Abstract
Ionizing radiation (IR) is an integral component of our lives due to highly prevalent sources such as medical, environmental, and/or accidental. Thus, understanding of the mechanisms by which radiation toxicity develops is crucial to address acute and chronic health problems that occur following IR exposure. Immediate formation of IR-induced free radicals as well as their persistent effects on metabolism through subsequent alterations in redox mediated inter- and intracellular processes are globally accepted as significant contributors to early and late effects of IR exposure. This includes but is not limited to cytotoxicity, genomic instability, fibrosis and inflammation. Damage to the critical biomolecules leading to detrimental long-term alterations in metabolic redox homeostasis following IR exposure has been the focus of various independent investigations over last several decades. The growth of the “omics” technologies during the past decade has enabled integration of “data from traditional radiobiology research”, with data from metabolomics studies. This review will focus on the role of tetrahydrobiopterin (BH4), an understudied redox-sensitive metabolite, plays in the pathogenesis of post-irradiation normal tissue injury as well as how the metabolomic readout of BH4 metabolism fits in the overall picture of disrupted oxidative metabolism following IR exposure.
Highlights
Both targeted radiotherapy to treat malignancies and nuclear/accidental irradiation exposure are known to cause injury to normal tissues, limiting the therapeutic dose range in clinical settings or causing mass casualties [1,2,3]
Our data demonstrated that when exposed to a non-lethal dose of Ionizing radiation (IR), Gfrp overexpressing mice exhibited a significant accumulation of metabolites associated with oxidative stress and lipid peroxidation
Metabolic oxidative stress has been widely accepted as a significant contributor for the early and late effects of IR injury
Summary
Both targeted radiotherapy to treat malignancies and nuclear/accidental irradiation exposure are known to cause injury to normal tissues, limiting the therapeutic dose range in clinical settings or causing mass casualties [1,2,3]. A metabolomics approach offers to detect and quantitate changes in the levels of metabolites that directly reflect the overall physiological status of an individual [9] It provides a systems wide biological snapshot of the net expression of metabolites from several known pathways in response to exogenous challenges such as IR. While radiolysis of water leads to the rapid generation of reactive oxygen species (ROS) resulting in oxidative stress [10,11], which is characterized by dramatic effects on cellular function; including gene expression, transcription factor activation, redox sensitive signaling pathways All of these effects contribute to IR-induced signaling and adaptive responses, which feed into endogenous metabolism. IR dependent metabolomics changes have already been reported in human cell lines and mouse urine, indicating multiple oxidation sensitive targets in their metabolic profiles shortly following exposure [17,18,19]
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