Radiation-induced bystander effects in vivo are sex specific.

Ionizing radiation (IR) effects span beyond the area of direct exposure and can be observed in neighboring and distant naïve cells and organs. This phenomenon is termed a 'bystander effect'. IR effects in directly exposed tissue in vivo are epigenetically mediated and distinct in males and females. Yet, IR-induced bystander effects have never been explored in a sex-specificity domain. We used an in vivo mouse model, whereby the bystander effects are studied in spleen of male and female animals subjected to head exposure when the rest of the body is protected by a medical-grade lead shield. We analyzed the induction of DNA damage and alterations in global DNA methylation. Molecular parameters were correlated with cellular proliferation and apoptosis levels. The changes observed in bystander organs are compared to the changes in unexposed animals and animals exposed to predicted and measured scatter doses. We have found the selective induction of DNA damage levels, global DNA methylation, cell proliferation and apoptosis in exposed and bystander spleen tissue of male and female mice. Sex differences were significantly diminished in animals subjected to a surgical removal of gonads. These data constitute the first evidence of sex differences in radiation-induced bystander effects in mouse spleen in vivo. We show the role of sex hormones in spleen bystander responses and discuss implications of the observed changes.

Fractionated low-dose exposure to ionizing radiation leads to DNA damage, epigenetic dysregulation, and behavioral impairment.

Studies of Fractionated Exposure to Low Doses of Ionizing Radiation (FELDIR) has become of increasing importance to clinical interventions. Its consequences on DNA damage, physical, and mental health have been insufficiently investigated, however. The goal of this study was to determine the effects of FELDIR on the brain using a mouse model. We addressed the levels of DNA damage, global genomic methylation, and DNA methylation machinery in cerebellum, frontal lobe, olfactory bulb and hippocampal tissues, as well as behavioral changes linked to FELDIR exposure. The results reveal increased levels of DNA damage, as reflected by increased occurrence of DNA Strand Breaks (SBs) and dysregulation of stress-response kinase p38. FELDIR also resulted in initial loss of global genomic methylation and altered expression of methyltransferases DNMT1 (down-regulation) and DNMT3a (up-regulation), as well as methyl-binding protein MeCP2 (up-regulation). FELDIR-associated behavioral changes included impaired skilled limb placement on a ladder rung task, increased rearing activity in an open field, and elevated anxiety-like behaviors. The said alterations showed significant dose and tissue specificity. Thus, FELDIR represents a critical impact on DNA integrity and behavioral outcomes that need to be considered in the design of clinical intervention studies.