Spontaneous p53 activation in middle-aged C57BL/6 mice mitigates the lifespan-extending adaptive response induced by low-dose ionizing radiation.

Understanding the biological effects of low-dose (<100 mGy) ionizing radiation (LDR) is technically challenging. We investigated age-dependent LDR effects using adaptive response experiments in young (7-to 12-week-old) and middle-aged (40-to 62-week-old) C57BL/6 mice. Compared with 3 Gy irradiation, 0.02 Gy preirradiation followed by 3 Gy irradiation prolonged life in young mice but not middle-aged mice. Preirradiation also suppressed irradiation-induced 53BP1 repair foci in the small intestines, splenic apoptosis, and p53 activity in young mice but not middle-aged mice. Young p53+/- C57BL/6 mice did not show these adaptive responses, indicating that insufficient p53 function in young mice mitigated the adaptive responses. Interestingly, p53 activation in middle-aged mice spontaneously became approximately 4.5-fold greater than that in young mice, possibly masking LDR stresses. Furthermore, adaptive responses in young mice, but not in middle-aged mice, suppressed some senescence-associated secretory phenotype (SASP) factors (IL-6, CCL2, CCL5, CXCL1). Thus, LDR-induced adaptive responses associated with specific SASP factors may be attenuated by a combination of reduced DNA damage sensor/transducer function and chronic p53 activation in middle-aged mice.

Relationship between haematological data and radiation doses of TEPCO workers before and after the FDNNP accident.

We evaluated the correlation between radiation dose and the medical examination data of Tokyo Electric Power Company Holdings, Inc (TEPCO) employees working during the Fukushima Daiichi Nuclear Power Plant (FDNPP) accident in 2011. This study included 2164 male TEPCO workers who received periodic medical examinations from March 2006 to January 2013. First, we conducted log-linear regression analyses using the haematological data of 585 emergency workers and confounding factors to examine the effect of internal radiation exposure in March 2011. Since external radiation exposure was a major influence, we then evaluated the correlation between both internal and external radiation dose and the haematological data of 1801 emergency workers and confounding factors before and after the accident. Among 585 workers, internal radiation exposure in March 2011 alone was mainly due to thyroid doses (0.1-10 Gy) but not to bone marrow (BM) doses (0.01-1 mGy). Compared to before and after the accident, we found that the levels of monocytes, eosinophils (Eos) and basophils increased slightly, whereas the frequency of smoking and alcohol consumption decreased substantially. External dose exposure was positively correlated with haemoglobin (Hb), red blood cell and Eos but negatively correlated with age, haematocrit and frequency of alcohol consumption. Among these variables, Hb exhibited the strongest correlation with external dose. Regarding the correlation with Hb, although there is a possibility that confounding factors other than exposure were not evaluated, our findings on emergency workers can serve as a reference for the evaluation of health conditions during the emergency period of future nuclear-related accidents.

Long Bones Exhibit Adaptive Responses to Chronic Low-Dose-Rate Ionizing Radiation despite its Lifespan-Shortening and Carcinogenic Effects on C57BL/6 Mice.

Ionizing radiation (IR) is a well-known carcinogen. High-dose-rate (HDR) IR is known to damage long bones (in terms of mass and structure), but the relationships among dose rates (particularly low-dose-rate [LDR] IR), long-bone condition, cancer incidence, and lifespan shortening remain elusive. The aim of this study was to elucidate the effects of LDR-IR on long-bone condition by comparing the long-term consequences of HDR- and LDR-IR exposure in mice. We utilized micro-computed tomography (µCT) scans of the long bones at similar ages (mean 77-96 weeks) to compare mice receiving approximately equivalent total doses of internal LDR-IR or external HDR-IR starting at 4 weeks of age, and their respective control groups. The lifespan-shortening effects of LDR-IR and HDR-IR were similar in these mixed-sex cohorts. Notably, compared to HDR-IR mice, mice internally exposed to chronic LDR-IR with continuous hypohematopoiesis showed a significantly higher trabecular bone connective density [femur: 247% (p = 0.0042), tibia: 169% (p = 0.0005)] and midshaft cortical bone thickness/area (femur: 130% [p = 0.0079]/120% [p = 0.021], tibia: 148% [p = 0.0004]/129% [p = 0.002]). Consistent with this result, when comparing 26-32 weeks post-IR with 2-8 weeks post-IR, compared to HDR-IR-treated mice, LDR-IR-treated mice exhibited higher levels of an osteoblast marker (OPG; p = 0.67 for HDR-IR, p = 0.068 for LDR-IR) and lower levels of an osteoclast marker (CTX-I; p = 0.0079 for HDR-IR, p = 0.72 for LDR-IR) despite significantly higher levels of inflammatory markers (CCL2 and CXCL1; p = 0.36-0.8 for HDR-IR, p = 0.013-0.041 for LDR-IR). These results suggest that long bones under chronic LDR-IR stress may exhibit an adaptive response to stresses such as chronic inflammation associated with IR-induced lifespan shortening. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Comparison of the fertility of tumor suppressor gene-deficient C57BL/6 mouse strains reveals stable reproductive aging and novel pleiotropic gene.

