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This report tests the hypotheses that cancer proneness elevates risk from a high radiation exposure and that the risk response to high doses is qualitatively similar to that from low doses. Groups of about 170 female mice heterozygous for Trp53 (Trp53(+/-)) and their normal female littermates (Trp53(+/+)) were exposed at 7-8 weeks of age to (60)Co...
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Women with familial or genetic aggregation of breast cancer are offered screening outside the population screening programme. However, the possible benefit of mammography screening could be reduced due to the risk of radiation-induced tumours. A systematic search was conducted addressing the question of how low-dose radiation exposure affects breas...
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Citations
... We first found that the life-elongation effects of LDR in young C57BL/6 mice disappeared in middle-aged C57BL/6 mice (0.02 + 3 Gy vs. 3 Gy in Fig. 2) at the organismal level (Fig. 9, right). Although the Kaplan-Meier survival curves in this study were consistent with previously reported Kaplan-Meier survival curves during the adaptive response [33][34][35] , a limitation of this study was the lack of detailed pathological diagnoses in all mice. The shorter mean lifespan of the controls in experiment 1 (103.6 ± 31.9) compared to that of the controls in experiment 2 (113.9 ± 24.9) may have been due to an experimental bias in selecting mice that survived to at least 40-62 weeks of age, as the mice in experiment 2 were irradiated at 40-62 weeks of age (Fig. 2). ...
Understanding the biological effects of low-dose (<100 mGy) ionizing radiation (LDR) is technically challenging. We investigated age-dependent LDR effects using adaptive response experiments in young (7-to 12-week-old) and middle-aged (40-to 62-week-old) C57BL/6 mice. Compared with 3 Gy irradiation, 0.02 Gy preirradiation followed by 3 Gy irradiation prolonged life in young mice but not middle-aged mice. Preirradiation also suppressed irradiation-induced 53BP1 repair foci in the small intestines, splenic apoptosis, and p53 activity in young mice but not middle-aged mice. Young p53 +/− C57BL/6 mice did not show these adaptive responses, indicating that insufficient p53 function in young mice mitigated the adaptive responses. Interestingly, p53 activation in middle-aged mice spontaneously became approximately 4.5-fold greater than that in young mice, possibly masking LDR stresses. Furthermore, adaptive responses in young mice, but not in middle-aged mice, suppressed some senescence-associated secretory phenotype (SASP) factors ( IL-6, CCL2 , CCL5 , CXCL1 ). Thus, LDR-induced adaptive responses associated with specific SASP factors may be attenuated by a combination of reduced DNA damage sensor/transducer function and chronic p53 activation in middle-aged mice.
... Transformation-related protein 53 (Trp53) knockout mice used in other studies, exon 2 -6 has been replaced by the neo gene insert [144][145][146] . Also in Tp53 tm1[EGFP-pac] rats, exon 2 -5 fragment of Tp53 gene is replaced by a reporter gene cassette 147 . ...
