Finnish Institute of Occupational Health , Helsinki, Finland 00251.
Institute of Environmental Medicine (IMM), Karolinska Institutet , 171 77 Stockholm, Sweden.
ACS Nano. 2017 Apr 25;11(4):3786-3796. doi: 10.1021/acsnano.6b08650. Epub 2017 Apr 11.
Understanding the complex molecular alterations related to engineered nanomaterial (ENM) exposure is essential for carrying out toxicity assessment. Current experimental paradigms rely on both in vitro and in vivo exposure setups that often are difficult to compare, resulting in questioning the real efficacy of cell models to mimic more complex exposure scenarios at the organism level. Here, we have systematically investigated transcriptomic responses of the THP-1 macrophage cell line and lung tissues of mice, after exposure to several carbon nanomaterials (CNMs). Under the assumption that the CNM exposure related molecular alterations are mixtures of signals related to their intrinsic properties, we inferred networks of responding genes, whose expression levels are coordinately altered in response to specific CNM intrinsic properties. We observed only a minute overlap between the sets of intrinsic property-correlated genes at different exposure scenarios, suggesting specific transcriptional programs working in different exposure scenarios. However, when the effects of the CNM were investigated at the level of significantly altered molecular functions, a broader picture of substantial commonality emerged. Our results imply that in vitro exposures can efficiently recapitulate the complex molecular functions altered in vivo. In this study, altered molecular pathways in response to specific CNM intrinsic properties have been systematically characterized from transcriptomic data generated from multiple exposure setups. Our computational approach to the analysis of network response modules further revealed similarities between in vitro and in vivo exposures that could not be detected by traditional analysis of transcriptomics data. Our analytical strategy also opens a possibility to look for pathways of toxicity and understanding the molecular and cellular responses identified across predefined biological themes.
了解与工程纳米材料 (ENM) 暴露相关的复杂分子改变对于进行毒性评估至关重要。目前的实验范式依赖于体外和体内暴露设置，这些设置往往难以比较，导致质疑细胞模型在模拟更复杂的生物体水平暴露场景方面的实际效果。在这里，我们系统地研究了 THP-1 巨噬细胞系和小鼠肺组织在暴露于几种碳纳米材料 (CNM) 后的转录组反应。假设 CNM 暴露相关的分子改变是与其固有特性相关的信号的混合物，我们推断出响应基因的网络，其表达水平在响应特定的 CNM 固有特性时协同改变。我们仅在不同暴露场景下的固有特性相关基因集之间观察到微小的重叠，这表明在不同暴露场景下存在特定的转录程序。然而，当在显着改变的分子功能水平上研究 CNM 的作用时，出现了一个更广泛的实质性共性的图景。我们的结果表明，体外暴露可以有效地重现体内改变的复杂分子功能。在这项研究中，从多个暴露设置生成的转录组数据中，系统地描述了响应特定 CNM 固有特性的改变的分子途径。我们对网络响应模块的分析方法进一步揭示了体外和体内暴露之间的相似性，这些相似性无法通过传统的转录组数据分析检测到。我们的分析策略还为寻找毒性途径和理解跨预定义生物学主题确定的分子和细胞反应开辟了可能性。
