Search

The rationale of this study stems from the concern of a radiation-induced accident or terrorist-mediated nuclear attack resulting in large populations of people exposed to nonlethal radiation doses or after a course of definitive radiation therapy which could substantially increase the risk for cancer induction after exposure. Currently, there are no safe and effective interventions to reduce this increased cancer risk to humans. We have tested the hypothesis that the mTOR inhibitor, rapamycin, administered in the diet of mice would reduce or delay radiation-induced cancer when given after radiation exposure. A total-body irradiation (TBI) of 3 Gy was administered to female C3H/Hen mice. Immediately after TBI, along with untreated control groups, animals were placed on chow containing different concentrations of encapsulated rapamycin (14, 40, 140 mg/kg chow). Animals remained on the respective control or rapamycin diets and were followed for their entire lifespan (total of 795 mice). The endpoint for the study was tumor formation (not to exceed 1 cm) or until the animal reached a humane endpoint at which time the animal was euthanized and evaluated for the presence of tumors (pathology evaluated on all animals). Kaplan-Meier survival curves revealed that all three concentrations of rapamycin afforded a significant survival advantage by delaying the time at which tumors appeared and reduction of the incidence of certain tumor types such as hepatocellular carcinomas. The survival advantage was dependent on the rapamycin concentration used. Further, there was a survival advantage when delaying the rapamycin chow by 1 month after TBI. Rapamycin is FDA-approved for human use and could be considered for use in individuals exposed to nonlethal TBI from a nuclear accident or attack or after significant therapeutic doses for cancer treatment., (© 2024 by Radiation Research Society. All rights of reproduction in any form reserved.)

The genomic landscape neighboring large deletions including the hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus on human X chromosome in 6-thioguanine-resistant mutants originating from immortalized human fibroblast cells exposed to X rays was characterized by real-time quantitative PCR (qPCR)-based analyses. Among the 13 mutant clones with large deletions extending over several Mb, including the HPRT locus, revealed by 10 conventional sequence-tagged site (STS) markers, three clones bearing the largest deletions were selected for further qPCR analysis using another 21 STS markers and 15 newly designed PCR primer pairs. The results indicated that the major deletions were in very specific regions between the 130-Mb and 140-Mb positions containing the HPRT locus on the X chromosome and, contrary to our initial expectations, additional minor deletions were distributed in a patchwork pattern. These findings strongly indicate that the complex deletion patterns in the affected chromosome are related to the radiation track structure with spatially heterogeneous energy deposition and the specific structure of the chromatin-nuclear membrane complex. The uncovered complex deletion patterns are in agreement with the idea of complex chromatin damage, which is frequently associated with carcinogenesis., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

Ionizing radiation induces DNA damage to cycling cells which, if left unrepaired or misrepaired, can cause cell inactivation or heritable, viable mutations. The latter can lead to cell transformation, which is thought to be an initial step of cancer formation. Consequently, the study of radiation-induced cell transformation promises to offer insights into the general properties of radiation carcinogenesis. As for other end points, the effectiveness in inducing cell transformation is elevated for radiation qualities with high linear energy transfer (LET), and the same is true for cancer induction. In considering DNA damage as a common cause of both cell death and transformations, a worthwhile approach is to apply mathematical models for the relative biological effectiveness (RBE) of cell killing to also assess the carcinogenic potential of high-LET radiation. In this work we used an established RBE model for cell survival and clinical end points, the local effect model (LEM), to estimate the transformation probability and the carcinogenic potential of ion radiation. The provided method consists of accounting for the competing processes of cell inactivation and induction of transformations or carcinogenic events after radiation exposure by a dual use of the LEM. Correlations between both processes inferred by the number of particle impacts to individual cells were considered by summing over the distribution of hits that individual cells receive. RBE values for cell transformation in vitro were simulated for three independent data sets, which were also used to gauge the approach. The simulations reflect the general RBE systematics both in magnitude and in energy and LET dependence. To challenge the developed method, in vivo carcinogenesis was investigated using the same concepts, where the probability for cancer induction within an irradiated organ was derived from the probability of finding carcinogenic events in individual cells. The predictions were compared with experimental data of carcinogenesis in Harderian glands of mice. Again, the developed method shows the same characteristics as the experimental data. We conclude that the presented method is helpful to predictively assess RBE for both neoplastic cell transformation and tumor induction after ion exposure within a wide range of LET values. The theoretical concept requires a non-linear component in the photon dose response for carcinogenic end points as a precondition for the observed enhanced effects after ion exposure, thus contributing to a long debate in epidemiology. Future work will use the method for assessing cancer induction in radiation therapy and exposure scenarios frequently discussed in radiation protection., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

