A. Tsyb Medical Radiological Research Centre-Branch of the National Medical Research Radiological Centre of the Ministry of Health of the Russian Federation, Koroleva 4, Obninsk 249030, Russia.
State Research Center-Burnasyan Federal Medical Biophysical Center of Federal Medical Biological Agency, Moscow 123098, Russia.
Int J Mol Sci. 2019 May 29;20(11):2645. doi: 10.3390/ijms20112645.
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.
DNA 双链断裂（DSB）是电离辐射（IR）诱导的最有害的 DNA 损伤之一。尽管辐射诱导的 DSB 的诱导和修复在急性照射下得到了很好的研究，但对慢性 IR 暴露产生的 DSB 的反应知之甚少，尤其是在人类干细胞中。本研究旨在比较慢性γ辐射（0.1 mGy/min）与急性照射（30 mGy/min）在 30、100、160、240 和 300 mGy 累积剂量下对人骨髓间充质干细胞（MSCs）中 DSB 标志物（γH2AX 和磷酸化激酶 ATM、pATM 焦点）形成的影响。在急性照射后，观察到两种 γH2AX 和 pATM 焦点的数量以及共定位的 γH2AX/pATM 焦点（“真实”DSB）呈线性剂量依赖性增加。相比之下，MSCs 对慢性低剂量率 IR 暴露的反应偏离了线性，呈现出阈值模型，γH2AX、pATM 焦点和 γH2AX/pATM 焦点都呈现出“平台”。在长时间的慢性暴露期间，以低速率形成的新 DSB 与消除 DSB 的一部分之间达到平衡的状态，被提出作为低剂量率照射后非线性 DSB 反应的机制解释。这一概念得到了在暴露停止后 6 小时观察到大量 DSB 消除的支持。我们的结果表明，在慢性低剂量率 IR 暴露下，人 MSCs 中的 γH2AX 和 pATM 焦点表现出非线性剂量反应，并显示出存在阈值，这可能对人类的辐射防护具有意义。
