Effects of Chronic LOw-dose Gamma Irradiation on GAstrointestinal Tumorigenesis - CLOGIGAT

Natural and man-made sources of ionising radiation contribute to human exposures and are a recognised hazard for human health. Risk estimates for radiation-induced cancer in humans are based on epidemiological data mainly from the Japanese atomic bomb survivor studies. This group received mostly external radiation, mainly as gamma rays, at high dose rate for a short period, and exposures were mostly at high total doses. Many animal studies have been undertaken on the quantitative effects of exposure to ionising radiation. However, these have concentrated on the quantitative effects at high doses and dose rates obtained by from acute exposures to high and low LET radiation. There is little information about effects from chronic exposure to low-dose rate radiation. The main aim of this project is thus to investigate the etiology of chronically induced gastrointestinal tumours in the Apc+/Min model following low or high dose ionising radiation. We used the novel but well characterised ApcMin/+, which has been used for acute radiation studies at Public Health England through many years. A second aim was to investigate genotoxic effects of chronic low dose ionising radiation vs high dose ionizing radiation and the role of APC+/Min for genotoxicity, and the relationship between blood based genotoxicity analyses and development of tumours. Third, we aimed at profiling epigenetic changes, in the form of expression of miRNAs following low dose IR and investigate its relationship with development of gastrointestinal tumours. We examined the quantitative effects of exposure to low-dose rate gamma radiation in ApcMin/+ mice. The mice were chronically exposed to 1,7 and 3,2 Gy gamma rays at a rate of 2,2 mGy/h; another batch of mice were given an acute dose of 3 Gy/h. The numbers of gastrointestinal tumours as well as blood-based genotoxicity assays were compared, between low and high dose-rate exposures and with those in previous studies obtained from acute high-dose rate (28.8 Gy/h) X-ray studies. The project demonstrates that low dose rate gamma irradiation did induce gastrointestinal cancer, although at very low levels compared with similar total doses of high dose rate X-rays. This implies that the dose effectiveness factor for risk assessment may be significant. Moreover, previous results demonstrating a genotoxic effect of human relevant low dose rate gamma irradiation was confirmed, in another mouse line. The genotoxicity observed in blood was not associated with Apc+/Min genotype, and it remains to be assessed whether it is assessed with the gastrointestinal cancer incidences. Altogether the project has led to novel important data regarding low dose rate ionizing radiation in a radioprotective perspective.

Natural and man-made sources of ionising radiation contribute to human exposures and are a recognised hazard for human health. Risk estimates for radiation-induced cancer in humans are based on epidemiological data mainly from the Japanese atomic bomb su rvivor studies. This group received mostly external radiation, mainly as gamma rays, at high dose rate for a short period, and exposures were mostly at high total doses. Many animal studies have been undertaken on the quantitative effects of exposure to ionising radiation. However, these have concentrated on the quantitative effects at high doses and dose rates obtained by from acute exposures to high and low LET radiation. There is little information about effects from chronic exposure to low-dose ra te radiation. This project - approved by the DoReMi NoE - will examine the quantitative effects of exposure to low-dose rate gamma radiation in a mouse model, the novel but well characterised ApcMin/+. This model has been used for acute radiation st udies at Public Health England. The mice will be chronically exposed to 1, 2 or 3 Gy gamma rays at a rate of 1.6 mGy/h; other mice will be given an acute dose at 3 Gy/h. The numbers of gastrointestinal tumours induced in this study as well as blood-based genotoxicity assays and miRNA expression will be compared, between low and high dose-rate exposures and with those in previous studies obtained from acute high-dose rate (28.8 Gy/h) x-ray studies. The results will enable a dose rate effectiveness va lue to be calculated for acute vs. chronic exposure to gamma rays, for a well-defined endpoint of direct relevance to human health. The data are therefore highly useful for estimation of DDREF values for low-dose rate vs. high-dose rate exposures. Moreov er, the study gives information regarding the importance of the Min-mutation for mutagenesis in blood cells, and regarding the potential of radiation induced epigenetic changes represented as miRNA profiles.