Abstract
Exposure of the skin to ionizing radiation leads to characteristic reactions that will often turn into a pathophysiological process called the cutaneous radiation syndrome. The study of this disorder is crucial to finding diagnostic and prognostic bioindicators of local radiation exposure or radiation effects. It is known that irradiation alters the serum proteome content and potentially post-translationally modifies serum proteins. In this study, we investigated whether localized irradiation of the skin alters the serum glycome. Two-dimensional differential in-gel electrophoresis of serum proteins from a man and from mice exposed to ionizing radiation showed that potential post-translational modification changes occurred following irradiation. Using a large-scale quantitative mass-spectrometry-based glycomic approach, we performed a global analysis of glycan structures of serum proteins from non-irradiated and locally irradiated mice exposed to high doses of γ-rays (20, 40, and 80 Gy). Non-supervised descriptive statistical analyses (principal component analysis) using quantitative glycan structure data allowed us to discriminate between uninjured/slightly injured animals and animals that developed severe lesions. Decisional statistics showed that several glycan families were down-regulated whereas others increased, and that particular structures were statistically significantly changed in the serum of locally irradiated mice. The observed increases in multiantennary N-glycans and in outer branch fucosylation and sialylation were associated with the up-regulation of genes involved in glycosylation in the liver, which is the main producer of serum proteins, and with an increase in the key proinflammatory serum cytokines IL-1β, IL-6, and TNFα, which can regulate the expression of glycosylation genes. Our results suggest for the first time a role of serum protein glycosylation in response to irradiation. These protein-associated glycan structure changes might signal radiation exposure or effects.
Highlights
From the ‡Institut de Radioprotection et de Surete Nucleaire (IRSN), DRPH, SRBE, LRTE, 92260 Fontenay-aux-Roses, France; ¶Unitede Glycobiologie Structurale et Fonctionnelle, UMR8576, Universitedes Sciences et Techniques de Lille, 59655 Villeneuve D’Ascq, France; ʈInstitut de Radioprotection et de Surete Nucleaire (IRSN), DRPH, 92260 Fontenay-aux-Roses, France; **Hopital d’Instruction des Armees Percy, 92140 Clamart, France
Using two-dimensional differential in-gel electrophoresis (DIGE) coupled with mass spectrometry, we have shown that the serum proteome content is deeply altered from 1 day to 1 month following exposure of the skin to high doses of ionizing radiation [16]
Mass Spectrometry Glycan Profile Analysis—Because glycan moieties seemed to be important in explaining proteome changes during cutaneous radiation syndrome (CRS) in mice, we focused on the analysis of glycan modifications at day 14 post-irradiation
Summary
From the ‡Institut de Radioprotection et de Surete Nucleaire (IRSN), DRPH, SRBE, LRTE, 92260 Fontenay-aux-Roses, France; ¶Unitede Glycobiologie Structurale et Fonctionnelle, UMR8576, Universitedes Sciences et Techniques de Lille, 59655 Villeneuve D’Ascq, France; ʈInstitut de Radioprotection et de Surete Nucleaire (IRSN), DRPH, 92260 Fontenay-aux-Roses, France; **Hopital d’Instruction des Armees Percy, 92140 Clamart, France. Advanced techniques focusing on different cytogenetic, genetic, physical, and immunohistochemical parameters are used to estimate the dose received [6] These techniques are more appropriate for whole-body irradiation than for localized exposure, need to be performed by skilled people, and mostly are time consuming. New tools still have to be discovered to enable better prediction of the severity of localized injuries These markers will help clinicians make the right decisions in a timely manner and choose the most suitable therapeutic strategy. Cytokines play a role in mediating the inflammation process and stimulate or repress acute phase protein (APP) synthesis in the liver [15], assisting the repair of the tissue This inflammation process that occurs following localized radiation injury is a complex and in part specific mechanism that is only beginning to be elucidated. Investigations of the quantitative (expression levels) and qualitative (post-translational modifications) changes of blood proteins are crucial if we are to understand radiation-induced inflammation and discover new bioindicators of radiation exposure and radiation effects
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