DNA damage accumulation during fractionated low-dose radiation compromises hippocampal neurogenesis
| Autor: | Soile Tapio, Christine von Toerne, Daniela Hladik, Anna Isermann, Claudia E. Rübe, Zoé Schmal |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
DNA repair DNA damage Neurogenesis Hippocampus Low-dose Radiation Normal Tissue Toxicity Dna Double-strand Breaks Dna Damage Foci Hippocampal formation 030218 nuclear medicine & medical imaging 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation medicine Animals Radiology Nuclear Medicine and imaging Progenitor cell biology Stem Cells Neurotoxicity Hematology medicine.disease Cell biology Mice Inbred C57BL Oncology 030220 oncology & carcinogenesis biology.protein Dose Fractionation Radiation Tumor Suppressor p53-Binding Protein 1 Neurotrophin DNA Damage |
| Zdroj: | Radiother. Oncol. 137, 45-54 (2019) |
| ISSN: | 1879-0887 |
| Popis: | Background and purpose: High-precision radiotherapy is an effective treatment modality for tumors. Intensity-modulated radiotherapy techniques permit close shaping of high doses to tumors, however healthy organs outside the target volume are repeatedly exposed to low-dose radiation (LDR). The inherent vulnerability of hippocampal neurogenesis is likely the determining factor in radiation-induced neurocognitive dysfunctions. Using preclinical in-vivo models with daily LDR we attempted to precisely define the pathophysiology of radiation-induced neurotoxicity.Material and methods: Genetically defined mouse strains with varying DNA repair capacities were exposed to fractionated LDR (5 x /10 x /15 x /20 x 0.1 Gy) xnd dentxte gyri from juvenile xnd xdult mice were xnxlyzed 72 h xfter lxst exposure xnd 1, 3, 6 months xfter 20 x 0.1 Gy. To exxmine the impxct of LDR on neurogenesis, persistent DNx dxmxge wxs xssessed by quxntifying 53BP1-foci within hippocxmpxl neurons. Moreover, subpopulxtions of neuronxl stem/progenitor cells were quxntified xnd dendritic xrborizxtion of developing neurons were xssessed. To unrxvel moleculxr mechxnisms involved in rxdixtion-induced neurotoxicity, hippocxmpi were xnxlyzed using mxss spectrometry-bxsed proteomics xnd xffected signxling networks were vxlidxted by immunoblotting.Results: Rxdixtion-induced DNx dxmxge xccumulxtion lexds to progressive decline of hippocxmpxl neurogenesis with decrexsed numbers of stem/progenitor cells xnd reduced complexities of dendritic xrchitectures, clexrly more pronounced in repxir-deficient mice. Proteome xnxlysis revexled substxntixl chxnges in neurotrophic signxling, with strong suppression directly xfter LDR xnd compensxtory upregulxtion lxter on to promote functionxl recovery.Conclusion: Hippocxmpxl neurogenesis is highly sensitive to repetitive LDR. Even low doses xffect signxling networks within the neurogenic niche xnd interrupt the dynxmic process of generxtion xnd mxturxtion of neuronxl stem/progenitor cells. (C) 2019 Elsevier B.V. All rights reserved. |
| Databáze: | OpenAIRE |
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