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四氧化三铁纳米颗粒暴露促进非酒精性脂肪性肝炎小鼠进展的作用机制研究

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林晓君, 赵甲亭, 郭晨, 宋慧东, 陈汉清. 四氧化三铁纳米颗粒暴露促进非酒精性脂肪性肝炎小鼠进展的作用机制研究[J]. 生态毒理学报, 2023, 18(2): 297-307. doi: 10.7524/AJE.1673-5897.20221125002
引用本文: 林晓君, 赵甲亭, 郭晨, 宋慧东, 陈汉清. 四氧化三铁纳米颗粒暴露促进非酒精性脂肪性肝炎小鼠进展的作用机制研究[J]. 生态毒理学报, 2023, 18(2): 297-307. doi: 10.7524/AJE.1673-5897.20221125002
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Lin Xiaojun, Zhao Jiating, Guo Chen, Song Huidong, Chen Hanqing. Effect of Iron Oxide Nanoparticle on Progression of Nonalcoholic Steatohepatitis in Mice[J]. Asian journal of ecotoxicology, 2023, 18(2): 297-307. doi: 10.7524/AJE.1673-5897.20221125002
Citation: Lin Xiaojun, Zhao Jiating, Guo Chen, Song Huidong, Chen Hanqing. Effect of Iron Oxide Nanoparticle on Progression of Nonalcoholic Steatohepatitis in Mice[J]. Asian journal of ecotoxicology, 2023, 18(2): 297-307. doi: 10.7524/AJE.1673-5897.20221125002
shu

四氧化三铁纳米颗粒暴露促进非酒精性脂肪性肝炎小鼠进展的作用机制研究

  • 1. 广州医科大学附属市十二医院, 广州 510515;

  • 2. 中国科学院纳米生物效应与安全性重点实验室, 中国科学院高能物理研究所, 北京 100049;

  • 3. 临床医学与创新转化中心, 广州市第一人民医院, 广州 510180;

  • 4. 华南理工大学附属第二医院消化内科, 广州 510006;

  • 5. 卫生毒理学与卫生化学学系, 首都医科大学公共卫生学院, 北京 100069

    • 作者简介: 林晓君(1992—)，女，硕士研究生，研究方向为职业卫生，E-mail: linxiaojun200808@163.com
    通讯作者: 宋慧东, E-mail: 2354412112@qq.com ;  陈汉清, E-mail: chenhq921@163.com
  • 基金项目:

    国家自然科学基金面上项目(32171370)；广东省基础与应用基础研究基金自然科学基金面上项目(2022A1515010415)；广州市科学技术局重点研发计划项目(202206010061)；广州市医学重点学科建设项目(2021-2023年)；广州市卫生健康科技重大项目(2021A031003)

  • 中图分类号: X171.5

Effect of Iron Oxide Nanoparticle on Progression of Nonalcoholic Steatohepatitis in Mice

  • 1. The Affiliated Guangzhou Twelfth Hospital of Guangzhou Medical University, Guangzhou 510515, China;

  • 2. CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, China;

  • 3. Center for Medical Research on Innovation and Translation, Guangzhou First People's Hospital, Guangzhou 510180, China;

  • 4. Department of Gastroenterology and Hepatology, the Second Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China;

  • 5. Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing 100069, China

    • Corresponding authors: Song Huidong, 2354412112@qq.com ;  Chen Hanqing, chenhq921@163.com
  • Fund Project:

  • 摘要: 医用及工业纳米材料的环境健康效应评价及其潜在生物安全性研究已成为纳米生物学及预防医学领域的研究热点。本研究拟探讨氨基修饰的四氧化三铁纳米颗粒(amino-modified iron oxide nanoparticles, NH2-Fe3O4NPs)尾静脉单次5 mg·kg-1给药1周后对非酒精性脂肪性肝炎(nonalcoholic steatohepatitis, NASH)模型小鼠肝脏功能及疾病进展的影响。本研究首先合成生物相容性好的NH2-Fe3O4NPs，利用透射电子显微镜(transmission electron microscopy, TEM)、扫描电子显微镜(scanning electron microscopy, SEM)和动态光散射(dynamic light scattering, DLS)等技术表征其表面形貌结构、粒径分布、zeta电位、水合粒径等物理化学性质。接着，将24只C57BL6/J小鼠随机分为4组，分别为等量磷酸盐缓冲液(phosphate buffer saline, PBS)给药组(对照组)、NH2-Fe3O4NPs尾静脉单次5 mg·kg-1给药1周正常小鼠组(暴露组)、蛋氨酸-胆碱缺乏饮食(methionine- and choline-deficient, MCD)诱导组(NASH模型组)、NH2-Fe3O4NPs尾静脉单次5 mg·kg-1给药NASH模型小鼠1周暴露组(NASH模型暴露组)。研究结果表明，NH2-Fe3O4NPs暴露正常健康小鼠，引起小鼠轻微的肝损伤；NH2-Fe3O4NPs暴露NASH模型小鼠，引起肝脏铁沉积并加重MCD饮食诱导的小鼠肝脏损伤，如提高血清生化指标丙氨酸转氨酶(alanine aminotransferase, ALT)和天门冬氨酸氨基转移酶(aspartate aminotransferase, AST)水平，激活固醇调节元件结合蛋白-1c (sterol regulatory element-binding protein-1c, SREBP-1c)介导的肝脏脂肪从头合成代谢，引起肝脏脂滴沉积和氧化应激，加剧肝脏组织病理学损伤，促进肝脏炎症反应和肝纤维化。综上，本研究发现，相比正常健康小鼠，NH2-Fe3O4NPs暴露加重MCD饮食诱导的小鼠肝脏脂肪变性、炎症反应、肝纤维化和肝脏损伤，加速NASH小鼠疾病进展。本研究结果将为纳米材料的生物医学应用，特别是对NASH这一患病群体的生物学效应与安全性评价机制提供重要的实验支撑和理论依据。
    Abstract: The increasing application of nanomaterials on biomedical and industrial fields have raised public concerns to assess their potential effect on environment and public health. This present study aims to explore the effects of amino-modified iron oxide nanoparticles (NH2-Fe3O4NPs) on the pathogenesis and progress of nonalcoholic steatohepatitis (NASH) in mice. The morphology and size of the synthesized NH2-Fe3O4NPs were characterized by transmission electron microscopy (TEM), scanning EM (SEM), zeta potential, and dynamic light scattering (DLS). Then we explored the hepatic effects of biocompatible NH2-Fe3O4NPs against methionine- and choline-deficient (MCD) diet-induced NASH mice. Compared with healthy mice, NH2-Fe3O4NP exposure significantly increased hepatic iron accumulation and aggravated MCD-induced hepatic steatosis and liver injury in mice, including higher levels of plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic oxidative stress, sterol regulatory element-binding protein-1c (SREBP-1c)-mediated de novo lipogenesis, and liver fibrosis. This study provides the evidence that it is necessary to consider the potential hepatic effect of nanomaterial exposure on the clinical pathogenesis and progression of NASH.
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  • Dadfar S M, Roemhild K, Drude N I, et al. Iron oxide nanoparticles: Diagnostic, therapeutic and theranostic applications[J]. Advanced Drug Delivery Reviews, 2019, 138: 302-325
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  • 收稿日期:  2022-11-25
林晓君, 赵甲亭, 郭晨, 宋慧东, 陈汉清. 四氧化三铁纳米颗粒暴露促进非酒精性脂肪性肝炎小鼠进展的作用机制研究[J]. 生态毒理学报, 2023, 18(2): 297-307. doi: 10.7524/AJE.1673-5897.20221125002
引用本文: 林晓君, 赵甲亭, 郭晨, 宋慧东, 陈汉清. 四氧化三铁纳米颗粒暴露促进非酒精性脂肪性肝炎小鼠进展的作用机制研究[J]. 生态毒理学报, 2023, 18(2): 297-307. doi: 10.7524/AJE.1673-5897.20221125002
shu
Lin Xiaojun, Zhao Jiating, Guo Chen, Song Huidong, Chen Hanqing. Effect of Iron Oxide Nanoparticle on Progression of Nonalcoholic Steatohepatitis in Mice[J]. Asian journal of ecotoxicology, 2023, 18(2): 297-307. doi: 10.7524/AJE.1673-5897.20221125002
Citation: Lin Xiaojun, Zhao Jiating, Guo Chen, Song Huidong, Chen Hanqing. Effect of Iron Oxide Nanoparticle on Progression of Nonalcoholic Steatohepatitis in Mice[J]. Asian journal of ecotoxicology, 2023, 18(2): 297-307. doi: 10.7524/AJE.1673-5897.20221125002
shu