Recently reported studies considering nonlinearity in the effects of low-dose space radiation have assumed a nontargeted mechanism. To date, few analyses have been performed to assess whether a nontargeted term is supported by the available data. The Harderian gland data from Alpen et al. (published in 1993 and 1994), and Chang et al. (2016) provide the most diversity of ions and energies in a tumor induction model, including multiple high-energy and charge particles. These data can be used to investigate various nonlinearity assumptions against a linear model, including nontargeted effects in the low-dose region or cell sterilization at high doses. In this work, generalized linear models were used with the log complement link function to analyze the binomial data from the studies independently and combined. While there was some evidence of nonlinearity that was best described by a cell-sterilization model, the linear model was adequate to describe the data. The current data do not support the addition of a nontargeted effects term in any model. While adequate data are available in the low-dose region (<0.5 Gy) to support a nontargeted effects term if valid, additional data in the 1-2 Gy region are necessary to achieve power for cell-sterilization analysis validation. The current analysis demonstrates that the Harderian gland tumor data do not support the use of a nontargeted effects term in human cancer risk models., (©2020 by Radiation Research Society. All rights of reproduction in any form reserved.)

Radiation-induced cancer is an ongoing and significant problem, with sources that include clinics worldwide in which 3.1 billion radiology exams are performed each year, as well as a variety of other scenarios such as space travel and nuclear cleanup. These radiation exposures are typically anticipated, and the exposure is typically well below 1 Gy. When radiation-induced (actually ROS-induced) DNA mutation is prevented, then so too are downstream radiation-induced cancers. Currently, there is no protection available against the effects of such <1 Gy radiation exposures. In this study, we address whether the new PrC-210 ROS-scavenger is effective in protecting p53-deficient (p53 -/- ) mice against X-ray-induced accelerated tumor mortality; this is the most sensitive radiation tumorigenesis model currently known. Six-day-old p53 -/- pups received a single intraperitoneal PrC-210 dose [0.5 maximum tolerated dose (MTD)] or vehicle, and 25 min later, pups received 4.0 Gy X-ray irradiation. At 5 min postirradiation, blood was collected to quantify white blood cell c-H2AX foci. Over the next 250 days, tumor-associated deaths were recorded. Findings revealed that when administered 25 min before 4 Gy X-ray irradiation, PrC-210 reduced DNA damage (c-H2AX foci) by 40%, and in a notable coincidence, caused a 40% shift in tumor latency/incidence, and the 0.5 MTD PrC210 dose had no discernible toxicities in these p53 -/- mice. Essentially, the moles of PrC-210 thiol within a single 0.5 MTD PrC-210 dose suppressed the moles of ROS generated by 40% of the 4 Gy X-ray dose administered to p53 -/- pups, and in doing so, eliminated the lifetime leukemia/lymphoma risk normally residing "downstream" of that 40% of the 4 Gy dose. In conclusion: 1. PrC-210 is readily tolerated by the 6-day-old p53 -/- mice, with no discernible lifetime toxicities; 2. PrC-210 does not cause the nausea, emesis or hypotension that preclude clinical use of earlier aminothiols; and 3. PrC-210 significantly increased survival after 4 Gy irradiation in the p53 -/- mouse model.

