Abstract
In this study, an untargeted metabolomics approach was used to assess the effects of proton irradiation (1 Gy of 150 MeV) on the metabolome and DNA methylation pattern in the murine hippocampus and left ventricle of the heart 22 weeks following exposure using an integrated metabolomics-DNA methylation analysis. The integrated metabolomics-DNA methylation analysis in both tissues revealed significant alterations in aminoacyl-tRNA biosynthesis, but the direction of change was tissue-dependent. Individual and total amino acid synthesis were downregulated in the left ventricle of proton-irradiated mice but were upregulated in the hippocampus of proton-irradiated mice. Amino acid tRNA synthetase methylation was mostly downregulated in the hippocampus of proton-irradiated mice, whereas no consistent methylation pattern was observed for amino acid tRNA synthetases in the left ventricle of proton-irradiated mice. Thus, proton irradiation causes long-term changes in the left ventricle and hippocampus in part through methylation-based epigenetic modifications. Integrated analysis of metabolomics and DNA methylation is a powerful approach to obtain converging evidence of pathways significantly affected. This in turn might identify biomarkers of the radiation response, help identify therapeutic targets, and assess the efficacy of mitigators directed at those targets to minimize, or even prevent detrimental long-term effects of proton irradiation on the heart and the brain.
Highlights
Protons are a major component of galactic cosmic rays (GCR) and solar particle events (SPE) (Lloyd et al, 2018)
In the second, targeted phase, in which we show that radiation altered metabolite abundance as well as methylation of the amino-tRNA biosynthesis pathway, we focused on the 15 identified amino acids of the amino-tRNA biosynthesis pathways as well as the methylation status of their tRNA synthetases and did not adjust for multiple comparisons
Of the 52 identified KEGG pathways, no pathways were significantly altered by proton irradiation in hippocampal tissue, several pathways trended toward significance
Summary
Protons are a major component of galactic cosmic rays (GCR) and solar particle events (SPE) (Lloyd et al, 2018). Proton irradiation as part of the space radiation environment of astronauts during missions may pose a significant long-term hazard (Simonsen et al, 1993; Cucinotta et al, 2013). This radiation exposure is pertinent to cancer patients treated with protons (ICoR Units, 2007; Merchant et al, 2008; Lukens et al, 2015; Lupu-Plesu et al, 2017). The brain is sensitive to detrimental effects of proton irradiation in humans following cancer treatment (Merchant et al, 2008; Armstrong, 2012). The hippocampus might be especially sensitive to effects of proton irradiation (Rabinow et al, 2006; Bellone et al, 2014; Rudobeck et al, 2014; Parihar et al, 2015; Raber et al, 2015; Sokolova et al, 2015; Impey et al, 2016)
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