Toxicogenomics analysis of dynamic dose-response in macrophages highlights molecular alterations relevant for multi-walled carbon nanotube-induced lung fibrosis

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.