色谱

色谱 ›› 2012, Vol. 30 ›› Issue (02): 123-127.DOI: 10.3724/SP.J.1123.2011.12059

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利用代谢组学技术研究全氟辛酸的人肝脏毒性机制

彭思远1, 严丽娟2, 张洁1*, 申河清1*   

  1. 1. 中国科学院城市环境与健康重点实验室, 中国科学院城市环境研究所, 福建 厦门 361021; 2. 厦门出入境检验检疫局, 福建 厦门 361012
  • 收稿日期:2011-12-19 修回日期:2012-01-12 出版日期:2012-02-28 发布日期:2012-03-22
  • 通讯作者: 申河清,博士,研究员,博士生导师,主要从事暴露科学和健康效应的研究. E-mail: hqshen@iue.ac.cn.张洁,博士,副研究员,主要从事污染物的环境和人群暴露及其毒理作用机制研究. E-mail: jzhang@iue.ac.cn.
  • 基金资助:

    中国科学院知识创新工程重要方向项目(KZCX2-EW-QN408)、“百人计划”项目和厦门市科技项目(3502Z20112017).

Hepatotoxicity of perfluorooctanoic acid in human hepatocytes using metabonomics

PENG Siyuan1, YAN Lijuan2, ZHANG Jie1*, SHEN Heqing1*   

  1. 1. CAS Key Laboratory of Urban Environment and Health, Institute of Urban Environment, Chinese Academy of Sciences, Xiamen 361021, China; 2. Xiamen Entry-Exit Inspection and Quarantine Bureau, Xiamen 361012, China
  • Received:2011-12-19 Revised:2012-01-12 Online:2012-02-28 Published:2012-03-22

PDF

540

被引次数

21

摘要： 采用超高效液相色谱-飞行时间质谱联用系统研究暴露于不同浓度全氟辛酸(PFOA)72 h的正常人L-02肝细胞内代谢谱的变化。将主成分分析法用于数据分析和生物标志物的初步筛选。在正离子和负离子扫描模式下,对照组和暴露组均可得到较好区分并呈现出明显的剂量-效应关系,筛选鉴定了18种与全氟辛酸毒性密切相关的潜在生物标志物,包括肉碱和酰肉碱、核苷及其同源物、氨基酸及其同源物等。在暴露组中,在脂肪酸代谢中起关键作用的肉碱类代谢物的含量变化显著,其中肉碱含量随剂量的升高呈现明显的下降趋势,而酰肉碱则呈现相反的变化趋势,表明全氟辛酸可通过诱导胆固醇等脂类物质代谢相关基因的异常表达从而扰乱胆碱类物质的正常合成和代谢。除了变化最显著的胆碱代谢通路之外,全氟辛酸的肝脏毒性还与三羧酸循环、嘌呤代谢、氨基酸代谢和核酸代谢等多个通路相关。这些结果表明,PFOA在体内经过长时间累积可通过干扰众多的代谢通路从而破坏人体的正常生理机能,造成潜在的健康危害。

关键词: 超高效液相色谱, 代谢组学, 肝脏毒性, 全氟辛酸, 质谱

Abstract: Ultra performance liquid chromatography coupled to orthogonal acceleration time-of-flight mass spectrometry was used to study metabolic profiling of L-02 human liver cell exposed to different doses of perfluorooctanoic acid (PFOA) for 72 h. Principle component analysis method was used for group differentiation and biomarker screening. Dose-dependent distribution of the treated samples with different doses could be observed in scores plots obtained under both positive and negative ionization modes. Furthermore, eighteen metabolites were identified as potential biomarkers which were closely related with the toxicity of PFOA. The identified biomarkers included carnitine and acylcarnitines, nucleosides and nucleoside conjugates, amino acids and amino acid conjugates etc. Among them, significant changes of carnitine and its metabolites were observed in the control group and dose groups, which play an important role in fatty acid metabolism. Meanwhile, some genes involved in cholesterol biosynthesis were upregulated dramatically using gene microarray analysis. The disturbance of cholesterol biosynthesis could have adverse impact on fatty acid metabolism, consequently induce the decrease of carnitine and increase of acylcarnitines in treated groups. Additionally, purine metabolism, tricarboxylic acid cycle, glycosphingolipid metabolism and amino acid metabolism may also be involved in the toxic response to PFOA.

Key words: hepatotoxicity, mass spectrometry (MS), perfluorooctanoic acid, metabonomics, ultra performance liquid chromatography (UPLC)