Atm deficiency enhances the induction and persistence of Fe-ion-induced cytogenetic damage in mouse splenocytes

Abstract

High-charge and high-energy (HZE) particles, including iron (Fe) ions, are an important component of space-relevant radiation and induce complex DNA damage that can lead to genomic instability. Ataxia telangiectasia mutated (ATM) is a central DNA damage-response kinase, but the influence of Atm status on low-dose Fe-ion-induced cytogenetic damage in vivo remains unclear. In this study, Rosa26 direct-repeat GFP reporter mice carrying Atm+/+, Atm+/− or Atm−/− genotypes were exposed to 0 or 0.2 Gy Fe-ions (500 MeV/u; LET 200 keV/μm). Splenocytes were collected at 24 h and 30 days after irradiation and analysed for micronucleus formation and chromosomal aberrations using cytokinesis-block micronucleus assay, peptide nucleic acid-fluorescence in situ hybridization and multicolour fluorescence in situ hybridization. Fe-ion irradiation increased micronucleus frequencies in all genotypes at 24 h, with the most pronounced response in Atm−/− mice. At 30 days, micronuclei remained detectable, particularly in Atm−/− mice, indicating persistence of cytogenetic damage. Chromosomal aberration analysis showed a similar genotype-dependent pattern, with irradiated Atm−/− mice exhibiting markedly higher frequencies of breaks/fragments, dicentric chromosomes and fusion-type aberrations than Atm+/+ or Atm+/− mice. Although aberration frequencies declined between 24 h and 30 days, residual aberrations persisted in Atm−/− splenocytes. These findings demonstrate that ATM plays a critical role in suppressing both the induction and persistence of low-dose Fe-ion-induced genomic instability in vivo. The results also support the broader concept that genetic background and DNA damage-response capacity are important determinants of individual susceptibility to high-LET, space-relevant radiation.