Abstract

Exposure to asbestos fibres causes pathological changes in the pleural cavity including malignant mesothelioma.  Length-dependent retention of asbestos fibres in the pleural cavity is crucial for disease development.  Chronic inflammation plays a key role in carcinogenesis and epigenetic events, rather than driver mutations, are considered to be major causative factors.  New advanced materials such as carbon nanotubes offer an exciting frontier for innovation but safety is imperative. Prior to understanding the risks posed by exposure to asbestos, it was considered a wonder material with numerous applications yet a tragic legacy arose from its widespread use. Knowledge of the sequence of events from exposure to asbestos to the formation of mesothelioma is vital for identifying any risks posed by new fibres. Certain forms of carbon nanotubes (CNT) are similar to asbestos in terms of their high aspect-ratio and thus may pose an asbestos-like inhalation hazard, however the molecular mechanisms underlying their carcinogenic potential have not been fully explored.

Using a model of direct injection into the pleural cavity, we compared the molecular changes which occur at the mesothelium after exposure to occupationally-relevant concentrations of short/long asbestos fibres and short/long CNT over 20 months. We show a common pro-oncogenic activity of long CNT and long asbestos throughout disease progression. Key molecular events encompass changes in gene expression/signaling pathway activation, oxidative DNA damage, increased mitosis and proliferation.  Instillation of long CNTs into the pleural cavity of mice induces chronic inflammation and pro-oncogenic changes leading to development of mesothelioma, with deletion of p19/Arf and silencing of p16/Ink4a and NF2.  Epigenetic changes induced by pathogenic fibres occur at the pre-neoplastic stage of disease and thus may play a role in progression of pleural inflammatory lesions to malignant mesothelioma.

Our data demonstrate that exposure to long-fibre CNT induces development of pleural mesothelioma, replicating the pathogenesis of human disease and highlighting commonality in the hazard mechanism of long pathogenic fibres at the molecular level. Crucially, our findings reinforce concerns that long-fibre carbon nanotubes (and potentially other high-aspect-ratio fibres) may present the same carcinogenic hazard as asbestos. However, we found that it was only CNTs which were long, thin and bio-persistent (those which aren’t broken down and expelled by the immune system) which posed a hazard. Thus, our findings open up the possibility of more effective/efficient screening of advanced fibres to better identify/mitigate risks and ensure safety.