Short and long-term effects of exposure to low dose and low dose rate of gamma radiation : using in vitro and in vivo models

Abstract: Assessment of human health risks from exposure to ionizing radiation (IR) is mainly based on the extrapolation of results from epidemiological studies on populations exposed to relatively high doses and often at high dose rates (HDR). Risk estimates after exposure to low doses and in particular at low dose rates (LDR) remain controversial due to a lack of epidemiological evidence. Therefore, high priority is given to strengthening the evidence on which risk assessments can be based for low doses and LDR. It is known that the cytotoxicity of radiation decreases by decreasing dose rate. Less is known about the effects of LDR on mutation rates and premature senescence compared to HDR. We established 2 cell lines with low expression of two proteins, MTH1 or MYH, both involved in the protection of cells from mutation induction by reactive oxygen species (ROS). The cells were exposed to different doses at different dose rates, and the levels of mutation were studied. The results showed a possible dose-rate threshold for mutations for the MTH1/MYH double knockdown cells.Next, we studied the effect of dose rate on adaptive response (AR). AR is defined as the ability of a low dose of ionizing radiation to induce enhanced resistance in cells subsequently exposed to a high dose. We established dose response relations for survival and mutations for MCF-10A cells exposed/non-exposed to an adaptive dose of 50 mGy at different dose rates, followed by exposure to different high doses. We found no protective effect of 50 mGy on survival. However, we observed that 50 mGy the adaptive dose reduced the mutation frequency induced by 1 Gy challenging dose. The protection level was higher when 50 mGy was delivered at LDR.A significant amount of data suggests that oxidative stress, induced for example by LDR, can contribute to senescence. We cultured VH10 cells, beginning with passage 13, during chronic LDR exposure. The cells were passaged every week for 6 weeks until they stopped proliferating due to premature senescence at passage 19. Passage 8 VH10 cells were cultured correspondingly but without irradiation until they stopped proliferating at passage 23 in response to replicative senescence. The DNA repair kinetics and the levels of DNA damage that were localized in the telomeres of young, middle-aged, premature senescent and replicative senescent cells were investigated. The young cells repaired DSB significantly faster than the senescent cells; premature and replicative senescent cells accumulated more DNA damage in the telomeres; and as compared to middle-aged cells, young cells cope with oxidative stress of chronic irradiation more effectively.The transgenerational effects of IR were studied in Drosophila embryos. The exposed embryos were followed up for abnormality during embryogenesis until adult stage and up to 12 generations. We found that radiation induced an A5pig- phenotype (depigmented area in the A5 segment of the male body) that was transmitted up to 12 generations. This phenomenon did not follow the Mendelian inheritance model, which indicates the influence of mechanisms other than mutagenesis e.g. epigenetic mechanism.We showed that; LDR is less cytotoxic than HDR but both induce equal levels of mutation per unit dose; LDR induces premature senescence; LDR may be more effective than HDR in inducing adaptive response; and LDR and HDR exposure of Drosophila embryos can induce an abnormal phenotype that can be transmitted through generations.