Introduction: Intensity-modulated radiotherapy (IMRT) involves exposure of large volumes of healthy tissue to a low-dose. This is thought to increase the risk of a radiation-induced second cancer (SC) compared to 3D-conformal radiotherapy (3D-CRT). As a consequence, patients with radiotherapy curable diseases such as pediatric and juvenile Hodgkin's Lymphoma (HL) are not treated with IMRT techniques thereby accepting high(er) doses to the heart and breast. The purpose was to test this dogma in cancer-susceptible rats irradiated either with a highly conformal volumetric-modulated arc therapy (VMAT, a rotational IMRT) or a conventional 3D-CRT in form of two opposite anterior-posterior / posterior-anterior (AP/PA) technique. Methods: Heterozygous Tumor protein 53 knockout rats belonging to four treatment groups of n = 15 animals each were irradiated with either 3×5 Gy or 3×8 Gy doses delivered with VMAT or AP/PA to a mediastinal planning target volume (PTV). Two control groups were given anesthesia only (AN, n = 15) or anesthesia with additional cone-beam computed tomography (CBCT) scanning (CBCT, n = 15). Animals were followed up to tumor detection using high-resolution CT. Tumors were scored according to the volume in which they occurred: low dose volume (LDV, receiving lower than 50% of target doses), bordering high dose volume (BHDV, 50% - 90%), high dose volume (HDV, > 90%) or non-irradiated volume (NIRV). Tumor and healthy tissues were characterized by histology. The analysis of loss of heterozygosity (LOH) of Tp53, were performed using Polymerase Chain Reaction (PCR) and sequencing. Tumor development after VMAT vs. AP/PA compared using Fisher’s exact test, Kaplan-Meier analysis, and the Mann-Whitney test (α < 0.05). Results: In 84/90 animals, at least one tumor was detected, while six were lost due to other causes. In AN- and CBCT- control groups, all tumors were found in the body volumes corresponding to the NIRV of irradiated animals. By contrast (p = 0.0001), in the irradiated groups, 17/29 (after 3×5 Gy) and 16/28 (after 3×8 Gy) of all tumors were found in the volumes exposed to doses 0.75 – 24 Gy. The majority (23/33) of these irradiated volume-associated tumors were found inside the HDV, whereas only n = 3 tumors were detected in the BHDV and n = 7 in the LDV (combined 3×5 Gy and 3×8 Gy groups). Notably, no increased tumor induction was observed in the volume irradiated with VMAT compared to AP/PA (14/28 vs. 19/29, p = 0.44). The attained age from birth, for control rat groups and groups treated with 3×5 Gy were similar, while decreased significantly in 3×8 Gy VMAT (p = 0.02) and AP/PA (p = 0.0005) due to earlier tumor appearance compared to controls. A maximum decrease in time to tumor (TTT), from treatment to appearance, compared to AN/CBCT revealed for tumors within the BHDV/HDV after 3×8 Gy treatment (p < 0.0001). All lymphomas and most soft tissue sarcomas were specifically developed in the irradiated volume without regard to radiation doses and techniques. LOH was not significantly specific for tumors in the irradiated volume or for the shortening of the TTT, and no inflammatory background in irradiated rat lungs was observed. Conclusions: The present results do not support the hypothesis that the enlarged low-dose volume generated in highly conformal radiotherapy techniques is associated with a higher SC risk. In contrast, the results show that higher local doses to normal tissue can accelerate the development of radiation-associated lymphoma and sarcoma, regardless of the RT technique used, LOH in tumors, or an inflammatory background in the lungs.
... We irradiated mice with 1 and 3 Gy of X-rays and measured blood cell metabolites after 2 and 6 days. The threshold dose for mortality in human adults exposed acutely to ionizing radiation has been reported as 1 Gy [28], and exposure to 3 Gy has been shown to shorten lifespan in C57BL/6 mice [29]. The recommended time frame for performing biodosimetry assays and triage is within 2 days of exposure for individuals with physical injuries and within 6 days for 1,000,000 victims [30], guiding our choice of doses and measurement points. ...
Biodosimetry is a useful method for estimating personal exposure doses to ionizing radiation. Studies have identified metabolites in non-cellular biofluids that can be used as markers in biodosimetry. Levels of metabolites in blood cells may reflect health status or environmental stresses differentially. Here, we report changes in the levels of murine blood cell metabolites following exposure to X-rays in vivo. Levels of blood cell metabolites were measured by capillary electrophoresis time-of-flight mass spectrometry. The levels of 100 metabolites were altered substantially following exposure. We identified 2-aminobutyric acid, 2-deoxycytidine, and choline as potentially useful markers of radiation exposure and established a potential prediction panel of the exposure dose using stepwise regression. Levels of blood cell metabolites may be useful biomarkers in estimating exposure doses during unexpected radiation incidents.
... A reduced latency time for radiation-associated tumors was statistically significant only after 3 × 8 Gy but the fact that tumors also appeared in the irradiated volume after 3 × 5 Gy before spontaneous tumors developed in the NIRV suggests a minor latency shortening. These results extend earlier findings of shortened tumor latency after whole-body irradiation of mice with 1-4 Gy which may be related to induction of an inflammatory microenvironment [23][24][25] . However, in the present system, the rate of inflammatory foci in the irradiated lungs (largely in the LDV) was not increased and even showed a trend for a decrease after irradiation. ...
