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

Radiother. Oncol. 137, 45-54 (2019)
DOI
Postprint online available 05/2020 Open Access Green as soon as is submitted to ZB.
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×/10×/15×/20×0.1 Gy) and dentate gyri from juvenile and adult mice were analyzed 72 h after last exposure and 1, 3, 6 months after 20 × 0.1 Gy. To examine the impact of LDR on neurogenesis, persistent DNA damage was assessed by quantifying 53BP1-foci within hippocampal neurons. Moreover, subpopulations of neuronal stem/progenitor cells were quantified and dendritic arborization of developing neurons were assessed. To unravel molecular mechanisms involved in radiation-induced neurotoxicity, hippocampi were analyzed using mass spectrometry-based proteomics and affected signaling networks were validated by immunoblotting. Results: Radiation-induced DNA damage accumulation leads to progressive decline of hippocampal neurogenesis with decreased numbers of stem/progenitor cells and reduced complexities of dendritic architectures, clearly more pronounced in repair-deficient mice. Proteome analysis revealed substantial changes in neurotrophic signaling, with strong suppression directly after LDR and compensatory upregulation later on to promote functional recovery. Conclusion: Hippocampal neurogenesis is highly sensitive to repetitive LDR. Even low doses affect signaling networks within the neurogenic niche and interrupt the dynamic process of generation and maturation of neuronal stem/progenitor cells.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Dna Damage Foci ; Dna Double-strand Breaks ; Hippocampus ; Low-dose Radiation ; Neurogenesis ; Normal Tissue Toxicity
Reviewing status