36 Comparative analysis of early transcriptomic changes in the lung of F344 rats exposed to different carbon nanotubes and chemical carcinogens

We previously investigated the carcinogenic potential of different types of carbon nanotubes (CNTs) in rats. Rigid and straight CNTs (MWCNT-7 and MWCNT-N) caused lung cancer and pleural mesothelioma. Thin and tangled CNTs (MWCNT-B, DWCNT and SWCNT) induced lung cancer. Exposure to carbon nano horns (CNHs) and carbon nano brushes (CNBs) did not cause lung or pleural tumours. To obtain molecular insights into CNT-induced lung carcinogenicity, we performed a transcriptomic analysis of lung tissues of male F344 rats exposed to four doses of carcinogenic CNTs (MWCNT-7, MWCNT-N, MWCNT-B, DWCNT, SWCNT) or non-carcinogenic CNH injected by TIPS at total dose of 0.5 mg/rat and compared it with those induced by DHPN (a known chemical carcinogen) injected intraperitoneally at total dose of 1,000 mg/rat. Pulmonary toxicity and the entire gene expression profiles were analysed six weeks after the final dose. The RNA- sequencing analysis identified a large number of significantly differentially expressed genes between groups. The GO enrichment analysis revealed that the genes of phagocytes regulating migration and chemotaxis up-regulated in carcinogenic CNTs versus non-carcinogenic CNH. The KEGG analysis revealed that exposure to carcinogenic CNTs up-regulated inflammation-elicited signalling pathways: cytokine signalling pathways, cytokine-cytokine receptor interaction, IL-17 signalling pathway and TNF signalling pathway. Interestingly, the gene expression profile of carcinogenic CNT was totally different compared to that of DPHN-treated rats. qRT-PCR indicated that expression of inflammatory cytokines, Ccl2, Ccl3, Ccl9, Il-1b and TGF-b up-regulated by carcinogenic CNTs but not by DHPN. Our findings support a scenario of inflammation-induced carcinogenesis and contribute to a better understanding of the molecular mechanism of CNT carcinogenicity.