Although the risk of breast cancer after high-dose-rate irradiation has been firmly established, however, the risk incurred for low-dose-rate irradiation is not well understood. Here we provide experimental evidence for dose rate and age dependencies induced by continuous γ-ray irradiation on mammary carcinogenesis. Female rats received continuous whole-body irradiation at one of the following time points: at 7 weeks of age (denoted adults) at a dose rate of 3-60 mGy/h (4 Gy total); or at either 3 weeks (denoted juveniles) or 7 weeks of age at a dose rate of 6 mGy/h (1-8 Gy total). Additional rats were acutely irradiated at 13 weeks of age at a dose rate of 30 Gy/h (0.5-4 Gy total). We observed the incidence of mammary tumors by weekly palpation until they were 90 weeks old and after pathological inspection upon autopsy. The tumor incidence rate for each group was characterized by Cox regression analysis. When adult rats were irradiated at 60 mGy/h for a total of 4 Gy, their hazard ratio for mammary carcinoma significantly increased relative to nonirradiated controls; however, for adult rats irradiated at 3-24 mGy/h, even though they also received a total of 4 Gy, their hazard ratio for carcinoma incidence did not significantly increase. A larger increase in the incidence rate of carcinoma per dose was found for the juveniles than for the adults irradiated at 6 mGy/h, whereas age did not influence the effect of acute irradiation at 30 Gy/h; a threshold-like dose response was observed for irradiation at 6 mGy/h (threshold, ∼2.5 and ∼4 Gy for juveniles and adults, respectively). Regarding benign tumors of the mammary gland, a significant increase in their incidence was observed for irradiation down to 6 mGy/h, but not at 3 mGy/h and there was no evidence of age-dependent induction. Thus, induction of female rat mammary carcinogenesis by continuous γ-ray exposure was age dependent and drastically increased for adult rats that received between 24 and 60 mGy/h irradiation.

Amifostine is a potent antioxidant that protects against ionizing radiation effects. In this study, we evaluated the effect of Amifostine administered before total-body irradiation (TBI), at a drug dose that protects against TBI lethality, for potential protection against radiation-induced late effects such as a shortened lifespan and cancer. Three groups of mice were studied: 0 Gy control; 10.8 Gy TBI with Amifostine pretreatment; and 5.4 Gy TBI alone. Animals were monitored for their entire lifespan. The median survival times for mice receiving 0, 5.4 or 10.8 Gy TBI were 706, 460 and 491 days, respectively. Median survival of both irradiated groups was significantly shorter compared to nonirradiated mice ( P < 0.0001). Cancer incidence (hematopoietic and solid tumors) was similar between the irradiated groups and was significantly greater than for the 0 Gy controls. The ratio of hematopoietic-to-solid tumors differed among the groups, with the 5.4 Gy group having a higher incidence of hematopoietic neoplasms compared to the 10.8 Gy/Amifostine group (1.8-fold). Solid tumor incidence was greater in the 10.8 Gy/Amifostine group (1.6-fold). There are few mouse lifespan studies for agents that protect against radiation-induced lethality. Mice treated with 10.8 Gy/Amifostine yielded a lower incidence of hematopoietic neoplasms and higher incidence of solid neoplasms. In conclusion, mice protected from lethal TBI have a shortened lifespan, due in large part to cancer induction after exposure compared to nonexposed controls. Amifostine treatment did protect against radiation-induced hematopoietic tumors, while protection against solid neoplasms was significant but incomplete.