Tumor suppressor genes are involved in maintaining genome integrity during reproduction (e.g., meiosis). Thus, deleterious alleles in tumor suppressor-deficient mice would exhibit higher mortality during the perinatal period. A recent aging model proposes that perinatal mortality and age-related deleterious changes might define lifespan. This study aimed to quantitatively understand the relationship between reproduction and lifespan using three established tumor suppressor gene (p53, APC, and RECQL4)-deficient mouse strains with the same C57BL/6 background. Transgenic mice delivered slightly reduced numbers of 1st pups than wild-type mice [ratio: 0.81-0.93 (p = 0.1-0.61)] during a similar delivery period, which suggest that the tumor suppressor gene-deficient mice undergo relatively stable reproduction. However, the transgenic 1st pups died within a few days after birth, resulting in a further reduction in litter size at 3 weeks after delivery compared with that of wild-type mice [ratio: 0.35-0.68 (p = 0.034-0.24)] without sex differences, although the lifespan was variable. Unexpectedly, the significance of reproductive reduction in transgenic mice was decreased at the 2nd or later delivery. Because mice are easily affected by environmental factors, our data underscore the importance of defining reproductive ability through experiments on aging-related reproduction that can reveal a trade-off between fecundity and aging and identify RECQL4 as a novel pleiotropic gene.

Life-Prolonging Effects of Adipose Tissue-Derived Stem Cell Transplantation into Mice Exposed to a Lethal Dose of X-Rays.

In the event of a high-dose radiation exposure accident, adipose-derived stem cell (ADSC) transplantation might be used as an emergency medical treatment to compensate for bone marrow failure. To investigate the possible course of that treatment, we examined whether transplantation of ADSCs into whole-body X-ray irradiated mice would provide resistance to radiation damage. ADSCs were obtained from a primary culture of adipocytes from adipose tissue of syngeneic mice. The ADSCs were transplanted via an intravenous (i.v.) route after whole-body irradiation (6 Gy, X-rays) of the ICR mice. Fifty days after transplantation, the survival rate of the transplanted group was 40% higher than the control group, and the difference in survival rates was maintained in the following 200 days. After 400 days, however, the difference in survival rates became smaller and disappeared after 650 days. The results indicate that ADSC transplantation may reduce lethality from acute radiation bone marrow injury for several hundred days.

Human RECQL4 represses the RAD52-mediated single-strand annealing pathway after ionizing radiation or cisplatin treatment.

Ionizing radiation (IR) and cisplatin are frequently used cancer treatments, although the mechanisms of error-prone DNA repair-mediated genomic instability after anticancer treatment are not fully clarified yet. RECQL4 mutations mainly in the C-terminal region of the RECQL4 gene lead to the cancer-predisposing Rothmund-Thomson syndrome, but the function of RECQL4ΔC (C-terminus deleted) in error-prone DNA repair remains unclear. We established several RECQL4ΔC cell lines and found that RECQL4ΔC cancer cells, but not RECQL4ΔC nontumorigenic cells, exhibited IR/cisplatin hypersensitivity. Notably, RECQL4ΔC cancer cells presented increased RPA2/RAD52 foci after cancer treatments. RECQL4ΔC HCT116 cells exhibited increased error-prone single-strand annealing (SSA) activity and decreased alternative end-joining activities, suggesting that RECQL4 regulates the DNA repair pathway choice at double-strand breaks. RAD52 depletion by siRNA or RAD52 inhibitors (5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside [AICAR], (-)-epigallocatechin [EGC]) or a RAD52-phenylalanine 79 aptamer significantly restrained the growth of RAD52-upregulated RECQL4ΔC HCT116 cells in vitro and in mouse xenografts. Remarkably, compared to single-agent cisplatin or EGC treatment, cisplatin followed by low-concentration EGC had a significant suppressive effect on RECQL4ΔC HCT116 cell growth in vivo. Together, the regimens targeting the RAD52-mediated SSA pathway after anticancer treatment may be applicable for cancer patients with RECQL4 gene mutations.

