competitive binding assays that we established, we measured the binding affinity of nine OPEs with different substitution groups, including aromatic rings, chlorinated alkyl chains, and alkyl chains. Seven of the OPEs were found to bind to ERRγ, with tri-m-cresyl phosphate (TCrP) showing the highest binding affinity (K_d, 0.34 μM). By using an ERRγ-mediated luciferase reporter gene assay, we found seven OPEs showed inhibitory effects toward ERRγ. Both the binding affinity and the inhibitory effect of the OPEs correlate positively with the hydrophobicity of their substitution groups in the following rank order: aromatic rings > chlorinated alkyl chains > alkyl chains. On the basis of molecular docking, the mechanism of the inhibitory effect of OPEs was proposed to be ligand-triggered displacement of the activation function-2 helix from the active position in the receptor. The ERRγ pathway may provide a new mechanism for the endocrine disruption effects of OPEs.

更新日期：2018-01-30

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