Division of Radioprotectants, Department of Pharmacology and Molecular Therapeutics, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, 20814, USA.
Armed Forces Radiobiology Research Institute, Uniformed Services University of the Health Sciences, 4301, Jones Bridge Road, Bethesda, MD, 20814, USA.
Sci Rep. 2024 Oct 13;14(1):23930. doi: 10.1038/s41598-024-75225-3.
Exposure to ionizing radiation induces cellular and molecular damage leading to a cascade of events resulting in tissue and organ injury. Our study strives to characterize and validate metabolomic changes in preterminal stage (immediately prior to death) samples collected from rhesus macaques lethally irradiated with one of two different doses of radiation. Peripheral blood samples were collected pre-exposure, post-exposure, and at the preterminal stage of nonhuman primates (NHPs that did not survive exposure with 7.2 Gy or 7.6 Gy total-body radiation (LD)). We analyzed global metabolomic alterations using ultra-performance liquid chromatography (UPLC) quadrupole time-of-flight mass spectrometry (QTOF-MS) in serum samples collected at various timepoints in relation to radiation exposure. The goal of this study was to validate the metabolic shifts present in samples collected just prior to death, which were reported earlier in a preliminary study with a limited number of samples and a single dose of radiation. Here, we demonstrate that radiation exposure induced significant time-dependent metabolic alterations compared with pre-exposure samples. We observed significant metabolite dysregulation in animals exposed to 7.6 Gy compared to 7.2 Gy. Greater metabolic disruption was observed in the preterminal groups than all of the other post-irradiation timepoints in both cohorts. Metabolomic shifts in these preterminal groups also revealed consistent disturbances in sphingolipid metabolism, steroid hormone biosynthesis, and glycerophospholipid metabolism pathways. Overall, the sphingolipid metabolism pathway appears to be representative of the preterminal phenotype, confirming the results of our preliminary study. These results offer important and novel insights for identification and validation of biomarkers for lethality, and such observations would be valuable for triage during a radiological/nuclear mass casualty scenario.
接触电离辐射会导致细胞和分子损伤，从而引发一系列事件，导致组织和器官损伤。我们的研究旨在对恒河猴接受两种不同剂量辐射后致死前阶段（死亡前）采集的样本进行代谢组学特征描述和验证。采集恒河猴外周血样本，分别在照射前、照射后和非人类灵长类动物（未幸存于 7.2Gy 或 7.6Gy 全身照射（LD）的动物）致死前阶段采集。我们分析了用超高效液相色谱（UPLC）四极杆飞行时间质谱（QTOF-MS）检测的血清样本中的代谢组学变化，这些样本与辐射暴露的各个时间点相关。本研究的目的是验证之前在一项初步研究中报告的、在有限数量的样本和单次辐射剂量下采集的死亡前样本中存在的代谢变化。在这里，我们证明了与照射前样本相比，辐射暴露会引起明显的时间依赖性代谢改变。与 7.2Gy 相比，我们观察到暴露于 7.6Gy 的动物中有显著的代谢物失调。在两个队列中，与所有其他照射后时间点相比，致死前组观察到更大的代谢紊乱。这些致死前组的代谢组学变化还揭示了鞘脂代谢、类固醇激素生物合成和甘油磷脂代谢途径的一致紊乱。总体而言，鞘脂代谢途径似乎代表了致死前的表型，这证实了我们初步研究的结果。这些结果为致死性生物标志物的识别和验证提供了重要的新见解，并且在放射性/核大规模伤亡情况下的分诊中具有重要价值。
