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

计量
- 文章访问数: 104
- HTML全文浏览量: 16
- PDF下载量: 9
- 被引次数: 0
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

HTML全文

参考文献(39)

[1]	AHRENS L,BENSKIN J P,COUSINS I T,et al.Themed issues on per-and polyfluoroalkyl substances[J].Environmental Science:Water Research & Technology,2019,5:1808-1813.
[2]	DU D,LU Y L,ZHOU Y Q,et al.Perfluoroalkyl acids (PFAAs) in water along the entire coastal line of China:spatial distribution,mass loadings,and worldwide comparisons[J].Environment International,2022,169:107506.
[3]	SADIA M,NOLLEN I,HELMUS R,et al.Occurrence,fate,and related health risks of PFAS in raw and produced drinking water[J].Environmental Science & Technology,2023,57:3062-3074.
[4]	HOU M M,JIN Q,NA G S,et al.Emissions,isomer-specific environmental behavior,and transformation of OBS from one major fluorochemical manufacturing facility in China[J].Environmental Science & Technology,2022,56:8103-8113.
[5]	SHEN L A,ZHOU J,LIANG X X,et al.Different sources,fractionation,and migration of legacy and novel per-and polyfluoroalkyl substances between greenhouse and open-field soils[J].Environmental Science & Technology,2023,57:1670-1679.
[6]	XIE X,LU Y,WANG P,et al.Per-and polyfluoroalkyl substances in marine organisms along the coast of China[J].Science of the Total Environment,2023,876:162492.
[7]	CHEN Y,LV J,FU L,et al.Metabolome-wide association study of four groups of persistent organic pollutants and abnormal blood lipids[J].Environment International,2023,173:107817.
[8]	WANG B,YAO Y M,WANG Y,et al.Per-and polyfluoroalkyl substances in outdoor and indoor dust from mainland China:contributions of unknown precursors and implications for human exposure[J].Environmental Science & Technology,2022,56:6036-6045.
[9]	BUGSEL B,ZWIENER C.LC-MS screening of poly-and perfluoroalkyl substances in contaminated soil by Kendrick mass analysis[J].Analytical and Bioanalytical Chemistry,2020,412:4797-4805.
[10]	SZABO D,MARCHIANDI J,SAMANDRA S,et al.High-resolution temporal wastewater treatment plant investigation to understand influent mass flux of per-and polyfluoroalkyl substances (PFAS)[J].Journal of Hazardous Materials,2023,447:130854.
[11]	CHEN M,WANG Q,SHAN G Q,et al.Occurrence,partitioning and bioaccumulation of emerging and legacy per-and polyfluoroalkyl substances in Taihu Lake,China[J].Science of the Total Environment,2018,634:251-259.
[12]	ROSENMAI A K,NIELSEN F K,PEDERSEN M,et al.Fluorochemicals used in food packaging inhibit male sex hormone synthesis[J].Toxicology and Applied Pharmacology,2013,266:132-142.
[13]	CHEN P Y,WANG R H,YANG J,et al.Stronger estrogenic and antiandrogenic effects on zebrafish larvae displayed by 6∶2 polyfluoroalkyl phosphate diester than the 8∶2 congener at environmentally relevant concentrations[J].Science of the Total Environment,2019,695:133907.
[14]	CHEN P Y,YANG J,CHEN G,et al.Thyroid-disrupting effects of 6∶2 and 8∶2 polyfluoroalkyl phosphate diester (diPAPs) at environmentally relevant concentrations from integrated in silico and in vivo studies[J].Environmental Science & Technology Letters,2020,7:330-336.
[15]	LI C H,REN X M,CAO L Y,et al.Investigation of binding and activity of perfluoroalkyl substances to the human peroxisome proliferator-activated receptor beta/delta[J].Environmental Science:Processes & Impacts,2019,21:1908-1914.
[16]	REN X M,QIN W P,CAO L Y,et al.Binding interactions of perfluoroalkyl substances with thyroid hormone transport proteins and potential toxicological implications[J].Toxicology,2016,366:32-42.
[17]	LUCKHURST C A,STEIN L A,FURBER M,et al.Discovery of isoindoline and tetrahydroisoquinoline derivatives as potent,selective PPAR delta agonists[J].Bioorganic & Medicinal Chemistry Letters,2011,21:492-496.
[18]	ISO 7346-2,1996.Water quality-Determination of the acute lethal toxicity of substances to a fresh water fish [Brachydanio rerio namilton-Buchanan (Teleostei,Cyprinidae)]-Semi-static method[S].
[19]	GOLBRAIKH A,SHEN M,XIAO Z Y,et al.Rational selection of training and test sets for the development of validated QSAR models[J].Journal of Computer-Aided Molecular Design,2003,17:241-253.
