429 Signature of epigenetic alterations induced by carbon nanotube- in vitro, in vivo and in workers

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IntroductionGrowing indication of toxicity and production of carbon nanotubes (CNTs), have resulted in concern about adverse effect of occupational exposure. Research have suggested carcinogenic potential of some forms of CNTs (MWCNT-7 Mitsui) and asbestos-like pathogenesis. Studying epigenetic alterations (e.g. DNA methylation) could provide important additional evidence to determine CNT toxicity and disease progression.MethodsTo understand epigenetic effects of CNT (SWCNT and MWCNT), we designed a translational study incorporating in vitro and in vivo experiments. The changes were compared to results of asbestos exposure study. Changes in DNA methylation were studied at global (LC/MS-MS), genome wide (illumina 450 K), sequence specific levels (bisulfite pyrosequenceing). Changes in gene expression were studied using RNA-Seq. Finally, signatures obtained from these studies were validated in 23 workers exposed to MWCNT.ResultIn vitro, CNTs and asbestos induced gene specific DNA methylation changes. Asbestos exposure induced alterations in genes associated with Rho mediated signal transduction, HOX genes, WNT genes. Methylation and transcriptomic profiles of CNT exposed cells revealed alterations in DNA damage repair, tp53, cell cycle, protein phosphorylation pathways. Additionally, CNTs induced sequence specific changes in promoter region of several key genes including DNMT1, HDAC4, ATM, MAP3K10, PIK3R2 and MYO1C. Some of the genes, specifically ATM was also differentially methylated by SWCNTs and MWCNTs in the in vivo study. Based on these result, we studied some of these markers in MWCNT exposed workers, where we observed significant changes in sequence specific methylation for DNMT1, ATM, SKI and HDAC4 promoter CpGs.ConclusionEpigenetic cell responses provides important insights in potential health risks and underlying mechanisms. Hence, many of these genes have been associated with occupational asbestos and smoking induced diseases and cancer. Further research needs to confirm whether methylation alterations in this set of genes can be used in monitoring changes associated CNT exposure and effect.

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