Computed tomography (CT) scans are a routine diagnostic imaging technique that utilize low-energy X rays with an average absorbed dose of approximately 10 mGy per clinical whole-body CT scan. The growing use of CT scans in the clinic has raised concern of increased carcinogenic risk in patients exposed to ionizing radiation from diagnostic procedures. The goal of this study was to better understand cancer risk associated with low-dose exposures from CT scans. Historically, low-dose exposure preceding a larger challenge dose increases tumor latency, but does little to impact tumor frequency in Trp53 +/- mice. To assess the effects of CT scans specifically on tumor progression, whole-body CT scans (10 mGy/scan, 75 kVp) were started at four weeks after 4 Gy irradiation, to allow for completion of tumor initiation. The mice were exposed to weekly CT scans for ten consecutive weeks. In this study, we show that CT scans modify cellular end points commonly associated with carcinogenesis in cancer-prone Trp53 +/- heterozygous mice. At five days after completion of CT scan treatment, the multiple CT scans did not cause detectable differences in bone marrow genomic instability, as measured by the formation of micronucleated reticulocytes and H2AX phosphorylation in lymphoid-type cells, and significantly lowered constitutive and radiation induced levels of apoptosis. The overall lifespan of 4 Gy exposed cancer-initiated mice treated with multiple CT scans was increased by approximately 8% compared to mice exposed to 4 Gy alone (P < 0.017). Increased latency periods for lymphoma and sarcoma (P < 0.040) progression contributed to the overall increase in lifespan. However, repeated CT scans did not affect carcinoma latency. To our knowledge, this is the first reported study to show that repeated CT scans, when administered after tumor initiation, can improve cancer morbidity by delaying the progression of specific types of radiation-induced cancers in Trp53 +/- mice.

Health risks from space radiations, particularly from densely ionizing radiations, represent an important challenge for long-ranged manned space missions. Reliable methods are needed for scaling low-LET to high-LET radiation risks for humans, based on animal or in vitro studies comparing these radiations. The current standard metric, relative biological effectiveness (RBE) compares iso-effect doses of two radiations. By contrast, a proposed new metric, radiation effects ratio (RER), compares effects of two radiations at the same dose. This definition of RER allows direct scaling of low-LET to high-LET radiation risks in humans at the dose or doses of interest. By contrast to RBE, RER can be used without need for detailed information about dose response shapes for compared radiations. This property of RER allows animal carcinogenesis experiments to be simplified by reducing the number of tested radiation doses. For simple linear dose-effect relationships, RBE = RER. However, for more complex dose-effect relationships, such as those with nontargeted effects at low doses, RER can be lower than RBE. We estimated RBE and RER values and uncertainties using heavy ion ( 12 C, 28 Si, 56 Fe) and gamma-ray-induced tumors in a mouse model for intestinal cancer (APC 1638N/+ ), and used both RBE and RER to estimate low-LET to high-LET risk scaling factors. The data showed clear evidence of nontargeted effects at low doses. In situations, such as the ones discussed here where nontargeted effects dominate at low doses, RER was lower than RBE by factors around 2.8-3.5 at 0.03 Gy and 1.3-1.4 at 0.3 Gy. It follows that low-dose high-LET human cancer risks scaled from low-LET human risks using RBE may be correspondingly overestimated.

Exposure to ionizing radiation increases the incidence of acute myeloid leukemia (AML), which has been diagnosed in Japanese atomic bombing survivors, as well as patients treated with radiotherapy. The genetic basis for susceptibility to radiation-induced AML is not well characterized. We previously identified a candidate murine gene for susceptibility to radiation-induced AML (rAML): C-terminal binding protein (CTBP)-interacting protein (CTIP)/retinoblastoma binding protein 8 (RBBP8). This gene is essential for embryonic development, double-strand break (DSB) resection in homologous recombination (HR) and tumor suppression. In the 129S2/SvHsd mouse strain, a nonsynonymous single nucleotide polymorphism (nsSNP) in Ctip, Q418P, has been identified. We investigated the role of Q418P in radiation-induced carcinogenesis and its effect on CTIP function in HR. After whole-body exposure to 3 Gy of X rays, 11 out of 113 (9.7%) 129S2/SvHsd mice developed rAML. Furthermore, 129S2/SvHsd mouse embryonic fibroblasts (MEFs) showed lower levels of recruitment of HR factors, Rad51 and replication protein A (RPA) to radiation-induced foci, compared to CBA/H and C57BL/6 MEFs, isolated from rAML-sensitive and resistant strains, respectively. Mitomycin C and alpha particles induced lower levels of sister chromatid exchanges in 129S2/SvHsd cells compared to CBA/H and C57BL/6. Our data demonstrate that Q418P nsSNP influences the efficiency of CTIP function in HR repair of DNA DSBs in vitro and in vivo, and appears to affect susceptibility to rAML.