[20]	CRAMER R D,PATTERSON D E,BUNCE J D.Comparative molecular field analysis (CoMFA).1.Effect of shape on binding of steroids to carrier proteins.Journal of the American Chemical Society,1988,110:5959-5967.
[21]	KLEBE G,ABRAHAM U,MIETZNER T.Molecular similarity indices in a comparative analysis (CoMSIA) of drug molecules to correlate and predict their biological activity[J].Journal of Medicinal Chemistry,1994,37:4130-4146.
[22]	CAPPEL D,DIXON S L,SHERMAN W,et al.Exploring conformational search protocols for ligand-based virtual screening and 3-D QSAR modeling[J].Journal of Computer-Aided Molecular Design,2015,29:165-182.
[23]	GADE D R,MAKKAPATI A,YARLAGADDA R B,et al.Elucidation of chemosensitization effect of acridones in cancer cell lines:combined pharmacophore modeling,3D QSAR,and molecular dynamics studies[J].Computational Biology and Chemistry,2018,74:63-75.
[24]	YANG X H,OU W,XI Y,et al.Emerging polar phenolic disinfection byproducts are high-affinity human transthyretin disruptors:an in vitro and in silico Study[J].Environmental Science & Technology,2019,53:7019-7028.
[25]	CAO H M,ZHOU Z,WANG L,et al.Screening of potential PFOS alternatives to decrease liver bioaccumulation:experimental and computational approaches[J].Environmental Science & Technology,2019,53:2811-2819.
[26]	REN J Z,JI X,GAO W,et al.3D-QSAR-based molecular design to discover ultrahigh active N-phenylpyrazoles as insecticide candidates[J].Journal of Agricultural and Food Chemistry,2023,71:4258-4271.
[27]	PU Q K,HAN Z Z,LI X A,et al.Designing and screening of fluoroquinolone substitutes using combined in silico approaches:biological metabolism-bioconcentration bilateral selection and their mechanism analyses[J].Green Chemistry,2022,24:3778-3793.
[28]	CHEN QC,TAN HY,YU HX,et al.Activation of steroid hormone receptors:shed light on the in silico evaluation of endocrine disrupting chemicals[J].Science of the Total Environment,2018,631/632:27-39.
[29]	谭皓月,张荣,陈钦畅,等.基于计算毒理的环境污染物-生物大分子的相互作用研究[J].科学通报,2022,67:4180-4191.
[30]	Kortagere S,Krasowski M D,Reschly E J,et al.Evaluation of computational docking to identify pregnane x receptor agonists in the ToxCast database[J].Environ Health Perspect,2010,118:1412-1417.
[31]	CHEN P Y,WANG Q,CHEN M,et al.Antagonistic estrogenic effects displayed by bisphenol AF and perfluorooctanoic acid on zebrafish (Danio rerio) at an early developmental stage[J].Environmental Science & Technology Letters,2018,5:655-661.
[32]	SODERSTROM S,LILLE-LANGOY R,YADETIE F,et al.Agonistic and potentiating effects of perfluoroalkyl substances (PFAS) on the Atlantic cod (Gadus morhua) peroxisome proliferator-activated receptors (Ppars)[J].Environment International,2022,163:107203.
[33]	ALLEN T E H,GOODMAN J M,GUTSELL S,et al.Using 2D structural alerts to define chemical categories for molecular initiating events[J].Toxicological Sciences,2018,165:213-223.
[34]	YI S J,CHEN P Y,YANG L P,et al.Probing the hepatotoxicity mechanisms of novel chlorinated polyfluoroalkyl sulfonates to zebrafish larvae:implication of structural specificity[J].Environment International,2019,133:105262.
[35]	KHAZAEE M,CHRISTIE E,CHENG W X,et al.Perfluoroalkyl acid binding with peroxisome proliferator-activated receptors alpha,gamma,and delta,and fatty acid binding proteins by equilibrium dialysis with a comparison of methods[J].Toxics,2021,9:45.
[36]	POULSEN L L,SIERSBK M,MANDRUP S.PPARs:fatty acid sensors controlling metabolism[J].Seminars in Cell & Developmental Biology,2012,23:631-639.
[37]	SUN W Q,ZHANG X M,QIAO Y,et al.Exposure to PFOA and its novel analogs disrupts lipid metabolism in zebrafish[J].Ecotoxicology and Environmental Safety,2023,259:115020.
[38]	WANG Z R,YAO J Z,GUO H,et al.Comparative hepatotoxicity of a novel perfluoroalkyl ether sulfonic acid,Nafion byproduct 2 (H-PFMO2OSA),and legacy perfluorooctane sulfonate (PFOS) in adult male mice[J].Environmental Science & Technology,2022,56:10183-10192.
[39]	WANG Z R,ZANG L,REN W L,et al.Bile acid metabolism disorder mediates hepatotoxicity of Nafion by-product 2 and perfluorooctane sulfonate in male PPARα-KO mice[J].Science of the Total Environment,2023,876:162579.