Efficient Identification and Comprehension of Molecular Pathways Associated with Irradiation Induced Hepatic Carcinogenesis
As human exploration into deep space continues to expand in the future, risk prediction for irradiation-induced diseases will become an increasingly important task. It will be critical to identify the biological effects of high-charge, high energy (HZE) and low energy 137Cs γ rays, which are the major components of space irradiation on the human body during longer stay in deep space, including a mission to Mars. It has been shown that there is a significant increase in incidence of Hepatocellular carcinoma (HCC), after exposure to low dose HZE. There is, however, limited knowledge of the effects of low dose irradiation on the formation of HCC. To address this gap in knowledge, RNA-Seq and MALDI-MSI were used to assess the effects of space irradiation on the pathogenesis of HCC. In particular, RNA-seq was used to determine transcriptional changes, and MALDI-MSI to determine lipid changes, in the hepatic microenvironment of ion irradiated compared to non-irradiated controls, in two different strains of mice, at five different time points post-irradiation. For our RNA-Seq datasets, we first present a novel pipeline to perform gene co-expression network analysis, and use this to show that mitochondrial pathways are dysregulated in response to 56Fe irradiation compared to non-irradiated control, in the wildtype mouse strain (C57BL/6NCrl.) Next we performed a comparative transcriptomic analysis in a mouse model for irradiation-induced HCC (C3H/HeNCrl), in order to assess the carcinogenic effects of 600 MeV/n 56Fe (0.2 Gy), 1 GeV/n 16O (0.2 Gy), and 350 MeV/n 28Si (0.2 Gy), compared to non-irradiated control. Our data demonstrated a clear difference in the effects of these HZE ions, particularly immunological, suggesting different molecular mechanisms of tumorigenesis for each ion. Additionally, we observed novel, functionally unannotated transcripts that were significantly affected by HZE. The biological functions of these transcripts were investigated using Self-Organizing Maps (SOMs). Finally, we used MALDI-MSI to identify lipid changes 12 months post-exposure to low dose 28Si and 137Cs γ rays’ irradiation. We identified a number of lipid species; in particular, we have confirmed the identity of GSL; which is of special interest because its up-regulation have been reported in patients with HCC.