A systems toxicology approach on the mechanism of uptake and toxicity of MWCNT in Caenorhabditis elegans
A systems toxicology approach on the mechanism of uptake and toxicity of MWCNT in Caenorhabditis elegans
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DOI：
10.1016/j.cbi.2015.06.031
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发表时间：
2015-09-05
影响因子：
5.1
通讯作者：
Choi, Jinhee
中科院分区：
文献类型：
--
作者：
Eom, Hyun-Jeong;Roca, Carlos P.;Choi, Jinhee
在工业和生物医学过程中使用的碳纳米管（CNT）数量的增加带来了无意释放到环境中的风险增加，需要进行全面的危害和风险评估。在这项研究中，原始的和羟基化（OH-）多壁碳纳米管（MWCNTs）的毒性进行了研究，线虫采用综合系统毒理学方法。为了深入了解多壁碳纳米管的毒性机制，本研究采用基因芯片和蛋白质组学技术对多壁碳纳米管的毒性机制进行了研究。elegans，然后进行途径分析。途径分析的结果表明，内吞作用，吞噬作用，氧化应激和内质网（ER）的压力，作为潜在的机制的吸收和毒性，随后使用这些途径的基因的功能丧失突变体进行了研究。在暴露于OH-MWCNT后，吞噬相关基因（即ced-10和rab-7）的表达显著增加，同时这些基因的功能丧失突变体（如ced-10（n3246）和rab-7（ok 511））挽救了毒性。Hsp-4（gk 514）突变体对OH-MWCNT的敏感性增加，沿着Hsp-4在基因和蛋白水平的表达降低，提示MWCNT可能影响线虫内质网应激反应。总的来说，结果表明吞噬作用是多壁碳纳米管吸收的潜在机制，ER和氧化应激是潜在的毒性机制。在这项研究中应用的综合系统毒理学方法提供了一个全面的了解多壁碳纳米管在线虫，这可能最终被用来开发一个“不良后果途径（AOP）”，最近引入的概念作为一个概念框架，连接分子水平的反应，更高层次的影响的毒性机制。(C)2015爱思唯尔爱尔兰有限公司版权所有。
The increased volumes of carbon nanotubes (CNTs) being utilized in industrial and biomedical processes carries with it an increased risk of unintentional release into the environment, requiring a thorough hazard and risk assessment. In this study, the toxicity of pristine and hydroxylated (OH-) multiwall CNTs (MWCNTs) was investigated in the nematode Caenorhabditis elegans using an integrated systems toxicology approach. To gain an insight into the toxic mechanism of MWCNTs, microarray and proteomics were conducted for C. elegans followed by pathway analyses. The results of pathway analyses suggested endocytosis, phagocytosis, oxidative stress and endoplasmic reticulum (ER) stress, as potential mechanisms of uptake and toxicity, which were subsequently investigated using loss-of-function mutants of genes of those pathways. The expression of phagocytosis related genes (i.e. ced-10 and rab-7) were significantly increased upon exposure to OH-MWCNT, concomitantly with the rescued toxicity by loss-of-function mutants of those genes, such as ced-10(n3246) and rab-7(ok511). An increased sensitivity of the hsp-4(gk514) mutant by OH-MWCNT, along with a decreased expression of hsp-4 at both gene and protein level suggests that MWCNTs may affect ER stress response in C elegans. Collectively, the results implied phagocytosis to be a potential mechanism of uptake of MWCNTs, and ER and oxidative stress as potential mechanisms of toxicity. The integrated systems toxicology approach applied in this study provided a comprehensive insight into the toxic mechanism of MWCNTs in C elegans, which may eventually be used to develop an "Adverse Outcome Pathway (AOP)", a recently introduced concept as a conceptual framework to link molecular level responses to higher level effects. (C) 2015 Elsevier Ireland Ltd. All rights reserved.