A long-standing hypothesis in radiotherapy is that intensity-modulated radiotherapy (IMRT) increases the risk of second cancer due to low-dose exposure of large volumes of normal tissue. Therefore, young patients are still treated with conventional techniques rather than with modern IMRT. We challenged this hypothesis in first-of-its-kind experiments using an animal model. Cancer-prone Tp53+/C273X knockout rats received mediastinal irradiation with 3 × 5 or 3 × 8 Gy using volumetric-modulated arc therapy (VMAT, an advanced IMRT) or conventional anterior-posterior/posterior-anterior (AP/PA) beams using non-irradiated rats as controls (n = 15/group, ntotal = 90). Tumors were assigned to volumes receiving 90–107%, 50–90%, 5–50%, and <5% of the target dose and characterized by histology and loss-of-heterozygosity (LOH). Irradiated rats predominantly developed lymphomas and sarcomas in areas receiving 50–107% (n = 26) rather than 5–50% (n = 7) of the target dose. Latency was significantly shortened only after 3 × 8 Gy vs. controls (p < 0.0001). The frequency (14/28 vs. 19/29; p = 0.29) and latency (218 vs. 189 days; p = 0.17) of radiation-associated tumors were similar after VMAT vs. AP/PA. LOH was strongly associated with sarcoma but not with treatment. The results do not support the hypothesis that IMRT increases the risk of second cancer. Thus the current practice of withholding dose-sparing IMRT from young patients may need to be re-evaluated.
... The foundation of radiation risk study calculations is based on the linear no-threshold (LNT) hypothesis, a linear extrapolation of data from high doses that asserts that exposure to any radiation dose, no matter how low, increases cancer risk (5,6). While it has been established that exposure to large doses of ionizing radiation decreases survival in many organisms (7)(8)(9)(10), the LNT hypothesis has been invalidated as viable model to predict biological effects of radiation doses below 500 mGy (11,12). At low-dose and low-doserate exposures, the biological response to low-dose radiation is not linear, primarily because of the induction of protective mechanisms, which increase high-fidelity DNA repair (13)(14)(15), improve immune surveillance (16,17) and increase endogenous antioxidant systems (18)(19)(20)(21). ...
... Numerous radiation exposure and longevity studies involving both animals and humans have been published, which support the notion of beneficial effects of low-dose radiation for cancer and other disease end points (12,22). Recently, it has been reported that in Trp53 þ/female mice, the life-shortening effect of acute radiation exposure is 38.9 6 1.9 days per Gy (10). Applying the LNT hypothesis, the life-shortening effect from a 10 mGy exposure would be less than a day. ...
... James et al. reported that mice exposed to doses between 5 and 40 mGy/day increased proliferation of splenic T cells (57). More recently, Ina et al. demonstrated that chronic lifetime exposure to c radiation in immunecompromised MRL-lpr/lpr mice significantly increased lifespan, relative to unirradiated controls (10). The prolongation in lifespan was associated with radiation-induced immunological modifications that ameliorated the ensuing autoimmune diseases (27,29). ...
There is growing concern over the effects of medical diagnostic procedures on cancer risk. Although numerous studies have demonstrated that low doses of ionizing radiation can have protective effects including reduced cancer risk and increasing lifespan, the hypothesis that any radiation exposure increases cancer risk still predominates. In this study, we investigated cancer development and longevity of cancer-prone Trp53(+/-) mice exposed at 7-8 weeks of age to a single 10 mGy dose from either a diagnostic CT scan or gamma radiation. Mice were monitored daily for adverse health conditions until they reached end point. Although the median lifespan of irradiated mice was extended compared to control animals, only CT scanned mice lived significantly longer than control mice (P < 0.004). There were no differences in the frequency of malignant cancers between the irradiated and control groups. Exposure to a single CT scan caused a significant increase in the latency of sarcoma and carcinoma (P < 0.05), accounting for the increased lifespan. This study demonstrates that low-dose exposure, specifically a single 10 mGy CT scan, can prolong lifespan by increasing cancer latency in cancer-prone Trp53(+/-) mice. The data from this investigation add to the large body of evidence, which shows that risk does not increase linearly with radiation dose in the low-dose range.
