Abstract:Exposure to ionizing radiation induces a cascade of molecular events that ultimately impact endogenous metabolism. Qualitative and quantitative characterization of metabolomic profiles is a pragmatic approach to studying the risks of radiation exposure since it provides a phenotypic readout. Studies were conducted in irradiated nonhuman primates (NHP) to investigate metabolic changes in plasma and plasma-derived exosomes. Specifically, rhesus macaques (Macaca mulatta) were exposed to cobalt-60 gamma-radiation … Show more
“…These are striking findings given that none of these compounds were significantly changed in total plasma profiling, suggesting they are EV-specific and functionally relevant. Lipid accumulation has previously been associated with whole-body ionizing radiation exposure 35 , and dyslipidemia is an outcome we have observed in other radiation studies 22 .Figure 2EVs can be profiled for markers of inflammation post-cranial irradiation. Box plots for key metabolites implicated in an inflammatory response ( A ) 2 days or ( B ) 2 weeks after 9 Gy cranial radiation exposures.…”
Section: Resultsmentioning
confidence: 55%
“…While many researchers are studying the diagnostic and therapeutic capabilities of EVs 13–20 , their role in the context of ionizing radiation exposure remain unclear. Previous studies have shown that EV secretion is increased with ionizing radiation exposure in a time and dose dependent manner 21,22 . Others have described a potential role of EVs in the bystander effect during cancer treatment 23–26 .…”
Ionizing radiation exposure to the brain is common for patients with a variety of CNS related malignancies. This exposure is known to induce structural and functional alterations to the brain, impacting dendritic complexity, spine density and inflammation. Over time, these changes are associated with cognitive decline. However, many of these impacts are only observable long after irradiation. Extracellular vesicles (EVs) are shed from cells in nearly all known tissues, with roles in many disease pathologies. EVs are becoming an important target for identifying circulating biomarkers. The aim of this study is to identify minimally invasive biomarkers of ionizing radiation damage to the CNS that are predictors of late responses that manifest as persistent cognitive impairments. Using a clinically relevant 9 Gy irradiation paradigm, we exposed mice to cranial (head only) irradiation. Using metabolomic and lipidomic profiling, we analyzed their plasma and plasma-derived EVs two days and two weeks post-exposure to detect systemic signs of damage. We identified significant changes associated with inflammation in EVs. Whole-plasma profiling provided further evidence of systemic injury. These studies are the first to demonstrate that profiling of plasma-derived EVs may be used to study clinically relevant markers of ionizing radiation toxicities to the brain.
“…These are striking findings given that none of these compounds were significantly changed in total plasma profiling, suggesting they are EV-specific and functionally relevant. Lipid accumulation has previously been associated with whole-body ionizing radiation exposure 35 , and dyslipidemia is an outcome we have observed in other radiation studies 22 .Figure 2EVs can be profiled for markers of inflammation post-cranial irradiation. Box plots for key metabolites implicated in an inflammatory response ( A ) 2 days or ( B ) 2 weeks after 9 Gy cranial radiation exposures.…”
Section: Resultsmentioning
confidence: 55%
“…While many researchers are studying the diagnostic and therapeutic capabilities of EVs 13–20 , their role in the context of ionizing radiation exposure remain unclear. Previous studies have shown that EV secretion is increased with ionizing radiation exposure in a time and dose dependent manner 21,22 . Others have described a potential role of EVs in the bystander effect during cancer treatment 23–26 .…”
Ionizing radiation exposure to the brain is common for patients with a variety of CNS related malignancies. This exposure is known to induce structural and functional alterations to the brain, impacting dendritic complexity, spine density and inflammation. Over time, these changes are associated with cognitive decline. However, many of these impacts are only observable long after irradiation. Extracellular vesicles (EVs) are shed from cells in nearly all known tissues, with roles in many disease pathologies. EVs are becoming an important target for identifying circulating biomarkers. The aim of this study is to identify minimally invasive biomarkers of ionizing radiation damage to the CNS that are predictors of late responses that manifest as persistent cognitive impairments. Using a clinically relevant 9 Gy irradiation paradigm, we exposed mice to cranial (head only) irradiation. Using metabolomic and lipidomic profiling, we analyzed their plasma and plasma-derived EVs two days and two weeks post-exposure to detect systemic signs of damage. We identified significant changes associated with inflammation in EVs. Whole-plasma profiling provided further evidence of systemic injury. These studies are the first to demonstrate that profiling of plasma-derived EVs may be used to study clinically relevant markers of ionizing radiation toxicities to the brain.
“…Several biomarkers have been approved for various injuries by regulatory bodies around the world, but none of these approved biomarkers are for radiation-induced injuries. Multiple molecular pathways and potential biomarkers for radiation injury are being identified and validated by a large number of investigators 4 , 8 – 13 .…”
The field of biodosimetry has seen a paradigm shift towards an increased use of molecular phenotyping technologies including omics and miRNA, in addition to conventional cytogenetic techniques. Here, we have used a nonhuman primate (NHP) model to study the impact of gamma-irradiation on alterations in blood-based gene expression. With a goal to delineate radiation induced changes in gene expression, we followed eight NHPs for 60 days after exposure to 6.5 Gy gamma-radiation for survival outcomes. Analysis of differential gene expression in response to radiation exposure yielded 26,944 dysregulated genes that were not significantly impacted by sex. Further analysis showed an increased association of several pathways including IL-3 signaling, ephrin receptor signaling, ErbB signaling, nitric oxide signaling in the cardiovascular system, Wnt/β-catenin signaling, and inflammasome pathway, which were associated with positive survival outcomes in NHPs after acute exposure to radiation. This study provides novel insights into major pathways and networks involved in radiation-induced injuries that may identify biomarkers for radiation injury.
“…Despite the encouraging results collected herein, the full power of EV metabolomics is yet to be realized. We have used examples from biological pathologies, but the metabolome changes from physical stimuli can also be detected—as in the case of primates exposed to damaging radiation [46], which could potentially prove useful in monitoring exposure levels of radiotherapy technicians. Moreover, the metabolomics of pathogen EVs may further the understanding of infection from bacterial species [47].…”
Cell-secreted extracellular vesicles (EVs) have rapidly gained prominence as sources of biomarkers for non-invasive biopsies, owing to their ubiquity across human biofluids and physiological stability. There are many characterisation studies directed towards their protein, nucleic acid, lipid and glycan content, but more recently the metabolomic analysis of EV content has also gained traction. Several EV metabolite biomarker candidates have been identified across a range of diseases, including liver disease and cancers of the prostate and pancreas. Beyond clinical applications, metabolomics has also elucidated possible mechanisms of action underlying EV function, such as the arginase-mediated relaxation of pulmonary arteries or the delivery of nutrients to tumours by vesicles. However, whilst the value of EV metabolomics is clear, there are challenges inherent to working with these entities—particularly in relation to sample production and preparation. The biomolecular composition of EVs is known to change drastically depending on the isolation method used, and recent evidence has demonstrated that changes in cell culture systems impact upon the metabolome of the resulting EVs. This review aims to collect recent advances in the EV metabolomics field whilst also introducing researchers interested in this area to practical pitfalls in applying metabolomics to EV studies.
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