Chromosomal instability in unirradiated hemaopoietic cells induced by macrophages exposed in vivo to ionizing radiation.
The tumorigenic potential of ionizing radiation has conventionally been attributed to DNA damage in irradiated cells induced at the time of exposure. Recently, there have been an increasing number of reports of damage in unirradiated cells that are either neighbors or descendants of irradiated cells, respectively, regarded as bystander effects and genomic instability and collectively termed nontargeted effects. In this study, we show that descendants of normal murine hemaopoietic clonogenic stem cells exposed to bone marrow-conditioned medium derived from gamma-irradiated mice exhibit chromosomal instability unlike the descendants of directly gamma-irradiated cells. The instability is expressed in bone marrow cells of the radiation-induced acute myeloid leukemia (r-AML) susceptible strain (CBA/Ca) but not in mice resistant to r-AML (C57BL/6). Furthermore, crossgenetic experiments show the induction of the instability phenotype requires both the producer and responder cells to be of the susceptible CBA/Ca genotype. Macrophages are the source of the bystander signals, and the signaling mechanism involves tumor necrosis factor-alpha, nitric oxide, and superoxide. The findings show a genotype-dependent chromosomal instability phenotype induced by radiation-induced macrophage-mediated bystander signaling. As the majority of accidental, occupational, and therapeutic exposures to ionizing radiation are partial body exposures, the findings have implications for understanding the consequences of such exposure.
Lorimore
Sally A
SA
Division of Pathology and Neuroscience, Cancer Biology and Clinical Pathology Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, United Kingdom.
Chrystal
Jennifer A
JA
Robinson
Joanne I
JI
Coates
Philip J
PJ
Wright
Eric G
EG
D000818:Animals; D024201:Bystander Effect / Q000502:physiology / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects; D043171:Chromosomal Instability / Q000502:physiology* / Q000528:radiation effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism / Q000502:physiology* / Q000528:radiation effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008954:Models, Biological; D011839:Radiation, Ionizing; D014410:Tumor Stem Cell Assay
D017077:Culture Media, Conditioned