... Cells deficient in p53 protein have abrogated cell cycle arrest and reduced p53-dependent apoptosis (Livingstone et al. 1992, Muller andVousden 2013). In vivo, reduced levels of functional p53 protein in heterozygous (Trp53+/-) mice results in decreased survival and a shorter tumour latency period in Trp53+/-mice relative to wild-type mice , Carlisle et al. 2010. Null mice (Trp53-/-) develop tumours earlier than heterozygotes, with a correspondingly shorter lifespan (Donehower and Lozano 2009). ...
Apoptotic and DNA damage endpoints are frequently used as surrogate markers of cancer risk, and have been well-studied in the Trp53+/- mouse model. We report the effect of differing Trp53 gene status on the dose response of ionizing radiation exposures (0.01-2 Gy), with the unique perspective of determining if effects of gene status remain at extended time points. Here we report no difference in the dose response for radiation-induced DNA double-strand breaks in bone marrow and genomic instability (MN-RET levels) in peripheral blood, between wild-type (Trp53+/+) and heterozygous (Trp53+/-) mice. The dose response for Trp53+/+ mice showed higher initial levels of radiation-induced lymphocyte apoptosis relative to Trp53+/- between 0 and 1 Gy. Although this trend was observed up to 12 hours post-irradiation, both genotypes ultimately reached the same level of apoptosis at 14 hours, suggesting the importance of late-onset p53-independent apoptotic responses in this mouse model. Expected radiation-induced G1 cell cycle delay was observed in Trp53+/+ but not Trp53+/-. Although p53 has an important role in cancer risk, we have shown its influence on radiation dose response can be temporally variable. This research highlights the importance of caution when using haematopoietic endpoints as surrogates to extrapolate radiation-induced cancer risk estimation.
... Differences are found not only in the survival-dose LD50 but also in the length of survival under repeated radiation exposures. [100]. ...
... When looking for mouse test results that can provide meaningful information for resettlement of the Fukushima evacuees, the author focused on the life span test under chronic-or at least multiple irradiations at low dose rates. With mutational anomalies, radiation exposure promotes the generation and retention of tumors under certain conditions [100]. ...
In nuclear safety, the source term is introduced to provide adequate isolation of the nuclear hazards from the public, by establishing a concept of ‘effective distance.’ This combines a geographical distance to the site boundary and an effective ‘distance’ with the use of engineered safety features (i.e., a containment system and its cooling system), combined with evacuation procedures to prevent radiation injury. Severe accidents occur when these safety systems failed to function. This basic safety approach was once again jeopardized by the Fukushima accident, which followed the Chernobyl accident. The factors that mitigated the effluent releases however depend greatly on the intrinsic safety features combined with the accident management. The multi-layered retention/decontamination factors that a nuclear power plant possesses should be incorporated in specifying the environmental source term. The Fukushima accident provides a reasonable upper bound with respect to environmental releases due to a LUHS (loss of ultimate heat sink), which triggered a prolonged SBO (station blackout).
Due to the anticipated radiological consequences, the Japanese Government issued a series of evacuation orders, resulting in the evacuation of approximately 160,000 people from the Fukushima area. The prolonged evacuation is believed to be the cause of over one thousand “disaster-related (pre-mature) deaths (DRDs)” which have been reported among the evacuees due to psychosomatic effects (48%) and the disruption of medical and social welfare facilities (18%). In the future these types of deaths should be avoided.
... In a similar way, these SNPs may additionally be expected to influence other human diseases impacted by p53 functionality, such as atherosclerosis. In terms of radiation protection, it is therefore important to know if the presence of reduced p53 functionality may alter the risk of either cancer or noncancer diseases (21)(22)(23)(24)(25)(26)(27) including atherosclerosis, in persons exposed to either high or low doses of radiation. ...