[Relationship to Carcinogenesis of Repetitive Low-Dose Radiation Exposure].

We studied the carcinogenic effects caused by repetitive irradiation at a low dose, which has received attention in recent years, and examined the experimental methods used to evaluate radiation-induced carcinogenesis. For this experiment, we selected a mouse with as few autochthonous cancers as possible. Skin cancer was selected as the target for analysis, because it is a rare cancer in mice. Beta-rays were selected as the radiation source. The advantage of using beta-rays is weaker penetration power into tissues, thus protecting organs, such as the digestive and hematogenous organs. The benefit of our experimental method is that only skin cancer requires monitoring, and it is possible to perform long-term experiments. The back skin of mice was exposed repetitively to beta-rays three times a week until the occurrence of cancer or death, and the dose per exposure ranged from 0.5 to 11.8 Gy. With the high-dose range (2.5-11.8 Gy), the latency period and carcinogenic rate were almost the same in each experimental group. When the dose was reduced to 1-1.5 Gy, the latency period increased, but the carcinogenic rate remained. When the dose was further reduced to 0.5 Gy, skin cancer never happened, even though we continued irradiation until death of the last mouse in this group. The lifespan of 0.5 Gy group mice was the same as that of the controls. We showed that the 0.5 Gy dose did not cause cancer, even in mice exposed repetitively throughout their life span, and thus refer to 0.5 Gy as the threshold-like dose.

Efficacy of hyperbaric oxygen therapy combined with mild hyperthermia for improving the anti-tumour effects of carboplatin.

PURPOSE: The aim of this study was to evaluate the effects of hyperbaric oxygen therapy (HBO) on the enhancement of hyperthermic chemosensitisation to carboplatin at mild temperatures in experimental tumours. METHODS: SCCVII carcinoma in C3H/He mice was used to assess tumour growth delay. The mice received intraperitoneal injections of carboplatin. For HBO treatment, the mice were exposed to HBO at 2.0 atmospheres of absolute oxygen for 60 min. For mild hyperthermia (HT), treatment at 41.5 °C for 30 min was performed. The tumour tissue pO2 levels were measured with a digital pO2 monitor during and immediately after treatment. RESULTS: The average time taken to reach a threefold relative tumour size was significantly longer after treatment with carboplatin combined with mild HT and HBO than after treatment with carboplatin and mild HT. The relative sizes of the tumours after the combined treatment were smallest when the treatment sequence was carboplatin, mild HT, and HBO. The tumour tissue pO2 values were significantly higher immediately after mild HT followed by HBO than immediately after HBO followed by mild HT. The tumour tissue pO2 levels during mild HT and HBO generally increased, although the patterns of the increases varied. CONCLUSION: The administration of HBO increased the effects of hyperthermic chemosensitisation to carboplatin at mild temperatures on experimental tumours, particularly when given in the sequence of carboplatin, mild HT, and HBO, a finding that supports previous clinical outcomes for a novel combined therapy using carboplatin plus HT and HBO.

What have we learned from a questionnaire survey of citizens and doctors both inside and outside Fukushima?: survey comparison between 2011 and 2013.

The disaster at the Fukushima Daiichi Nuclear Power Plant (FDNPP) remains unresolved because the estimated time to decommission a nuclear reactor appears to be approximately 40 years. The number of workers exposed to radiation doses ranging from 1 to 100 mSv continues to increase. To understand the accident progression at Fukushima and to anticipate what we should do in the future for occupational and environmental health, we performed a survey of citizens and doctors who lived inside and outside Fukushima in 2011 and 2013. In a comparison of these 2 years, the citizens inside Fukushima continue to suffer anxiety, although those living outside Fukushima tended to feel less anxious. Medical students who had recently studied radiation biology showed much less ongoing anxiety compared with other groups, suggesting that learning about the effects of radiation is essential to understanding one's own circumstances objectively and correctly. The lack of trust in the government and in the Tokyo Electric Power Company (TEPCO) in 2013 remains high in all groups. Therefore, long-term forthright explanations from the government, TEPCO, and radiation experts are indispensable not only to establish trust with people but also to alleviate psychological stress.

