DNA damage accumulation during fractionated low-dose radiation compromises hippocampal neurogenesis.

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