四氧化三铁纳米颗粒暴露促进非酒精性脂肪性肝炎小鼠进展的作用机制研究

    通讯作者: 宋慧东, E-mail: 2354412112@qq.com ;  陈汉清, E-mail: chenhq921@163.com
    作者简介: 林晓君(1992—)，女，硕士研究生，研究方向为职业卫生，E-mail: linxiaojun200808@163.com
  • 1. 广州医科大学附属市十二医院, 广州 510515;
  • 2. 中国科学院纳米生物效应与安全性重点实验室, 中国科学院高能物理研究所, 北京 100049;
  • 3. 临床医学与创新转化中心, 广州市第一人民医院, 广州 510180;
  • 4. 华南理工大学附属第二医院消化内科, 广州 510006;
  • 5. 卫生毒理学与卫生化学学系, 首都医科大学公共卫生学院, 北京 100069
  • 收稿日期:  2022-11-25
基金项目:

国家自然科学基金面上项目(32171370)；广东省基础与应用基础研究基金自然科学基金面上项目(2022A1515010415)；广州市科学技术局重点研发计划项目(202206010061)；广州市医学重点学科建设项目(2021-2023年)；广州市卫生健康科技重大项目(2021A031003)

摘要: 医用及工业纳米材料的环境健康效应评价及其潜在生物安全性研究已成为纳米生物学及预防医学领域的研究热点。本研究拟探讨氨基修饰的四氧化三铁纳米颗粒(amino-modified iron oxide nanoparticles, NH2-Fe3O4NPs)尾静脉单次5 mg·kg-1给药1周后对非酒精性脂肪性肝炎(nonalcoholic steatohepatitis, NASH)模型小鼠肝脏功能及疾病进展的影响。本研究首先合成生物相容性好的NH2-Fe3O4NPs，利用透射电子显微镜(transmission electron microscopy, TEM)、扫描电子显微镜(scanning electron microscopy, SEM)和动态光散射(dynamic light scattering, DLS)等技术表征其表面形貌结构、粒径分布、zeta电位、水合粒径等物理化学性质。接着，将24只C57BL6/J小鼠随机分为4组，分别为等量磷酸盐缓冲液(phosphate buffer saline, PBS)给药组(对照组)、NH2-Fe3O4NPs尾静脉单次5 mg·kg-1给药1周正常小鼠组(暴露组)、蛋氨酸-胆碱缺乏饮食(methionine- and choline-deficient, MCD)诱导组(NASH模型组)、NH2-Fe3O4NPs尾静脉单次5 mg·kg-1给药NASH模型小鼠1周暴露组(NASH模型暴露组)。研究结果表明，NH2-Fe3O4NPs暴露正常健康小鼠，引起小鼠轻微的肝损伤；NH2-Fe3O4NPs暴露NASH模型小鼠，引起肝脏铁沉积并加重MCD饮食诱导的小鼠肝脏损伤，如提高血清生化指标丙氨酸转氨酶(alanine aminotransferase, ALT)和天门冬氨酸氨基转移酶(aspartate aminotransferase, AST)水平，激活固醇调节元件结合蛋白-1c (sterol regulatory element-binding protein-1c, SREBP-1c)介导的肝脏脂肪从头合成代谢，引起肝脏脂滴沉积和氧化应激，加剧肝脏组织病理学损伤，促进肝脏炎症反应和肝纤维化。综上，本研究发现，相比正常健康小鼠，NH2-Fe3O4NPs暴露加重MCD饮食诱导的小鼠肝脏脂肪变性、炎症反应、肝纤维化和肝脏损伤，加速NASH小鼠疾病进展。本研究结果将为纳米材料的生物医学应用，特别是对NASH这一患病群体的生物学效应与安全性评价机制提供重要的实验支撑和理论依据。

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