Multiwalled Carbon Nanotubes as Physical Drivers of Chromosome Instability and Inflammatory Responses

Abstract

Multiwalled carbon nanotubes (MWCNTs) are widely used in industry; however, exposure to these fiber-like structures has beenassociated with acute and chronic toxicological effects. Upon inhalation, human epithelial cells internalize MWCNTs by macro-pinocytosis. Once internalized, MWCNTs have been associated with mesothelioma and inflammation pathologies, similar tothose induced by asbestos. While most previous studies have emphasized the chemical properties of MWNCTs as drivers of tox-icity, this article highlights their fibrous morphology as a key factor in their genotoxic potential. Exposure of retinal pigmentalepithelial cells to NM-401 MWCNT significantly increased the frequencies of lagging chromosomes, micronuclei, and binucleatedcells. Combined with time-lapse imaging, these findings revealed a mechanically driven process in which MWCNTs physicallyobstruct chromosome migration and impair the final stage of cytokinesis in epithelial cells. Such mechanical disruptions causeaberrant mitotic outcomes, a well-established source of chromosomal instability, and precursors of carcinogenesis. Moreover,MWCNTs induce cytoplasmic DNA mislocalization, which is sensed by cGAS and potentially triggers an innate immune responsein epithelial cells. Consistently, continuous fiber exposure upregulates type I interferon-related genes and pro-inflammatory cyto-kines in both macrophages and epithelial cells. Altogether, these findings indicate that the genotoxic effects of NM-401 MWCNTscontribute to the chronic inflammation observed in MWCNT-induced pulmonary fibrosis.