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

Abstract

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. .

Conditioning attenuates kidney and heart injury in rats following transient suprarenal occlusion of the abdominal aorta

“…In a similar manner, free radicals have a bivalent nature in IC; excess levels of ROS cause tissue damage, whereas small amounts protect cellular functions 50 . To this end, the IRI biology is highly reminiscent of the complexities in radiation-induced bystander/distant effect biology 34 . Within this frame, a systemic response has been depicted in out-of-field tissues upon irradiation verified by γH2AX foci suggesting DNA damage.…”

“…Within this frame, a systemic response has been depicted in out-of-field tissues upon irradiation verified by γH2AX foci suggesting DNA damage. A hint for the underlying mechanism comes from the elevated circulating levels of certain cytokines including TGF-β1, which may play a role as mediators of non-targeted effects by promoting oxidative DNA damage at distant sites 34 .…”

“…2b). Additionally, prompted by previous findings linking Monocyte Chemoattractant Protein 1 (MCP-1) [alternatively knows as chemokine (C-C) ligand 2 (CCL2)] with DNA damage in out-of-field tissues following irradiation 34 , we examined the status of MCP-1/CCL2 in our setting but found no differences among the conditioned and unconditioned groups ( Supplementary Fig. 2c).…”

In Vivo Irradiation of Mice Induces Activation of Dendritic Cells

“…Doses up to 0.1 Gy can be acquired during medical-diagnostic procedures employing radiation exposure (i.e., whole-body CT scans, positron-emission tomography, or interventional radiology). Although local- or partial-body irradiation is generally used in clinical situations, it has been shown by Ventura et al that even local irradiation can elicit systemic immune responses and can modulate DC function at systemic level [49]. …”

Cancer Radiotherapy: Understanding the Price of Tumor Eradication

“…The defined geometry and coherence of the synchrotron beam delivers IR to small volumes with lower scatter, and the high dose rate (up to >1,000 Gy/sec) minimizes motion artifacts, but also introduces the "FLASH" effect (Durante et al, 2018). Ventura et al (2017) reported that that various synchrotron settings (IR dose, volume, beam modality) trigger similar systemic effects in normal mouse tissues of wild-type C57BL/6 mice. Depending on the level of scatter radiation (Lobachevsky et al, 2015b), these effects were attributed to either true abscopal signaling, or to direct low-dose scatter radiation.…”