The effects of short-term calorie restriction on mutations in the spleen cells of infant-irradiated mice

Abstract

The risk of cancer due to exposure to ionizing radiation is higher in infants than in adults. In a previous study, the effect of adult-onset calorie restriction (CR) on carcinogenesis in mice after early-life exposure to X-rays was examined (Shang, Y, Kakinuma, S, Yamauchi, K, et al. Cancer prevention by adult-onset calorie restriction after infant exposure to ionizing radiation in B6C3F1 male mice. Int J Cancer. 2014; 135: 1038-47). The results showed that the tumor frequency was reduced in the CR group. However, the mechanism of tumor suppression by CR is not yet clear. In this study, we examined the effects of CR on radiation-induced mutations using gpt delta mice, which are useful to analyze mutations in various tissues throughout the whole body. Infant male mice (1-week old) were exposed to 3.8 Gy X-rays and fed a control (95 kcal/week/mouse) or CR (65 kcal/week/mouse) diet from adult stage (7-weeks old). Mice were sacrificed at the age of 7 weeks, 8 weeks and 100 days, and organs (spleen, liver, lung, thymus) were harvested. Mutations at the gpt gene in the DNA from the spleen were analyzed by using a gpt assay protocol that detects primarily point mutations in the gpt gene. The results showed that mutation frequencies were decreased in CR groups compared with non-CR groups. Sequence analysis of the gpt gene in mutants revealed a reduction in the G:C to T:A transversion in CR groups. Since it is known that 8-oxoguanine could result in this base substitution and that CR has an effect of reducing oxidative stress, these results indicate that the suppression of oxidative stress by CR is the cause of the reduction of this transversion.

Reduced High-Dose Radiation-Induced Residual Genotoxic Damage by Induction of Radioadaptive Response and Prophylactic Mild Dietary Restriction in Mice

“… 47 , 49 On the other hand, a majority of studies in animal models and humans showed that dietary restriction-induced reduced mutations and radiocarcinogenesis are underlying mechanisms of increased antioxidant glutathione level, improved redox state, decreased mitochondrial ROS production, reduced oxidative stress and damage, and decreased chronic inflammation, leading to an overall reduction of steady-state oxidative damage to macromolecules including proteins, lipids and DNA in animals. 23 , 32 , 33 , 50 - 54 Meanwhile, RAR is also known as through mechanisms of increased antioxidant capability, decreased ROS production, reduced oxidative stress and damage, increased DNA repair and decreased chronic inflammation. 7 - 12…”

“…Pre-exposure caloric restriction could prevent the initiation of direct genotoxic leukemogenesis, and post-exposure could improve mitochondrial function, reduce production of reactive oxygen species, and relieve indirect and epigenetic leukemogenesis. 28 - 33 , 58 …”

“… 28 - 31 Furthermore, post-exposure onset of dietary intervention (calorie restriction) in animal models showed extended lifespan, reduced frequencies of radiocarcinogenesis (late-occurring tumor) and mutations. 32 , 33 These studies demonstrated that dietary restriction could generally prevent incidence of radiocarcinogenesis, irrespective of calorie restriction onset timing in terms of irradiation, in experimental models.…”

Mitigation of Iron Irradiation-Induced Genotoxicity and Genomic Instability by Postexposure Dietary Restriction in Mice

“…Studies showed that DR could lead to the reduction of oxidative damage to macromolecules [ 73 ], modulation of oxidative DNA damage, and enhancement of DNA repair via affection of adrenal metabolism, insulin metabolism, and various aspects of gene expression [ 16 , 74 ]. DR could also decrease IR-induced mutation frequencies via suppression of oxidative stress in a radiocarcinogenesis model in mice [ 39 ]. Through a process known as mitohormesis, a retrograde response, DR could increase formation of ROS within the mitochondria.…”

“…On the other hand, the mechanisms underlying postexposure onset DR-induced reduction of radiocarcinogenesis are still largely unknown. A few of studies in mouse models show that suppression of radiocarcinogenesis could be attributed to the reduced IR-induced mutations [ 38 , 39 ]. In this work, the impact of postexposure onset of DR on high-LET IR-induced acute genotoxicity and late GI was investigated in a mouse model measured as micronucleus erythrocytes in the bone marrow.…”