Chromosomal Instability in Unirradiated Hemopoietic Cells Resulting from a Delayed In vivo Bystander Effect of γ Radiation

Abstract

Untargeted effects of ionizing radiation (de novo effects in the unirradiated descendants or neighbors of irradiated cells) challenge widely held views about the mechanisms of radiationinduced DNA damage with implications for the health consequences of radiation exposures particularly in the context of the induction of malignancy. To investigate in vivo untargeted effects of sparsely ionizing (low linear energy transfer) radiation, a congenic sex-mismatch bone marrow transplantation protocol has been used to repopulate the hemopoietic system from a mixture of ;-irradiated and nonirradiated hemopoietic stem cells such that host-, irradiated donor-and unirradiated donor-derived cells can be distinguished. Chromosomal instability in the progeny of irradiated hemopoietic stem cells accompanied by a reduction in their contribution to the repopulated hemopoietic system is consistent with a delayed genomic instability phenotype being expressed in vivo. However, chromosomal instability was also shown in the progeny of the nonirradiated hemopoietic stem cells implicating a bystander mechanism. Studies of the influence of irradiated recipient stromal microenvironment and experiments replacing irradiated cells with irradiated cell-conditioned medium reveal the source of the in vivo bystander effect to be the descendants of irradiated cells, rather than irradiated cell themselves. Thus, it is possible that a radiation-induced genomic instability phenotype in vivo need not necessarily be a reflection of intrinsically unstable cells but the responses to ongoing production of inflammatory-type damaging signals as a long-term unexpected consequence of the initial single radiation exposure. (Cancer Res 2005; 65(13): 5668-73)

Indirect Macrophage Responses to Ionizing Radiation: Implications for Genotype-Dependent Bystander Signaling

“…Although macrophages do not respond to direct irradiation, their activities are altered in vivo after irradiation, with CBA/Ca hemopoietic tissues showing an M1-like phenotype that associates with potentially damaging inflammatory-type responses, compared with the induction of an anti-inflammatory phenotype and tissue reparative response seen in C57BL/6 tissues. These complex differences in macrophage function are likely to contribute to the medium and long-term outcomes of radiation exposure in the hemopoietic system by their involvement in the delayed and nontargeted effects exhibited in vivo (38)(39)(40). Importantly, a genotype-dependent, radiation-induced genomic instability phenotype in vivo need not necessarily be a reflection of intrinsically unstable cells but the responses to ongoing production of damage as a consequence of a persisting inflammatory-type response secondary to the initial radiationinduced injury.…”

Long-lived Inflammatory Signaling in Irradiated Bone Marrow Is Genome Dependent

“…However, a number of studies have shown damaging effects in nonirradiated cells as a consequence of communication between irradiated and nonirradiated cells and indicate additional mechanisms. The findings, generally termed nontargeted effects, are of 2 broad categories: effects in the unirradiated descendants of irradiated cells, collectively regarded as radiation-induced genomic instability and effects in unirradiated cells that have received signals produced by neighboring irradiated cells, collectively regarded as radiation-induced bystander effects (7)(8)(9)(10)(11)(12)(13)(14).…”

Heavy-Ion Microbeam Irradiation Induces Bystander Killing of Human Cells

“…Growing evidence indicates that the neighbors of surviving progeny exhibit bystander responses (Nagar & Morgan, 2005), and that the progeny of bystander cells show delayed phenotypes (Lorimore et al, 2005;Bowler et al, 2006). It is hence possible that death of plated bystander cells (e.g., via apoptosis as shown in Fig.…”