Localized Synchrotron Irradiation of Mouse Skin Induces Persistent Systemic Genotoxic and Immune Responses

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-11, Vol.77 (22), p.6389-6399
• Main Authors: Ventura, Jessica, Lobachevsky, Pavel N, Palazzolo, Jason S, Forrester, Helen, Haynes, Nicole M, Ivashkevich, Alesia, Stevenson, Andrew W, Hall, Christopher J, Ntargaras, Andreas, Kotsaris, Vasilis, Pollakis, Gerasimos Ch, Potsi, Gianna, Skordylis, Konstantinos, Terzoudi, Georgia, Pateras, Ioannis S, Gorgoulis, Vassilis G, Georgakilas, Alexandros G, Sprung, Carl N, Martin, Olga A
• Format: Article
• Language: English
• Subjects: Animal tissues; Animals; Apoptosis; Apoptosis - genetics; Apoptosis - radiation effects; Biological effects; Cancer; Cell death; Cytokines - blood; Cytokines - metabolism; DNA Breaks, Double-Stranded - radiation effects; DNA damage; Dose-Response Relationship, Radiation; Double-strand break repair; Duodenum; Eotaxin; Exposure; Genotoxicity; Health risks; Immune response; Interleukin 1; Interleukin 10; Ionizing radiation; Irradiation; Lesions; Leukocytes (neutrophilic); Lymphocytes; Lymphocytes T; Macrophages; Macrophages - metabolism; Macrophages - radiation effects; Mice; Mice, Inbred C57BL; Radiation Injuries, Experimental - genetics; Radiation Injuries, Experimental - metabolism; Radiation Injuries, Experimental - prevention & control; Radiation therapy; Skin; Skin - immunology; Skin - metabolism; Skin - radiation effects; Synchrotron radiation; Synchrotrons; Time Factors; Tissue inhibitor of metalloproteinase 1; Transforming growth factor-b1; Vascular endothelial growth factor; X-Rays
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-1066

The importance of nontargeted (systemic) effects of ionizing radiation is attracting increasing attention. Exploiting synchrotron radiation generated by the Imaging and Medical Beamline at the Australian Synchrotron, we studied radiation-induced nontargeted effects in C57BL/6 mice. Mice were locally irradiated with a synchrotron X-ray broad beam and a multiplanar microbeam radiotherapy beam. To assess the influence of the beam configurations and variations in peak dose and irradiated area in the response of normal tissues outside the irradiated field at 1 and 4 days after irradiation, we monitored oxidatively induced clustered DNA lesions (OCDL), DNA double-strand breaks (DSB), apoptosis, and the local and systemic immune responses. All radiation settings induced pronounced persistent systemic effects in mice, which resulted from even short exposures of a small irradiated area. OCDLs were elevated in a wide variety of unirradiated normal tissues. In out-of-field duodenum, there was a trend for elevated apoptotic cell death under most irradiation conditions; however, DSBs were elevated only after exposure to lower doses. These genotoxic events were accompanied by changes in plasma concentrations of macrophage-derived cytokine, eotaxin, IL10, TIMP1, VEGF, TGFβ1, and TGFβ2, along with changes in tissues in frequencies of macrophages, neutrophils, and T lymphocytes. Overall, our findings have implications for the planning of therapeutic and diagnostic radiation treatments to reduce the risk of radiation-related adverse systemic effects. .