State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China.
School of Environment and Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China.
Environ Sci Technol. 2020 Nov 17;54(22):14525-14534. doi: 10.1021/acs.est.0c04376. Epub 2020 Oct 29.
Organophosphate esters (OPEs) can exhibit various toxicities including endocrine disruption activity. Unfortunately, the low-dose endocrine-disrupting effects mediated by estrogen receptors (ERs) are commonly underestimated for OPEs and their metabolites. Here, structure-oriented research was performed to investigate the estrogenic/antiestrogenic effect of 13 OPEs (including three metabolites) and the potential mechanism. All of the OPEs exerted antiestrogenic activities in both E-screen and MVLN assays. OPEs with bulky substituents, such as phenyl rings (triphenyl phosphate (TPP), tricresyl phosphate (TCP), diphenylphosphoryl chloride, and diphenylphosphite) or relatively long alkyl chains (dibutylbutylphosphonate (DBBP)), exerted relatively strong ER antagonism potency at micromolar concentrations. The established quantitative structure-activity relationship indicated that the antiestrogenic activities of the OPEs mainly depended on the volume, leading eigenvalue, and hydrophobicity of the molecule. Molecular docking revealed that the three OPEs with the bulkiest substituents on the phosphate ester group (TPP, TCP, and DBBP) have a similar interaction mode to the classical ER antagonist 4-hydroxytamoxifen. The correlation between the antiestrogenic activity and the corresponding ER binding affinity was statistically significant, strongly suggesting that the OPEs possess the classical antagonism mechanism of interfering with the positioning of helix 12 in the ER.
有机磷酸酯 (OPEs) 可表现出多种毒性，包括内分泌干扰活性。不幸的是，对于 OPEs 及其代谢物，由雌激素受体 (ERs) 介导的低剂量内分泌干扰作用通常被低估。在这里，进行了面向结构的研究，以调查 13 种 OPEs（包括三种代谢物）的雌激素/抗雌激素作用及其潜在机制。所有 OPEs 在 E-screen 和 MVLN 测定中均表现出抗雌激素活性。具有大取代基的 OPEs，如苯基环（磷酸三苯酯 (TPP)、磷酸三邻甲苯酯 (TCP)、二氯磷酸二苯酯和亚磷酸二苯酯）或相对较长的烷基链（磷酸二丁基丁基酯 (DBBP)），在微摩尔浓度下表现出相对较强的 ER 拮抗作用。已建立的定量构效关系表明，OPEs 的抗雌激素活性主要取决于分子的体积、特征值和疏水性。分子对接表明，磷酸酯基团上取代基最大的三种 OPEs（TPP、TCP 和 DBBP）与经典 ER 拮抗剂 4-羟基他莫昔芬具有相似的相互作用模式。抗雌激素活性与相应的 ER 结合亲和力之间存在显著的相关性，这强烈表明 OPEs 具有干扰 ER 中螺旋 12 定位的经典拮抗机制。