Complex mixed radiation fields exist in interplanetary space, and little is known about their late effects on space travelers. In silico synergy analysis default predictions are useful when planning relevant mixed-ion-beam experiments and interpreting their results. These predictions are based on individual dose-effect relationships (IDER) for each component of the mixed-ion beam, assuming no synergy or antagonism. For example, a default hypothesis of simple effect additivity has often been used throughout the study of biology. However, for more than a century pharmacologists interested in mixtures of therapeutic drugs have analyzed conceptual, mathematical and practical questions similar to those that arise when analyzing mixed radiation fields, and have shown that simple effect additivity often gives unreasonable predictions when the IDER are curvilinear. Various alternatives to simple effect additivity proposed in radiobiology, pharmacometrics, toxicology and other fields are also known to have important limitations. In this work, we analyze upcoming murine Harderian gland (HG) tumor prevalence mixed-beam experiments, using customized open-source software and published IDER from past single-ion experiments. The upcoming experiments will use acute irradiation and the mixed beam will include components of high atomic number and energy (HZE). We introduce a new alternative to simple effect additivity, "incremental effect additivity", which is more suitable for the HG analysis and perhaps for other end points. We use incremental effect additivity to calculate default predictions for mixture dose-effect relationships, including 95% confidence intervals. We have drawn three main conclusions from this work. 1. It is important to supplement mixed-beam experiments with single-ion experiments, with matching end point(s), shielding and dose timing. 2. For HG tumorigenesis due to a mixed beam, simple effect additivity and incremental effect additivity sometimes give default predictions that are numerically close. However, if nontargeted effects are important and the mixed beam includes a number of different HZE components, simple effect additivity becomes unusable and another method is needed such as incremental effect additivity. 3. Eventually, synergy analysis default predictions of the effects of mixed radiation fields will be replaced by more mechanistic, biophysically-based predictions. However, optimizing synergy analyses is an important first step. If mixed-beam experiments indicate little synergy or antagonism, plans by NASA for further experiments and possible missions beyond low earth orbit will be substantially simplified.

A detailed understanding of the relationship between radiation-induced breast cancer and obesity is needed for appropriate risk management and to prevent the development of a secondary cancer in patients who have been treated with radiation. Our goal was to develop an animal model to study the relationship by combining two existing Sprague-Dawley rat models of radiation-induced mammary carcinogenesis and diet-induced obesity. Female rats were fed a high-fat diet for 4 weeks and categorized as obesity prone or obesity resistant based on their body weight at 7 weeks of age, at which time the rats were irradiated with 4 Gy. Control rats were fed a standard diet and irradiated at the same time and in the same manner. All rats were maintained on their initial diets and assessed for palpable mammary cancers once a week for the next 30 weeks. The obesity-prone rats were heavier than those in the other groups. The obesity-prone rats were also younger than the other animals at the first detection of mammary carcinomas and their carcinoma weights were greater. A tendency toward higher insulin and leptin blood levels were observed in the obesity-prone rats compared to the other two groups. Blood angiotensin II levels were elevated in the obesity-prone and obesity-resistant rats. Genes related to translation and oxidative phosphorylation were upregulated in the carcinomas of obesity-prone rats. Expression profiles from human breast cancers were used to validate this animal model. As angiotensin is potentially an important factor in obesity-related morbidities and breast cancer, a second set of rats was fed in a similar manner, irradiated and then treated with an angiotensin-receptor blocker, losartan and candesartan. Neither blocker altered mammary carcinogenesis; analyses of losartan-treated animals indicated that expression of renin in the renal cortex and of Agtr1a (angiotensin II receptor, type 1) in cancer tissue was significantly upregulated, suggesting the presence of compensating mechanisms for blocking angiotensin-receptor signaling. Thus, obesity-related elevation of insulin and leptin blood levels and an increase in available energy may facilitate sustained protein synthesis in cancer cells, which is required for rapid cancer development.

