首页|基于3D-QSAR的多氟烷基磷酸二酯对斑马鱼的脂毒性预测

基于3D-QSAR的多氟烷基磷酸二酯对斑马鱼的脂毒性预测

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为研究多氟烷基磷酸二酯(DiPAPs)对斑马鱼的脂毒性作用,构建15种全氟化合物与过氧化物酶体增殖物激活受体β(PPARβ)结合的三维定量构效关系模型(3D-QSAR),分别对6∶2和8∶2的DiPAPs与PPARβ结合亲和力进行预测;基于分子对接分别研究6∶2和8∶2 DiPAPs与PPARβ的相互作用;分别考察6∶2和8∶2 DiPAPs暴露对斑马鱼Pparβ表达的影响,对3D-QSAR预测结果进行验证.结果表明,6∶2和8∶2 DiPAPs的半数竞争效应浓度(pIC50)的预测值分别为3.73,3.63 mol/L,说明二者可能均具有过氧化物酶体增殖活性;6∶2和8∶2 DiPAPs主要通过氢键和疏水作用与PPARβ结合,且6∶2 DiPAP结合活性更强;二者分别暴露后,PPARβ表达量均显著上调,且50 ng/L6∶2 DiPAP组比50 ng/L 8∶2 DiPAP组的表达量更高,与模型预测结果一致.综上,6∶2和8∶2 DiPAPs可通过影响斑马鱼PPARβ的表达,产生脂毒性.研究结果可为评估DiPAPs这类新型全氟/多氟烷基化合物在水环境中的生态风险提供理论依据.
PREDICTION OF LIPOTOXICITY OF POLYFLUOROALKYL PHOSPHATE DIESTERS TO ZEBRAFISH BASED ON 3D-QSAR
To study the lipotoxicity of polyfluoroalkyl phosphate diesters(DiPAPs)to zebrafish,firstly,a three-dimensional quantitative structure-activity relationship(3D-QSAR)model of the binding of 15 perfluoroalkyl and polyfluoroalkyl substances(PFASs)with peroxisome proliferator-activated receptor β(PPARβ)was developed to predict the binding affinity of 6∶2 and 8∶2 DiPAPs,respectively.Afterward,the interactions between 6∶2 and 8∶2 DiPAPs and PPARβ were studied based on molecular docking.Finally,to verify the predicted results of the 3D-QSAR model,the effects of 6∶2 and 8∶2 DiPAPs on the expression of zebrafish PPARβ were investigated.The results show that the 50％inhibition concentration(pIC50)of 6∶2 and 8∶2 DiPAPs was 3.73 mol/L and 3.63 mol/L,respectively,indicating their potential peroxisome proliferation activities.6∶2 and 8∶2 DiPAPs could bind to PPARβ mainly through hydrogen bonding and hydrophobic interaction,and the binding activity of 6∶2 DiPAP was higher than that of 8∶2 DiPAP.After the exposure to 6∶2 and 8∶2 DiPAPs,the expressions of PPARβ were both significantly up-regulated.The expression in the 50 ng/L 6∶2 DiPAP group was significantly higher than that in the 50 ng/L 8∶2 DiPAP group,which was concordant with the predicted results by the 3D-QSAR model.In conclusion,6∶2 and 8∶2 DiPAPs could induce lipotoxicity by affecting the expressions of zebrafish PPARβ.This study can provide scientific pieces of evidence for risk assessment of DiPAPs,such as a class of emerging PFASs,in the aquatic environment.

polyfluoroalkyl phosphate diesters3D-QSARmolecular dockinglipotoxicityperoxisome proliferator-activated receptor

陈朋宇、胡宇熙、陈庚、赵娜、窦志超

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河海大学海洋学院江苏省海洋生物资源可持续利用工程研究中心,南京 210024

河海大学浅水湖泊综合治理与资源开发教育部重点实验室,南京 210024

中国科学院上海药物研究所,上海 201203

多氟烷基磷酸二酯 三维定量构效关系 分子对接 脂毒性 过氧化物酶体增殖物激活受体

国家自然科学基金江苏省自然科学基金中国博士后面上基金浅水湖泊综合治理与资源开发教育部重点实验室开放基金

42107289BK202103752023M730919B210204007

2024

10.13205/j.hjgc.202402029

环境工程
中冶建筑研究总院有限公司,中国环境科学学会环境工程分会

环境工程

CSTPCD
影响因子：0.958
ISSN：1000-8942
年,卷(期)：2024.42(2)
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