Abstract
DNA double-strand breaks (DSB) are among the most harmful DNA lesions induced by ionizing radiation (IR). Although the induction and repair of radiation-induced DSB is well studied for acute irradiation, responses to DSB produced by chronic IR exposures are poorly understood, especially in human stem cells. The aim of this study was to examine the formation of DSB markers (γH2AX and phosphorylated kinase ATM, pATM, foci) in human mesenchymal stem cells (MSCs) exposed to chronic gamma-radiation (0.1 mGy/min) in comparison with acute irradiation (30 mGy/min) at cumulative doses of 30, 100, 160, 240 and 300 mGy. A linear dose-dependent increase in the number of both γH2AX and pATM foci, as well as co-localized γH2AX/pATM foci (“true” DSB), were observed after an acute radiation exposure. In contrast, the response of MSCs to a chronic low dose-rate IR exposure deviated from linearity towards a threshold model, for γH2AX, pATM foci and γH2AX/pATM foci, with an indication of a “plateau”. The state of equilibrium between newly formed DSB at a low rate during the protracted exposure time and the elimination of a fraction of DSB is proposed as a mechanistic explanation of the non-linear DSB responses following a low dose-rate irradiation. This notion is supported by the observation of the elimination of a substantial fraction of DSB 6 h after the cessation of the exposures. Our results demonstrate non-linear dose responses for γH2AX and pATM foci in human MSCs exposed to low dose-rate IR and showed the existence of a threshold, which may have implications for radiation protection in humans.
Highlights
For the estimation of long-term stochastic radiation health effects, such as cancer, and for radiation protection purposes, a linear-non-threshold (LNT) model extrapolating the effects of high to low doses (≤100 mGy) is applied [1]
IInn ccoonnttrraasstt, lloowweerriinngg tthhee ddoossee rraattee aanndd pprroottrraaccttiinngg tthhee eexxppoossuurreewwoouullddaalllloowwffoorr mmuucchh more time for double-strand breaks (DSB) repair to complete the repair of slowly occurring DSB, so that by the time of the
The results of our study showing substantial differences in DNA damage dose-responses to chronic vs. acute irradiation are relevant to the ongoing controversy that surrounds the use of the LNT
Summary
For the estimation of long-term stochastic radiation health effects, such as cancer, and for radiation protection purposes, a linear-non-threshold (LNT) model extrapolating the effects of high to low doses (≤100 mGy) is applied [1]. The radiobiological effects and underlying mechanisms triggered by acute ionizing radiation (IR) exposures have been studied comprehensively. The effects of acute vs chronic IR exposure on the fundamental biological processes, such as DNA repair, cell death, epigenetic changes, carcinogenesis, and aging are the main source of the controversies. The efficiency and accuracy of DSB repair in somatic cells after acute and chronic IR exposures still remains contradictory [6,7]. Dose-rate influences the radiobiological effects and cancer risks [9], whether the efficiency and accuracy of DSB repair depends on dose-rate is still unclear
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