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 and plasma samples were collected prior to and after exposure to 5.8 Gy or 6.5 Gy radiation. Exosomes were isolated using ultracentrifugation and analyzed by untargeted profiling via ultra-performance liquid chromatography mass spectrometry (UPLC-MS) based metabolomic and lipidomic analyses, with the goal of identifying a molecular signature of irradiation. The enrichment of an exosomal fraction was confirmed using quantitative ELISA. Plasma profiling showed markers of dyslipidemia, inflammation and oxidative stress post-irradiation. Exosomal profiling, on the other hand, enabled detection and identification of low abundance metabolites that comprise exosomal cargo which would otherwise get obscured with plasma profiling. We discovered enrichment of different classes of metabolites including N-acyl-amino acids, Fatty Acid ester of Hydroxyl Fatty Acids (FAHFA’s), glycolipids and triglycerides as compared to the plasma metabolome composition with implications in mediation of systemic response to radiation induced stress signaling.
Highlights
Terrorist attacks with radiological dispersal device (RDD) or improvised nuclear device (IND) weapons are an ever-growing worldwide concern in government and public sectors as they become more violent and more sensational
We have shown that several biomolecules identified via plasma exosomal profiling are below limits of detection when profiling intact plasma; justifying the need to enrich this fraction for Mass Spectrometry (MS) analyses
Both of the doses used in this study induce H-ARS in nonhuman primates (NHP) with significant cytopenia, neutropenia and thrombocytopenia within two weeks of radiation exposure which makes these doses an optimal choice for investigating efficacy of promising radiation countermeasures [28]
Summary
Terrorist attacks with radiological dispersal device (RDD) or improvised nuclear device (IND) weapons are an ever-growing worldwide concern in government and public sectors as they become more violent and more sensational. Some victims may be asymptomatic while others may exhibit mild to severe symptoms, resulting in death in some cases It is a challenging task for medical responders to triage ionizing radiation-exposed victims into definable, treatment-susceptible groups in a mass casualty scenario. Minimally-exposed (
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