Reduction of high-dose-radiation-induced delayed genotoxic effects by radioadaptive response and mild diet restriction in mice

1. Objectives Radiation-induced adaptive response (AR) is a phenomenon manifesting as a priming low-dose-induced resistance to a subsequent challenge exposure at higher doses. Investigations of AR are expected to provide an important scientific basis for radiation risk estimates, protection and practical applications. AR has been demonstrated in a variety of in vitro and in vivo systems. In the in vitro studies, AR was reported to induce reduction of cell death, chromosomal aberrations, mutations and malignant transformation. Among the in vivo investigations, the mouse AR model (Yonezawa Effect) was characterized by significantly decreased mortality in the 30-day survival test. The underlying mechanism was due to radioresistance occurring in hematopoietic tissues. On the other hand, diet intervention showed a great impact on health in human and calorie restriction had beneficial effects on numerous diseases including cancer in animal models. In this study, by using the mouse AR model, we first verified AR induction under standard, high fat and very low fat diet with the 30-day survival test. Then we further investigated the residual damage in the hematopoietic system in surviving animals under different restriction of standard diet. We aimed at finding the diet intervention condition under which the priming irradiations could most efficiently relieve the detrimental late genotoxic effects induced by the challenge high dose of irradiations.2. Materials and Methods C57BL/6J Jms strain female mice were used. X-rays were generated at 200 kVp, using a 0.50-mm Al + 0.50-mm Cu filter. Three kinds of mouse diet were used including a standard diet, a high fat diet and a very low fat diet. For the mice fed with the standard diet, diet restriction was performed at 15%, 25%, 50% and 75% compared to the non-restriction group (100%). The animals were treated under these diet conditions from weaning to the end of the experimental period. Reproducibility of the Yonezawa Effect verified with 30-day survival test was confirmed by delivering a priming low dose at 0.5 Gy in combination with a challenge high dose at 7.5Gy to the mice at postnatal age of 6 and 8 weeks, respectively. A sublethal dose at 4.0 Gy was used in study on the residual damage in the hematopoietic system in surviving animals. The genotoxic effects were evaluated by measurement of the micronucleated polychromatic erythrocytes (MNPCEs) and micronucleated normochromatic erythrocytes (MNNCEs) in the bone marrow from animals 31 days after the challenge dose. All experimental protocols were approved by The Institutional Animal Care and Use Committee, and the experiments were performed in strict accordance with the NIRS Guidelines for the Care and Use of Laboratory Animals.3. Research Results Reproducibility of the Yonezawa Effect was confirmed with the 30-day survival test under our experimental setup in mice fed with the standard diet without restriction. AR was demonstrated in the animals fed with the standard diet at 15% and 25% restriction. In addition, based on the 30-day survival results, the animals with 15% diet restriction showed similar response to radiation compared to those fed without diet restriction, while the animals with 25% diet restriction showed increased radiosensitivities. On the other hand, AR was not demonstrated in the animals fed with high fat diet or very low fat diet, neither the animals fed with the standard diet at restriction of 50% and 75%. The genotoxic effects evaluated by MNPCEs and MNNCEs in the bone marrow cells showed that a mild restriction of the standard diet at 15% induced most efficiently suppressed genotoxic effects in animals both from the AR group and those receiving only the challenge dose.4. Discussion AR induced a protective effect on the hematopoietic system, which may play an important role in both rescue from acute lethal damage (mouse killing) and prevention of late detrimental consequences (delayed genotoxic effects) caused by exposure to a high challenge dose. Diet is one of the major factors to influence susceptibility to many diseases. Calorie restriction may lengthen the lifespan in some experimental models while malnutrition and near-starvation diets show varied adverse effects on health, leading to reduced life expectancy and increased health problem. Results in this study showed that diet intervention played a pivotal role in the response of the animals to radiation exposure, namely, a mild diet restriction could further suppress the delayed genotoxic effects from high dose radiation in the mouse AR model, while unbalanced diets and malnutrition could increase the radiosensitivities and even abolished a successful AR induction. These findings suggest that the AR-inducible low-dose of radiation and mild diet restriction may share some common pathways to activate mechanisms consequently resulting in suppression of the delayed genotoxic effects from exposure to high-dose irradiations. These findings provide new insight into the mechanistic study on both AR and mild diet restriction. These findings indicated that diet intervention could be a potential modifiable factor to detrimental radiation effects, and lifestyle management would be the initial therapies recommended for reducing risk from exposure to high-dose irradiations.The 2nd Global Chinese Congress of Radiation Research(GCCRR2014