广泛的时间转录组和microRNA分析确定了多壁碳纳米管在人肺细胞中诱导线粒体功能障碍的分子机制。

IF 3.6 3区 医学 Q3 NANOSCIENCE & NANOTECHNOLOGY
Nanotoxicology Pub Date : 2015-01-01 Epub Date: 2015-04-01 DOI:10.3109/17435390.2015.1017022
Penny Nymark, Peter Wijshoff, Rachel Cavill, Marcel van Herwijnen, Maarten L J Coonen, Sandra Claessen, Julia Catalán, Hannu Norppa, Jos C S Kleinjans, Jacob J Briedé
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引用次数: 25

摘要

了解工程纳米材料(ENM)的毒性途径是21世纪ENM风险评估的关键一步。与表型终点相关的分子机制是朝着开发基于关键事件的毒性试验迈出的一步,这可能允许根据其作用方式对ENM进行分组。本研究确定了暴露于研究最多的一种多壁碳纳米管(Mitsui MWCNT-7)后,人支气管上皮BEAS 2B细胞线粒体功能障碍的分子机制。石棉作为阳性对照,非致癌玻璃棉材料作为阴性纤维对照。MWCNTs在生物学相关剂量(0.25 μg/cm(2))和石棉在2 μg/cm(2)时观察到线粒体膜电位(MMP↓)降低,但玻璃棉没有。广泛的时间转录组学和microRNA表达分析确定了330个基因特征(包括26个已知线粒体功能的基因)与MWCNT和石棉诱导的MMP相关↓。49个MMP↓相关基因随着时间的推移(6个时间点)显示出高度相似的表达模式,并且发现大多数基因受两种强烈参与线粒体稳态的转录因子APP和NRF1的调控。此外,四种mirna与MMP↓相关,其中一种miR-1275被发现与大部分MMP↓相关基因呈负相关。在MMP↓相关基因和mirna中,糖异生、线粒体lc -脂肪酸β-氧化和纺锤体微管功能等细胞过程丰富。这些结果有望用于确定enm相关毒性途径的关键事件,以开发分子筛选技术。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Extensive temporal transcriptome and microRNA analyses identify molecular mechanisms underlying mitochondrial dysfunction induced by multi-walled carbon nanotubes in human lung cells.

Understanding toxicity pathways of engineered nanomaterials (ENM) has recently been brought forward as a key step in twenty-first century ENM risk assessment. Molecular mechanisms linked to phenotypic end points is a step towards the development of toxicity tests based on key events, which may allow for grouping of ENM according to their modes of action. This study identified molecular mechanisms underlying mitochondrial dysfunction in human bronchial epithelial BEAS 2B cells following exposure to one of the most studied multi-walled carbon nanotubes (Mitsui MWCNT-7). Asbestos was used as a positive control and a non-carcinogenic glass wool material was included as a negative fibre control. Decreased mitochondrial membrane potential (MMP↓) was observed for MWCNTs at a biologically relevant dose (0.25 μg/cm(2)) and for asbestos at 2 μg/cm(2), but not for glass wool. Extensive temporal transcriptomic and microRNA expression analyses identified a 330-gene signature (including 26 genes with known mitochondrial function) related to MWCNT- and asbestos-induced MMP↓. Forty-nine of the MMP↓-associated genes showed highly similar expression patterns over time (six time points) and the majority was found to be regulated by two transcription factors strongly involved in mitochondrial homeostasis, APP and NRF1. In addition, four miRNAs were correlated with MMP↓ and one of them, miR-1275, was found to negatively correlate with a large part of the MMP↓-associated genes. Cellular processes such as gluconeogenesis, mitochondrial LC-fatty acid β-oxidation and spindle microtubule function were enriched among the MMP↓-associated genes and miRNAs. These results are expected to be useful in the identification of key events in ENM-related toxicity pathways for the development of molecular screening techniques.

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来源期刊
Nanotoxicology
Nanotoxicology 医学-毒理学
CiteScore
10.10
自引率
4.00%
发文量
45
审稿时长
3.5 months
期刊介绍: Nanotoxicology invites contributions addressing research relating to the potential for human and environmental exposure, hazard and risk associated with the use and development of nano-structured materials. In this context, the term nano-structured materials has a broad definition, including ‘materials with at least one dimension in the nanometer size range’. These nanomaterials range from nanoparticles and nanomedicines, to nano-surfaces of larger materials and composite materials. The range of nanomaterials in use and under development is extremely diverse, so this journal includes a range of materials generated for purposeful delivery into the body (food, medicines, diagnostics and prosthetics), to consumer products (e.g. paints, cosmetics, electronics and clothing), and particles designed for environmental applications (e.g. remediation). It is the nano-size range if these materials which unifies them and defines the scope of Nanotoxicology . While the term ‘toxicology’ indicates risk, the journal Nanotoxicology also aims to encompass studies that enhance safety during the production, use and disposal of nanomaterials. Well-controlled studies demonstrating a lack of exposure, hazard or risk associated with nanomaterials, or studies aiming to improve biocompatibility are welcomed and encouraged, as such studies will lead to an advancement of nanotechnology. Furthermore, many nanoparticles are developed with the intention to improve human health (e.g. antimicrobial agents), and again, such articles are encouraged. In order to promote quality, Nanotoxicology will prioritise publications that have demonstrated characterisation of the nanomaterials investigated.
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