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Front Mol Biosci. 2019 Sep 10;6:77. doi: 10.3389/fmolb.2019.00077. eCollection 2019.

Integrated Metabolomics-DNA Methylation Analysis Reveals Significant Long-Term Tissue-Dependent Directional Alterations in Aminoacyl-tRNA Biosynthesis in the Left Ventricle of the Heart and Hippocampus Following Proton Irradiation.

Author information

1
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, United States.
2
Linus Pauling Institute, Oregon State University, Corvallis, OR, United States.
3
Department of Animal & Rangeland Sciences, Oregon State University, Corvallis, OR, United States.
4
Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR, United States.
5
Oregon Stem Cell Center and Department of Pediatrics, Oregon Health & Science University, Portland, OR, United States.
6
Oregon National Primate Research Center, Oregon Health & Science University, Portland, OR, United States.
7
Knight Cardiovascular Institute, Oregon Health & Science University, Portland, OR, United States.
8
Division of Neuroscience ONPRC, Departments of Neurology and Radiation Medicine, Oregon Health & Science University, Portland, OR, United States.

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.

KEYWORDS:

Parkinson's disease; hippocampus; integrated epigenetic metabolomics analysis; left ventricle; proton irradiation; radiation biomarkers

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