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

Abstract

Ionizing radiation is carcinogenic, but genotype is a key determinant of susceptibility. Mutational DNA damage is generally attributed to cause disease, but irradiation also affects multicellular interactions as a result of poorly understood bystander effects that may influence carcinogenic susceptibility. In this study, we show that the bone marrow of irradiated mice will retain the ability to kill hemopoietic clonogenic stem cells and to induce chromosomal instability for up to 3 months after irradiation. Chromosomal instability was induced in bone marrow cells derived from CBA/Ca mice, a strain that is susceptible to radiation-induced acute myeloid leukemia (r-AML), but not in C57BL6 mice that are resistant to r-AML. Similarly, clonogenic cell lethality was exhibited in C57BL/6 mice but not CBA/Ca mice. Mechanistic investigations revealed that these genotype-dependent effects involved cytokinemediated signaling and were mediated by a cyclooxygenase-2-dependent mechanism. Thus, our results suggested that inflammatory processes were responsible for mediating and sustaining the durable effects of ionizing radiation observed on bone marrow cells. Because most exposures to ionizing radiation are directed to only part of the body, our findings imply that genotype-directed tissue responses may be important determinants of understanding the specific consequence of radiation exposure in different individuals. Cancer Res; 71(20); 6485-91. Ó2011 AACR.

Response to Baverstock, K. Comments on Rithidech, K.N.; et al. Lack of Genomic Instability in Bone Marrow Cells of SCID Mice Exposed Whole-Body to Low-Dose Radiation. Int. J. Environ. Res. Public Health 2013, 10, 1356–1377.

“…In contrast, the results from our studies demonstrated that a single dose of 0.1 or 1.0 Gy of 137 Cs γ rays was capable of inducing genomic instability in bone marrow cells of exposed SCID and BALB/cJ, but not C57BL/6J mice. These findings indicate an influence of genetic background on radiosensitivity as previously reported by several investigators [29,30,31,32,33], and an important role of DNA-PKcs in DNA repair. Further, our findings in the mouse models support the observations of the linear relationship for human cancer that appears to hold to a dose of 0.1 Gy as suggested by several investigators [34,35,36,37].…”

Transmission of Signals from Rats Receiving High Doses of Microbeam Radiation to Cage Mates: An Inter-Mammal Bystander Effect

“…In vivo manifestations mostly involve shielding part of the body while targeting another part (Pazzaglia et al, 2009, Koturbash et al, 2011 or use of parabiotic animals, one partner being shielded by lead while the unshielded partner is exposed to X-irradiation (Woenckhaus 1930) and as such are really abscopal rather than true bystander effects. Other approaches involve irradiation in vivo followed by in vitro culture (Lorimore et al, 2011, Mukherjee et al, 2012, Rastogi et al, 2012. The data reported here are from high dose exposed rats.…”

Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury

“…microRNA expression) were detected as early as several hours after whole body irradiation of mice, and persisted for days, weeks, and even months after irradiation [79]. Together, the changes due to radiation-induced chronic inflammation and perturbations in oxidative metabolism can lead to genomic instability in targeted and non-targeted cells [81], causing serious health effects, including neurodegeneration, cardiovascular diseases and cancer [82; 83; 84]. …”