A multi-omics approach reveals mechanisms of nanomaterial toxicity and structure-activity relationships in alveolar macrophages
A multi-omics approach reveals mechanisms of nanomaterial toxicity and structure-activity relationships in alveolar macrophages
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DOI：
10.1080/17435390.2019.1684592
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发表时间：
2019-11-20
期刊：
影响因子：
5
通讯作者：
Schubert, Kristin
中科院分区：
文献类型：
--
作者：
Bannuscher, Anne;Karkossa, Isabel;Schubert, Kristin
鉴于大量释放的纳米材料及其高度可变的特性，需要根据纳米材料的影响采取新的分组方法。适当的分组要求将实验装置与更多结构相似的纳米材料相结合，并采用综合组学方法来确定作用模式。在这里，我们分析了七个良好的表征纳米材料，包括不同的化学组成，大小和化学表面修饰对大鼠肺泡巨噬细胞系NR 8383的影响。在孵育24小时后，使用包括非靶向蛋白质组学、靶向代谢组学和src同源性2（SH 2）分析的综合多组学方法，以2.5至10 μ g/cm（2）的三种剂量研究NM。通过使用加权基因相关网络分析（WGCNA）的综合数据，我们确定了分子途径与理化性质和毒理学终点的相关性。三种研究的SiO2变体在所有三种组学方法中诱导强烈的改变，因此被归类为“活性”。“两种有机酞菁显示出轻微的反应，Mn 2 O3诱导了与其他NM不同的分子反应模式。WGCNA显示，团聚体的大小和表面积以及LDH释放是与纳米毒理学相关的最重要的参数之一。此外，我们确定了可以作为代表性生物标志物候选者的关键驱动因素，支持多组学方法建立综合测试和评估方法（IATA）的价值。
In respect to the high number of released nanomaterials and their highly variable properties, novel grouping approaches are required based on the effects of nanomaterials. Proper grouping calls for a combination of an experimental setup with a higher number of structurally similar nanomaterials and for employing integrated omics approaches to identify the mode of action. Here, we analyzed the effects of seven well-characterized NMs comprising different chemical compositions, sizes and chemical surface modifications on the rat alveolar macrophage cell line NR8383. The NMs were investigated at three doses ranging from 2.5 to 10 mu g/cm(2) after 24 h incubation using an integrated multi-omics approach involving untargeted proteomics, targeted metabolomics, and src homology 2 (SH2) profiling. By using Weighted Gene Correlation Network Analysis (WGCNA) for the integrative data, we identified correlations of molecular pathways with physico-chemical properties and toxicological endpoints. The three investigated SiO2 variants induced strong alterations in all three omics approaches and were, therefore, be classified as "active." Two organic phthalocyanines showed minor responses and Mn2O3 induced a different molecular response pattern than the other NMs. WGCNA revealed that agglomerate size and surface area as well as LDH release are among the most important parameters correlating with nanotoxicology. Moreover, we identified key drivers that can serve as representative biomarker candidates, supporting the value of multi-omics approaches to establish integrated approaches to testing and assessment (IATAs).