基于3D-QSAR的多氟烷基磷酸二酯对斑马鱼的脂毒性预测

陈朋宇; 胡宇熙; 陈庚; 赵娜; 窦志超

doi:10.13205/j.hjgc.202402029

基于3D-QSAR的多氟烷基磷酸二酯对斑马鱼的脂毒性预测

doi: 10.13205/j.hjgc.202402029

陈朋宇^1,2, ,,
胡宇熙¹,
陈庚³,
赵娜¹,
窦志超¹

1. 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;
2. 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;
3. 中国科学院上海药物研究所, 上海 201203

基金项目:

中国博士后面上基金(2023M730919)

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(B210204007)

国家自然科学基金(42107289)

江苏省自然科学基金(BK20210375)

详细信息

作者简介:
陈朋宇(1990-),男,讲师,博士,主要从事水污染治理研究。chenpy@hhu.edu.cn

通讯作者:
陈朋宇(1990-),男,讲师,博士,主要从事水污染治理研究。chenpy@hhu.edu.cn

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出版历程
- 收稿日期: 2023-04-18
- 网络出版日期: 2024-04-28

PREDICTION OF LIPOTOXICITY OF POLYFLUOROALKYL PHOSPHATE DIESTERS TO ZEBRAFISH BASED ON 3D-QSAR

CHEN Pengyu^{1,2
, ,},
HU Yuxi¹,
CHEN Geng³,
ZHAO Na¹,
DOU Zhichao¹

1. Jiangsu Province Engineering Research Center for Marine Bio-resources Sustainable Utilization, College of Oceanography, Hohai University, Nanjing 210024, China;
2. Key Laboratory of Integrated Regulation and Resources Development of Shallow Lakes of Ministry of Education, Hohai University, Nanjing 210024, China;
3. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

摘要

摘要: 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/L 6∶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。
- 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
Abstract: 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 diesters /
- 3D-QSAR /
- molecular docking /
- lipotoxicity /
- peroxisome proliferator-activated receptor

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