Increased cancer risk remains a primary concern for travel into deep space and may preclude manned missions to Mars due to large uncertainties that currently exist in estimating cancer risk from the spectrum of radiations found in space with the very limited available human epidemiological radiation-induced cancer data. Existing data on human risk of cancer from X-ray and gamma-ray exposure must be scaled to the many types and fluences of radiations found in space using radiation quality factors and dose-rate modification factors, and assuming linearity of response since the shapes of the dose responses at low doses below 100 mSv are unknown. The goal of this work was to reduce uncertainties in the relative biological effect (RBE) and linear energy transfer (LET) relationship for space-relevant doses of charged-particle radiation-induced carcinogenesis. The historical data from the studies of Fry et al. and Alpen et al. for Harderian gland (HG) tumors in the female CB6F1 strain of mouse represent the most complete set of experimental observations, including dose dependence, available on a specific radiation-induced tumor in an experimental animal using heavy ion beams that are found in the cosmic radiation spectrum. However, these data lack complete information on low-dose responses below 0.1 Gy, and for chronic low-dose-rate exposures, and there are gaps in the LET region between 25 and 190 keV/μm. In this study, we used the historical HG tumorigenesis data as reference, and obtained HG tumor data for 260 MeV/u silicon (LET ∼70 keV/μm) and 1,000 MeV/u titanium (LET ∼100 keV/μm) to fill existing gaps of data in this LET range to improve our understanding of the dose-response curve at low doses, to test for deviations from linearity and to provide RBE estimates. Animals were also exposed to five daily fractions of 0.026 or 0.052 Gy of 1,000 MeV/u titanium ions to simulate chronic exposure, and HG tumorigenesis from this fractionated study were compared to the results from single 0.13 or 0.26 Gy acute titanium exposures. Theoretical modeling of the data show that a nontargeted effect model provides a better fit than the targeted effect model, providing important information at space-relevant doses of heavy ions.

During space travel astronauts are exposed to a variety of radiations, including galactic cosmic rays composed of high-energy protons and high-energy charged (HZE) nuclei, and solar particle events containing low- to medium-energy protons. Risks from these exposures include carcinogenesis, central nervous system damage and degenerative tissue effects. Currently, career radiation limits are based on estimates of fatal cancer risks calculated using a model that incorporates human epidemiological data from exposed populations, estimates of relative biological effectiveness and dose-response data from relevant mammalian experimental models. A major goal of space radiation risk assessment is to link mechanistic data from biological studies at NASA Space Radiation Laboratory and other particle accelerators with risk models. Early phenotypes of HZE exposure, such as the induction of reactive oxygen species, DNA damage signaling and inflammation, are sensitive to HZE damage complexity. This review summarizes our current understanding of critical areas within the DNA damage and oxidative stress arena and provides insight into their mechanistic interdependence and their usefulness in accurately modeling cancer and other risks in astronauts exposed to space radiation. Our ultimate goals are to examine potential links and crosstalk between early response modules activated by charged particle exposure, to identify critical areas that require further research and to use these data to reduced uncertainties in modeling cancer risk for astronauts. A clearer understanding of the links between early mechanistic aspects of high-LET response and later surrogate cancer end points could reveal key nodes that can be therapeutically targeted to mitigate the health effects from charged particle exposures.