A novel ATM/TP53/p21-mediated checkpoint only activated by chronic γ-irradiation.

Different levels or types of DNA damage activate distinct signaling pathways that elicit various cellular responses, including cell-cycle arrest, DNA repair, senescence, and apoptosis. Whereas a range of DNA-damage responses have been characterized, mechanisms underlying subsequent cell-fate decision remain elusive. Here we exposed cultured cells and mice to different doses and dose rates of γ-irradiation, which revealed cell-type-specific sensitivities to chronic, but not acute, γ-irradiation. Among tested cell types, human fibroblasts were associated with the highest levels of growth inhibition in response to chronic γ-irradiation. In this context, fibroblasts exhibited a reversible G1 cell-cycle arrest or an irreversible senescence-like growth arrest, depending on the irradiation dose rate or the rate of DNA damage. Remarkably, when the same dose of γ-irradiation was delivered chronically or acutely, chronic delivery induced considerably more cellular senescence. A similar effect was observed with primary cells isolated from irradiated mice. We demonstrate a critical role for the ataxia telangiectasia mutated (ATM)/tumor protein p53 (TP53)/p21 pathway in regulating DNA-damage-associated cell fate. Indeed, blocking the ATM/TP53/p21 pathway deregulated DNA damage responses, leading to micronucleus formation in chronically irradiated cells. Together these results provide insights into the mechanisms governing cell-fate determination in response to different rates of DNA damage.

Persistence of red blood cells with Pig-a mutation in p53 knockout mice exposed to X-irradiation.

The Pig-a mutation assay is becoming one of the major experimental procedures used to assess in vivo genotoxicity. The assay allows simple in vivo analysis and enables gene mutations in the hematopoietic system to be measured using high throughput flow cytometry. Previously, we demonstrated that X-irradiation increased the Pig-a mutant frequencies in red blood cells (RBCs) of mice in a radiation dose-dependent manner. In this study, to understand how RBCs with Pig-a mutation induced by X-irradiation persist, we compared Pig-a mutant frequencies between irradiated C57BL/6J (p53(+/+)) mice and irradiated p53 homozygous knockout (p53(-/-)) mice by using the RBC Pig-a assay. After the peak in radiation-induced Pig-a mutant frequencies, a gradual decrease in mutant frequencies in irradiated p53(-/-) mice was observed, while irradiated p53(+/+) mice had a rapid decrease, which suggests that RBCs with Pig-a mutation are eliminated normally in irradiated p53(+/+) mice but not in irradiated p53(-/-) mice due to lack of p53 function. In addition, we also found that the p53 function affected the regulation of Pig-a mutagenesis in aging mice. Our results suggest that p53 function, distinct types of mutation, and the life span of RBCs play key roles in the persistence of Pig-a mutation in the hematopoietic system of RBCs after irradiation.

p53-dependent delayed effects of radiation vary according to time of irradiation of p53 + / - mice.

We previously reported that in p53 (+ / -) mice that had been given a whole-body dose of 3 Gy at 8 weeks of age, p53-dependent delayed effects of radiation, as manifested in T-cell receptor (TCR) variant fractions (VF) instability in mouse splenocytes, were biphasic, namely, induction of TCR-VF mutation reappeared at 44 weeks. The manifestation of the delayed effects and the measures of biological markers varied according to the timing of irradiation. We also reported that the decrease in function of the p53 gene was related to the effects of a delayed mutation. In the present study, we investigated the functions and mutations of the p53 gene in old age for p53 (+ / -) mice following irradiation at various ages. p53 (+ / -) mice were given a whole-body dose of 3 Gy at 8, 28 or 40 weeks of age. There were significant differences for all variables tested at 8 weeks of age. This was similarly the case for mice irradiated at 28 weeks of age, in which there were also significant differences in TCR VF and the percentage of apoptosis. In mice irradiated at 40 weeks of age, there were significant differences for all considered variables except for the p53 allele. We demonstrated that the different patterns of delayed mutation of the p53 gene at 56 weeks of age depended on the age at which mice had undergone 3-Gy whole-body irradiation. Our conclusions are limited to variation in p53-dependent delayed effects according to the time of irradiation.

Biological and biochemical characterization of mice expressing prion protein devoid of the octapeptide repeat region after infection with prions.

