title: Accumulation of DNA damage in complex normal tissues after protracted low-dose radiation.
abstract: The biological consequences of low levels of radiation exposure and their effects on human health are unclear. Ionizing radiation induces a variety of lesions of which DNA double-strand breaks (DSBs) are the most biologically significant, because unrepaired or misrepaired DSBs can lead to genomic instability and cell death. Using repair-proficient mice as an in vivo system we monitored the accumulation of DNA damage in normal tissues exposed to daily low-dose radiation of 100mGy or 10mGy. Radiation-induced foci in differentiated and tissue-specific stem cells were quantified by immunofluorescence microscopy after 2, 4, 6, 8, and 10 weeks of daily low-dose radiation and DNA lesions were characterized using transmission electron microscopy (TEM) combined with immunogold-labeling. In brain, long-living cortical neurons had a significant accumulation of foci with increasing cumulative doses. In intestine and skin, characterized by constant cell renewal of their epithelial lining, differentiated enterocytes and keratinocytes had either unchanged or only slightly increased foci levels during protracted low-dose radiation. Significantly, analysis of epidermal stem cells in skin revealed a constant increase of 53BP1 foci during the first weeks of low-dose radiation even with 10mGy, suggesting substantial accumulations of DSBs. However, TEM analysis suggests that these remaining 53BP1 foci, which are predominantly located in compact heterochromatin, do not co-localize with phosphorylated Ku70 or DNA-PKcs, core components of non-homologous end-joining. The biological relevance of these persistent 53BP1 foci, particularly their contribution to genomic instability by genetic and epigenetic alterations, has to be defined in future studies.
authors.affiliation: Department of Radiation Oncology, Saarland University, Homburg, Saar, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schanz
authors.forename: Nadine
authors.initials: N
authors.lastname: Schuler
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Lorat
authors.forename: Li
authors.initials: L
authors.lastname: Fan
authors.forename: Lars
authors.initials: L
authors.lastname: Kaestner
authors.forename: Gunther
authors.initials: G
authors.lastname: Wennemuth
authors.forename: Christian
authors.initials: C
authors.lastname: Rübe
authors.forename: Claudia E
authors.initials: CE
authors.lastname: Rübe
mesh_terms: D053687:Adult Stem Cells / Q000737:chemistry / Q000528:radiation effects; D000818:Animals; D034961:Antigens, Nuclear / Q000032:analysis; D001923:Brain Chemistry / Q000528:radiation effects; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D051747:DNA-Activated Protein Kinase / Q000032:analysis; D004268:DNA-Binding Proteins / Q000032:analysis; D004307:Dose-Response Relationship, Radiation; D020895:Enterocytes / Q000737:chemistry / Q000528:radiation effects; D005720:Gamma Rays; D007422:Intestines / Q000737:chemistry / Q000528:radiation effects; D015603:Keratinocytes / Q000737:chemistry / Q000528:radiation effects; D000072200:Ku Autoantigen; D051379:Mice; D008810:Mice, Inbred C57BL; D046529:Microscopy, Electron, Transmission; D009474:Neurons / Q000737:chemistry / Q000528:radiation effects; D009687:Nuclear Proteins / Q000032:analysis; D012867:Skin / Q000737:chemistry / Q000528:radiation effects; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D034961:Antigens, Nuclear; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse; C000606509:Xrcc6 protein, human; C000606510:Xrcc6 protein, mouse; D000072200:Ku Autoantigen