基于3D-QSAR的多氟烷基磷酸二酯对斑马鱼的脂毒性预测

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

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(pIC_(50))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。

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 receptorβ(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 PPARβwere 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 PPARβwere investigated.The results show that the 50%inhibition concentration(pIC_(50))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 PPARβmainly 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 PPARβwere 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.