Accumulating lines of evidence indicate that the N-terminal domain of prion protein (PrP) is involved in prion susceptibility in mice. In this study, to investigate the role of the octapeptide repeat (OR) region alone in the N-terminal domain for the susceptibility and pathogenesis of prion disease, we intracerebrally inoculated RML scrapie prions into tg(PrPΔOR)/Prnp(0/0) mice, which express mouse PrP missing only the OR region on the PrP-null background. Incubation times of these mice were not extended. Protease-resistant PrPΔOR, or PrP(Sc)ΔOR, was easily detectable but lower in the brains of these mice, compared to that in control wild-type mice. Consistently, prion titers were slightly lower and astrogliosis was milder in their brains. However, in their spinal cords, PrP(Sc)ΔOR and prion titers were abundant and astrogliosis was as strong as in control wild-type mice. These results indicate that the role of the OR region in prion susceptibility and pathogenesis of the disease is limited. We also found that the PrP(Sc)ΔOR, including the pre-OR residues 23-50, was unusually protease-resistant, indicating that deletion of the OR region could cause structural changes to the pre-OR region upon prion infection, leading to formation of a protease-resistant structure for the pre-OR region.

[A questionnaire survey about public's image of radiation after the Fukushima Daiichi nuclear power plant accident].

A questionnaire survey about the public's image of radiation was performed after the Fukushima Daiichi nuclear power plant (FDNPP) accident. The survey was taken by general citizens (200 and 1640 in Fukushima and 52 outside of Fukushima) and doctors (63 in Fukushima and 1942 outside of Fukushima (53 in Oita, 44 in Sagamihara and 1,845 in Kitakyushu)) in and outside of Fukushima and second year medical students in the University of Occupational and Environmental Health, Japan. The questionnaire surveys were performed during lectures about radiation. The response rates were 86% for the general citizens in Fukushima, 91% for the general citizens outside of Fukushima, 86% for doctors in Fukushima, and 85% and 86% for doctors in Sagamihara and Oita, respectively. The questionnaire surveys were sent to clinics and hospitals in Fukushima where the general citizens answered with a response rate of 50%. When the questionnaire surveys were sent to clinics and hospitals in Kitakyushu, doctors answered, with a response rate of 17%. The percentages of anxiety about future radiation effects after the FDNPP accident were the highest among the general citizens (71.6% in Fukushima and 40.4% outside of Fukushima), in the middle among the doctors (30.2% in Fukushima and 26.2% outside of Fukushima) and the lowest among the medical students (12.2%). The doctors in Fukushima and the medical students were anxious about food and soil pollution. The general citizens and the doctors outside of Fukushima were anxious about health problems and food and soil pollution. We concluded that a high level of education about radiation decreased the anxiety about the radiation effects. It is important to spread knowledge about radiation.

Establishment of Methylation-Specific PCR for the Mouse p53 Gene.

Methylation-specific PCR (MSP) of the mouse p53 gene has not yet been reported. We searched the CpG islands, sequenced the bisulfited DNA, and designed PCR primers for methylation and unmethylation sites. DNA from a young mouse produced a strong PCR product with the unmethylated primer and a weaker band with the methylated primer. DNA from an old mouse produced bands of similar intensities with both primers. In radiation-induced tumors, DNA from an old mouse yielded similar bands with both types of primers. We suggest that MSP is a valuable technique for the epigenetic study of the mouse p53 gene.

Effects of a brain-engraftable microglial cell line expressing anti-prion scFv antibodies on survival times of mice infected with scrapie prions.

We first verified that a single chain Fv fragment against prion protein (anti-PrP scFv) was secreted by HEK293T cells and prevented prion replication in infected cells. We then stably expressed anti-PrP scFv in brain-engraftable murine microglial cells and intracerebrally injected these cells into mice before or after infection with prions. Interestingly, the injection before or at an early time point after infection attenuated the infection marginally but significantly prolonged survival times of the mice. These suggest that the ex vivo gene transfer of anti-PrP scFvs using brain-engraftable cells could be a possible immunotherapeutic approach against prion diseases.

Effects of calorie restriction on the age-dependent accumulation of mutations in the small intestine of lacZ-transgenic mice.