Recent epidemiological studies have suggested that radiation exposure from pediatric CT scanning is associated with small excess cancer risks. However, the majority of CT scans are performed on adults, and most radiation-induced cancers appear during middle or old age, in the same age range as background cancers. Consequently, a logical next step is to investigate the effects of CT scanning in adulthood on lifetime cancer risks by conducting adult-based, appropriately designed epidemiological studies. Here we estimate the sample size required for such studies to detect CT-associated risks. This was achieved by incorporating different age-, sex-, time- and cancer type-dependent models of radiation carcinogenesis into an in silico simulation of a population-based cohort study. This approach simulated individual histories of chest and abdominal CT exposures, deaths and cancer diagnoses. The resultant sample sizes suggest that epidemiological studies of realistically sized cohorts can detect excess lifetime cancer risks from adult CT exposures. For example, retrospective analysis of CT exposure and cancer incidence data from a population-based cohort of 0.4 to 1.3 million (depending on the carcinogenic model) CT-exposed UK adults, aged 25-65 in 1980 and followed until 2015, provides 80% power for detecting cancer risks from chest and abdominal CT scans.

Epidemiological data reveals the gastrointestinal (GI) tract as one of the main sites for low-LET radiation-induced cancers. Importantly, the use of particle therapy is increasing, but cancer risk by high-LET particles is still poorly understood. This gap in our knowledge also remains a major limiting factor in planning long-term space missions. Therefore, assessing risks and identifying predisposing factors for carcinogenesis induced by particle radiation is crucial for both astronauts and cancer survivors. We have previously shown that exposure to relatively high doses of high-energy (56)Fe ions induced higher intestinal tumor frequency and grade in the small intestine of Apc(Min/+) mice than γ rays. However, due to the high number of spontaneous lesions (∼30) that develop in Apc(Min/+) animals, this Apc mutant model is not suitable to investigate effects of cumulative doses <1 Gy, which are relevant for risk assessment in astronauts and particle radiotherapy patients. However, Apc(1638N/+) mice develop a relatively small number of spontaneous lesions (∼3 per animal) in both small intestine and colon, and thus we propose a better model for studies on radiation-induced carcinogenesis. Here, we investigated model particle radiation increases tumor frequency and grade in the entire gastrointestinal tract (stomach and more distal intestine) after high- and low-radiation doses whether in the Apc(1638N/+). We have previously reported that an increase in small intestinal tumor multiplicity after exposure to γ rays was dependent on gender in Apc(1638N/+) mice, and here we investigated responses to particle radiation in the same model. Phenotypical and histopathological observations were accompanied by late changes in number and position of mitotic cells in intestinal crypts from animals exposed to different radiation types.

Cancer of the prostate is a highly prevalent disease with a heterogeneous aetiology and prognosis. Current understanding of the biological mechanisms underlying the responses of prostate tissue to ionizing radiation exposure, including cancer induction, is surprisingly limited for both high- and low-dose exposures. As population exposure to radiation increases, largely through medical imaging, a better understanding of the response of the prostate to radiation exposure is required. Low-dose radiation-induced adaptive responses for increased cancer latency and decreased cancer frequency have been demonstrated in mouse models, largely for hematological cancers. This study examines the effects of high- and low-dose whole-body radiation exposure on prostate cancer development using an autochthonous mouse model of prostate cancer: TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP). TRAMP mice were exposed to single acute high (2 Gy), low (50 mGy) and repeated low (5 × 50 mGy) doses of X rays to evaluate both the potential prostate cancer promoting effects of high-dose radiation and low-dose adaptive response phenomena in this prostate cancer model. Prostate weights and histopathology were examined to evaluate gross changes in cancer development and, in mice exposed to a single 2 Gy dose, time to palpable tumor was examined. Proliferation (Ki-67), apoptosis, DNA damage (γ-H2AX) and transgene expression (large T-antigen) were examined within TRAMP prostate sections. Neither high- nor low-dose radiation-induced effects on prostate cancer progression were observed for any of the endpoints studied. Lack of observable effects of high- or low-dose radiation exposure suggests that modulation of tumorigenesis in the TRAMP model is largely resistant to such exposures. However, further study is required to better assess the effects of radiation exposure using alternative prostate cancer models that incorporate normal prostate and in those that are not driven by SV40 large T antigen.