Abstract
BackgroundTissue response to irradiation is not easily recapitulated by cell culture studies. The objective of this investigation was to characterize, the transcriptional response and the onset of regenerative processes in mouse skin irradiated with different doses of fast neutrons.Methodology/Principal FindingsTo monitor general response to irradiation and individual animal to animal variation, we performed gene and protein expression analysis with both pooled and individual mouse samples. A high-throughput gene expression analysis, by DNA oligonucleotide microarray was done with three months old C57Bl/6 mice irradiated with 0.2 and 1 Gy of mono-energetic 14 MeV neutron compared to sham irradiated controls. The results on 440 irradiation modulated genes, partially validated by quantitative real time RT-PCR, showed a dose-dependent up-regulation of a sub-class of keratin and keratin associated proteins, and members of the S100 family of Ca2+-binding proteins. Immunohistochemistry confirmed mRNA expression data enabled mapping of protein expression. Interestingly, proteins up-regulated in thickening epidermis: keratin 6 and S100A8 showed the most significant up-regulation and the least mouse-to-mouse variation following 0.2 Gy irradiation, in a concerted effort toward skin tissue regeneration. Conversely, mice irradiated at 1 Gy showed most evidence of apoptosis (Caspase-3 and TUNEL staining) and most 8-oxo-G accumulation at 24 h post-irradiation. Moreover, no cell proliferation accompanied 1 Gy exposure as shown by Ki67 immunohistochemistry.Conclusions/SignificanceThe dose-dependent differential gene expression at the tissue level following in vivo exposure to neutron radiation is reminiscent of the onset of re-epithelialization and wound healing and depends on the proportion of cells carrying multiple chromosomal lesions in the entire tissue. Thus, this study presents in vivo evidence of a skin regenerative program exerted independently from DNA repair-associated pathways.
Highlights
Treatment of radiation injuries still represents an essential challenge based on the uncertainty of many aspects of the pathophysiology of the biological effects of the radiation
Skin three-dimensional systems increase the fidelity of the tissues stress response [37,53], transcriptome of such systems only partially overlap with human skin biopsy expression profiles; such systems never replicate great variation among individual responses to radiation which is not predictable [22,24,54]
Genes S100A8 and S100A9, frequently co-expressed and forming a heterodimer, belong to a multigenic and multifunctional family of calcium-binding proteins, that has been identified in several inflammatory skin conditions such as psoriasis, atopy, and cancer [56,57,58]
Summary
Treatment of radiation injuries still represents an essential challenge based on the uncertainty of many aspects of the pathophysiology of the biological effects of the radiation. Epidemiological evidence from human populations demonstrates that high LET doses above 50–100 mSv for protracted exposure, or 10–50 mSv for acute exposure, increases the risk of cancers [1,9,10]. While these facts already justify the efforts to gain knowledge on biological effects of high LET radiation there is a possibility for the therapeutic use of this type of radiation [11]. Tissue response to irradiation is not recapitulated by cell culture studies. The objective of this investigation was to characterize, the transcriptional response and the onset of regenerative processes in mouse skin irradiated with different doses of fast neutrons
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