We recently described the effects of low-dose γ-radiation exposures on atherosclerosis in genetically susceptible (ApoE–/–) mice with normal p53 function. Doses as low as 25 mGy, given at either early or late stage disease, generally protected against atherosclerosis in a manner distinctly nonlinear with dose. We now report the influence of low doses (25–500 mGy) on atherosclerosis in ApoE–/– mice with reduced p53 function (Trp53+/–). Single exposures were given at either low or high dose rate (1 or 150 mGy/min) to female C57BL/6J ApoE–/– Trp53+/– mice. Mice were exposed at either early stage disease (2 months of age) and examined 3 or 6 months later, or at late stage disease (7 months of age) and examined 2 or 4 months later. In unirradiated mice, reduced p53 functionality elevated serum cholesterol and accelerated both aortic root lesion growth and severity in young mice. Radiation exposure to doses as low as 25 mGy at early stage disease, at either the high or the low dose rate, inhibited lesion growth, decreased lesion frequency and slowed the progression of lesion severity in the aortic root. In contrast, exposure at late stage disease produced generally detrimental effects. Both low-and high-dose-rate exposures accelerated lesion growth and high dose rate exposures also increased serum cholesterol levels. These results show that at early stage disease, reduced p53 function does not influence the protective effects against atherosclerosis of low doses given at low dose rate. In contrast, when exposed to the same doses at late stage disease, reduced p53 function produced detrimental effects, rather than the protective effects seen in Trp53 normal mice. As in the Trp53 normal mice, all effects were highly nonlinear with dose. These results indicate that variations in p53 functionality can dramatically alter the outcome of a low-dose exposure, and that the assumption of a linear response with dose for human populations is probably unwarranted.
... Post-irradiation nephritis or nephrosclerosis was common in mice receiving more than 4 Gy (Upton et al. 1960). Different authors also showed malignant tumours as a cause of delayed lethality in irradiated mice (Sasaki 1991; Maisin et al. 1996; Carlisle et al. 2010). Incidence of all malignant tumours increased significantly at an X-ray dose of 1.5 Gy (Mori-Chavez et al. 1970). ...
In the work presented here, changes in haematopoiesis of mice (B6129SF2/J) were studied 1 year after their whole-body exposure to a dose of 7 Gy (72% of mice survived). The irradiated mice were compared with non-irradiated younger (4 months of age) and older (16 months of age) mice. There was a significant increase in the relative abundance of primitive stem cells with long-term capability of the haematopoiesis recovery lin(-)/Sca-1(+)/CD117(+)/CD34(-) in the bone marrow of mice aged 16 months (irradiated and non-irradiated) compared with those aged 4 months. In terms of the ability to respond to further whole-body irradiation at a dose of 1 Gy, the presence of γH2A.X foci was studied in lin(-) bone marrow cells. There was a considerable number of persisting foci in lin(-) stem cells isolated from the bone marrow of the older irradiated mice. In the blood count from the peripheral blood of the older mice (both non-irradiated and irradiated at 7 Gy), there was a significant increase in granulocytes. In the group exposed to 7 Gy, the numbers of thrombocytes significantly increased, and on the contrary, the numbers of erythrocytes, the amount of haemoglobin, and haematocrit significantly decreased.
... Exposure of either Trp53 normal or cancer prone Trp53 heterozygous mice to doses from 1-4 Gy, given at high dose rate, resulted in a reduction in median lifespan that was a linear function of the dose, indicating that at high dose rate, the upper dose threshold for protective effects was below 1 Gy (Carlisle et al. 2009, in press). That result was consistent with the observations for malignant transformation of human cells in culture (Redpath et al. 2001). ...
Adaptive responses to low doses of low LET radiation occur in all organisms thus far examined, from single cell lower eukaryotes to mammals. These responses reduce the deleterious consequences of DNA damaging events, including radiation-induced or spontaneous cancer and non-cancer diseases in mice. The adaptive response in mammalian cells and mammals operates within a certain window that can be defined by upper and lower dose thresholds, typically between about 1 and 100 mGy for a single low dose rate exposure. However, these thresholds for protection are not a fixed function of total dose, but also vary with dose rate, additional radiation or non-radiation stressors, tissue type and p53 functional status. Exposures above the upper threshold are generally detrimental, while exposures below the lower threshold may or may not increase either cancer or non-cancer disease risk.
