A Systematic Review of Metabolomic and Lipidomic Candidates for Biomarkers in Radiation Injury

Abstract

A large-scale nuclear event has the ability to inflict mass casualties requiring point-of-care and laboratory-based diagnostic and prognostic biomarkers to inform victim triage and appropriate medical intervention. Extensive progress has been made to develop post-exposure point-of-care biodosimetry assays and to identify biomarkers that may be used in early phase testing to predict the course of the disease. Screening for biomarkers has recently extended to identify specific metabolomic and lipidomic responses to radiation using animal models. The objective of this review was to determine which metabolites or lipids most frequently experienced perturbations post-ionizing irradiation (IR) in preclinical studies using animal models of acute radiation sickness (ARS) and delayed effects of acute radiation exposure (DEARE). Upon review of approximately 65 manuscripts published in the peer-reviewed literature, the most frequently referenced metabolites showing clear changes in IR induced injury were found to be citrulline, citric acid, creatine, taurine, carnitine, xanthine, creatinine, hypoxanthine, uric acid, and threonine. Each metabolite was evaluated by specific study parameters to determine whether trends were in agreement across several studies. A select few show agreement across variable animal models, IR doses and timepoints, indicating that they may be ubiquitous and appropriate for use in diagnostic or prognostic biomarker panels.

Metabolomics-based predictive biomarkers of radiation injury and countermeasure efficacy: current status and future perspectives

“…The following are the most frequently altered metabolites in response to different doses of radiation (wide dose range with varying dose rates and different qualities) exposure that have been detected and validated in various animal models and in clinical patient samples: carnitine [11,[15][16][17][18][19] .…”

“…As a result of a decrease in glycolysis and tricarboxylic acid activity, succeeding pathways were also dysregulated (decreased fatty acid oxidation and increased ketogenesis) [34] . Creatinine and uric acid have been shown to decrease in response to irradiation in various animal models [16] . Several studies have demonstrated decreased circulating citrulline levels in murine and NHP models following irradiation [12,35,36] .…”

“…Long term damage (2 months) has been shown at lower doses (~2 Gy) which result in reduced nucleotide metabolism and inflammation in intestine [39] . Sphingolipid, a ceramide, has been shown to be increased after irradiation in the lung in addition to several cell types in mice [16] . Anti-ceramide antibody has been shown to protect mice from supralethal doses of radiation [40] .…”

Metabolomics in Radiation Biodosimetry: Current Approaches and Advances

“…Protocols routinely used for the preparation of samples including for liquid chromatography mass spectrometry (LC-MS) metabolomic analysis were published by Laiakis et al [21], as was a method which allows for the possibility of rapid preparation protocols for blood [113]. Vincente et al [29] recently published a detailed tabulation of different metabolite trends from various biosamples across multiple species, radiation doses, and time-points.…”

“…That review concluded that metabolomics had the potential to serve as an important means of accurately assessing radiation exposure. More recent reviews by Menon et al [28], Roh [20], and Vincente et al [29] have highlighted recent advances in radiation metabolomics as applied to biodosimetry. However, the metabolomics approach is a behemoth, with its own set of challenges ranging from specifics of sample preparation, technology and analysis employed, to the interpretation of output data and translation [30].…”