96 Longitudinal Profiling of Carbon Nanotube-Induced Sporadic Mesothelioma Development: Defining the Adverse Outcome Pathway for Disease Progression

Abstract Exposure to asbestos causes pathological changes in the pleural cavity, including malignant mesothelioma (MPM). Length-dependent retention of asbestos fibres in the pleural cavity is crucial for disease development. Chronic inflammation induced by biopersistent asbestos fibres plays a key role in carcinogenesis. Engineered CarbonNanoTubes (CNT) are similar to long-fibre asbestos (LFA) in terms of their high aspect-ratio and thus may pose an asbestos-like inhalation hazard, with evidence from our laboratory and others showing the carcinogenic potential of Long-CNT. Asbestos-induced MPM is diagnosed most commonly at late stage; as a result, little is known about the genetic or epigenetic aberrations occurring in pre-malignant pleural lesions and whether they align with deletions/mutations commonly found in end-stage asbestos-exposed patient tumours. Using a mouse model of direct injection into the pleural cavity, we compared the molecular changes that occur at the mesothelium following injection with an occupationally-relevant dose of Long-CNT or LFA over 20-months. We show a common molecular signature induced by Long-CNT and LFA throughout disease progression eventually leading to the development of sporadic MPM. DNA methylation, gene expression profiles, as well as specific genes are similarly altered in the presence of Long-CNT and LFA, at matched longitudinal exposure times. For the first time, these data uncover the Adverse Outcome Pathway (AOP) from initial Long-CNT exposure through to induction of pre-neoplastic lesions and the development of sporadic pleural mesothelioma, replicating the pathogenesis of end-stage asbestos-induced human disease. This reinforces concerns that high aspect-ratio CNT may pose an asbestos-like hazard, including sporadic malignant mesothelioma.