Abstract
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.
Highlights
Cognitive impairments due to radiation treatment for cancers of the central nervous system (CNS) are well documented[1,2]
We identified a drastic increase in the concentration of systemic Extracellular vesicles (EVs) derived from irradiated mice two days post-irradiation (Supplementary Fig. S1)
We have previously shown that cranial irradiation results in gross structural and functional changes in the brain that manifest over time
Summary
Cognitive impairments due to radiation treatment for cancers of the central nervous system (CNS) are well documented[1,2]. Changes in inflammation and oxidative stress follow cyclical patterns over protracted irradiation intervals, complicating predictive assessments of underlying biology, including efforts to identify circulating biomarkers specific to target tissues and constitutive cell types. We have recently reported on increased endoplasmic reticulum (ER) stress in the hippocampal tissue of this same cohort of mice, as early as two days post-exposure[31] In this follow-up study, we employed a combination of UPLC-MS, UPLC-MS/MS and GC-MS to characterize the metabolomic and lipidomic profiles of plasma and plasma-derived EVs in these mice. Whole plasma profiling yielded complementary information where we observed significant systemic down-regulation of β-hydroxybutyric acid, a neuroprotectant[32,33] and anti-inflammatory molecule[34] Taken together, these results demonstrate the utility of profiling EVs from peripheral blood in the context of cranial irradiation for early identification of normal tissue injury
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