156 Nitrogen-Doped Multi-Walled Carbon Nanotubes show Attenuated Pathogenicity in a Mouse Model of Pleural Exposure

Abstract

Abstract Engineered carbon nanotubes (CNT) are currently used in many industrial products. Multi-walled carbon nanotubes (MWCNT) exhibit unique physicochemical properties and due to their low density and small size are easily aerosolized, making workplace exposure a potential risk to human health. MWCNT are similar to Asbestos in terms of their high aspect-ratio and thus may pose an asbestos-like inhalation hazard, including sporadic pleural Mesothelioma. Mitsui-7 MWCNT (MWCNT-7) have been classified by IARC as a Group 2B carcinogen. Importantly, physicochemically-altered MWCNT synthesized with nitrogen (MWCNT-ND) have been found to elicit attenuated toxicity; however, their pathogenicity in the pleura is unknown. Using a mouse model of direct injection into the pleural cavity, we compared the molecular changes that occur at the mesothelium over 20-months following injection with an occupationally-relevant dose of MWCNT-7, MWCNT-ND, Asbestos or carbon black. When compared to Asbestos or MWCNT-7, mice injected with MWCNT-ND did not develop respiratory symptoms. In contrast, in cell lines established from pleural effusions from MWCNT-7 or Asbestos-exposed mice with pre-neoplastic lesions or tumours, Whole-Exome-Sequencing and RNASeq revealed common molecular changes in both lesions and tumours. This identified genes involved in driving progression of pleural inflammatory lesions to Mesothelioma, whereas pre-neoplastic lesion-derived cell lines allow dissection of the hazard mechanism of pathogenic fibres at the molecular level early in disease development and thus may help predict genotoxic potency in exposed human populations. Our data demonstrate that physicochemical alteration of MWCNT (e.g. synthesis with nitrogen) attenuates pathogenicity and may offer an alternative for use in industrial applications.