Chromosomal Instability in Unirradiated Hemaopoietic Cells Induced by Macrophages Exposed In vivo to Ionizing Radiation

Abstract

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 marrowconditioned medium derived from ;-irradiated mice exhibit chromosomal instability unlike the descendants of directly ;-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-A, nitric oxide, and superoxide. The findings show a genotypedependent 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.

Cell intrinsic and extrinsic factors synergize in mice with haploinsufficiency for Tp53, and two human del(5q) genes, Egr1 and Apc

“…We speculate that irradiation of recipient mice may have been responsible for the faster rate of anemia development, as ionizing radiation induces multiple changes in the BM stromal cell compartment. [35][36][37] For example, irradiated mesenchymal stromal cells have a high DNA double-strand break repair capacity, allowing them to survive radiation treatment and produce factors, such as tumor necrosis factor-a, transforming growth factor-b, and IL-6, cytokines known to influence the development of MDS and AML. 38,39 Because MDS patients with a del(5q) have a loss of EGR1 and APC in hematopoietic cells, we also tested whether transplantation of ) caused a deleterious phenotype; however, none of these mice showed defects in erythropoiesis or red blood cell production or other hematopoietic defects (supplementary Figure 5).…”

The effect of genetic background and dose on non-targeted effects of radiation

“…Indeed, TGF-β1 association in inter-cellular signalling has been described previously (Shao et al 2008), where it was demonstrated that TGF-β induced Ca Conversely, TNF-α is a pro-inflammatory cytokine, able to induce DNA damage (Fehsel et al 1991), and is also involved in other signalling pathways. TNF-α has been implicated in bystander signalling, when anti-TNF-α, (and dimethyl sulfoxide (DMSO)and 2-(4-Carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO)) were added to media from 4 Gy gamma whole body irradiated CBA and C57 incubated for 1h and placed onto fresh cells, a decrease in the chromosomal damage manifested in bystander cells was observed (Lorimore et al 2008), with no cross-signalling between C57 and CBA. In vivo production of TNF-α (and other cytokines) by peritoneal macrophages and splenocytes after whole body irradiation of BALB/c mice with single low doses of 0.1 or 0.2 Gy Xray has previously been shown (Cheda et al 2008).…”

“…Cytokines are involved in a range of cellular regulating pathways, and it is known that tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) levels are reported to change in response to irradiation (Facoetti et al 2006, Lorimore et al 2008, Burr et al 2010. TNF-α is involved in inflammatory responses, activating nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), mitogen-activated protein kinases (MAPK) pathways and apoptotic pathways.…”

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

“…Activation of, and interaction of, multiple signaling pathways has been shown to occur after exposure of cells to ionizing radiation (27) resulting in transcriptional induction of genes encoding inflammatory and immunomodulatory factors (28). Previous studies implicated proinflammatory cytokine signaling with the in vivo chromosomal instability phenotype (29) and involvement of COX-2 in cell line bystander responses in vitro (30). This study showed that both the nontargeted reduction in CFE and the chromosomal instability phenotype in bone marrow cells are mediated by signals converging on COX-2, the initial and rate-limiting enzymatic step in the metabolism of arachidonic acid to prostaglandins, which play important roles in modulating inflammatory processes (31)(32)(33).…”