Abstract Toxicogenomics approaches are increasingly used to gain mechanistic insight into the toxicity of engineered nanomaterials (ENMs). These emerging technologies have been shown to aid the translation of in vitro experimentation into relevant information on real-life exposures. Furthermore, integrating multiple layers of molecular alteration can provide a broader understanding of the toxicological insult. While there is growing evidence of the immunotoxic effects of several ENMs, the mechanisms are less characterized, and the dynamics of the molecular adaptation of the immune cells are still largely unknown. Here, we hypothesized that a multi-omics investigation of dynamic dose-dependent (DDD) molecular alterations could be used to retrieve relevant information concerning possible long-term consequences of the exposure. To this end, we applied this approach on a model of human macrophages to investigate the effects of rigid multi-walled carbon nanotubes (rCNTs). THP-1 macrophages were exposed to increasing concentrations of rCNTs and the genome-wide transcription and gene promoter methylation were assessed at three consecutive time points. The results suggest dynamic molecular adaptation with a rapid response in the gene expression and contribution of DNA methylation in the long-term adaptation. Moreover, our analytical approach is able to highlight patterns of molecular alteration in vitro that are relevant for the pathogenesis of pulmonary fibrosis, a known long-term effect of rCNTs exposure in vivo.

中文翻译：

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巨噬细胞动态剂量反应的毒理学分析突出了与多壁碳纳米管诱导的肺纤维化相关的分子改变

摘要毒性基因组学方法越来越多地用于获得对工程纳米材料 (ENM) 毒性的机械洞察。这些新兴技术已被证明有助于将体外实验转化为有关现实生活暴露的相关信息。此外，整合多层分子改变可以提供对毒理学损伤的更广泛理解。虽然越来越多的证据表明几种 ENM 具有免疫毒性作用，但其机制尚不明确，免疫细胞的分子适应动力学仍然在很大程度上未知。在这里，我们假设动态剂量依赖性 (DDD) 分子改变的多组学研究可用于检索有关暴露可能长期后果的相关信息。为此，我们将这种方法应用于人类巨噬细胞模型，以研究刚性多壁碳纳米管 (rCNT) 的影响。THP-1 巨噬细胞暴露于浓度不断增加的 rCNT，并在三个连续时间点评估全基因组转录和基因启动子甲基化。结果表明动态分子适应具有基因表达的快速反应和 DNA 甲基化在长期适应中的贡献。此外，我们的分析方法能够突出体外分子改变的模式，这些模式与肺纤维化的发病机制相关，这是体内 rCNTs 暴露的已知长期影响。THP-1 巨噬细胞暴露于浓度不断增加的 rCNT，并在三个连续时间点评估全基因组转录和基因启动子甲基化。结果表明动态分子适应具有基因表达的快速反应和 DNA 甲基化在长期适应中的贡献。此外，我们的分析方法能够突出体外分子改变的模式，这些模式与肺纤维化的发病机制相关，这是体内 rCNTs 暴露的已知长期影响。THP-1 巨噬细胞暴露于浓度不断增加的 rCNT，并在三个连续时间点评估全基因组转录和基因启动子甲基化。结果表明动态分子适应具有基因表达的快速反应和 DNA 甲基化在长期适应中的贡献。此外，我们的分析方法能够突出体外分子改变的模式，这些模式与肺纤维化的发病机制相关，这是体内 rCNTs 暴露的已知长期影响。