To understand the effect of calorie restriction on genome maintenance systems, the age-dependent accumulation of mutations in animals maintained on high and low calorie diets was examined using lacZ-transgenic mice. Mice were fed a diet of 95 kcal/w or 65 kcal/w from 2 to 17 months of age. The mutation frequencies in the lacZ gene in epithelial tissues from the small intestine were examined at 12 and 17 months. Mutation frequencies were found to be lower in mice fed with a low calorie diet than in mice fed with a high calorie diet at the two age points. The molecular nature of the mutations was examined with DNA sequencing. It showed a predominance of transversions from G:C to T:A, and this is a typical type of mutation induced by reactive oxygen species. The fraction of this type of mutation among the different types of mutations detected was not affected by calorie restriction. The percentage of the other types of mutation was not influenced either. These results suggest that calorie restriction reduces the age-dependent accumulation of mutations by stimulating or inducing various types of DNA protection and repair systems rather than protecting cells against any specific type of DNA alteration.

Dynamics of delayed p53 mutations in mice given whole-body irradiation at 8 weeks.

PURPOSE: Ionizing irradiation might induce delayed genotoxic effects in a p53-dependent manner. However, a few reports have shown a p53 mutation as a delayed effect of radiation. In this study, we investigated the p53 gene mutation by the translocation frequency in chromosome 11, loss of p53 alleles, p53 gene methylation, p53 nucleotide sequence, and p53 protein expression/phosphorylation in p53(+/+) and p53(+/-) mice after irradiation at a young age. METHODS AND MATERIALS: p53(+/+) and p53(+/-) mice were exposed to 3 Gy of whole-body irradiation at 8 weeks of age. Chromosome instability was evaluated by fluorescence in situ hybridization analysis. p53 allele loss was evaluated by polymerase chain reaction, and p53 methylation was evaluated by methylation-specific polymerase chain reaction. p53 sequence analysis was performed. p53 protein expression was evaluated by Western blotting. RESULTS: The translocation frequency in chromosome 11 showed a delayed increase after irradiation. In old irradiated mice, the number of mice that showed p53 allele loss and p53 methylation increased compared to these numbers in old non-irradiated mice. In two old irradiated p53(+/-) mice, the p53 sequence showed heteromutation. In old irradiated mice, the p53 and phospho-p53 protein expressions decreased compared to old non-irradiated mice. CONCLUSION: We concluded that irradiation at a young age induced delayed p53 mutations and p53 protein suppression.

The late effects of radiation on lifespan, lymphocyte proliferation and p53 haplodeficiency in mice.

PURPOSE: We investigated the effect of irradiation on the lifespan of eight-week-old mice, the number of lymphocytes in bone marrow and the levels of p53 protein expression in the splenocytes. METHODS AND MATERIALS: Eight-week-old mice, wild-type p53 (p53(+/+)) and heterozygous p53 (p53(+/-)), were irradiated with 3 Gy. The cell numbers and cell cycle phases of bone marrow cells were determined by flow cytometry. The splenocyte proliferation was evaluated by a fluorescent cell viability assay. The p53 expression was evaluated by Western blotting. RESULTS: The lifespan of the irradiated mice was shorter than that of the non-irradiated mice. In irradiated 72-week-old p53(+/+) mice and 56-week-old p53(+/-) mice, the number of lymphocytes in bone marrow decreased as compared to that in the non-irradiated mice. In 56-week-old p53(+/-) mice, the S- and G2/M-phases of lymphocytes in the irradiated mice were increased compared to that in the non-irradiated mice. The splenocyte proliferation in p53(+/+) mice decreased with age, and the proliferation in the irradiated mice was much lower than that in the non-irradiated mice. In 72-week-old p53(+/+) mice after re-irradiation, the p53 protein expression in the splenocytes of the irradiated mice was delayed as compared to those from the non-irradiated mice. CONCLUSION: We suggest that the decrease in the number of lymphocytes in bone marrow and the delayed p53 expression in splenocytes from the irradiated mice are related to the shortened lifespan after irradiation at a young age.

Radiation dose-rate effect on mutation induction in spleen and liver of gpt delta mice.

The effect of dose rate on radiation-induced mutations in two somatic tissues, the spleen and liver, was examined in transgenic gpt delta mice. These mice can be used for the detection of deletion-type mutations, and these are the major type of mutation induced by radiation. The dose rates examined were 920 mGy/min, 1 mGy/min and 12.5 microGy/min. In both tissues, the number of mutations increased with increasing dose at each of the three dose rates examined. The mutation induction rate was dependent on the dose rate. The mutation induction rate was higher in the spleen than in the liver at the medium dose rate but was similar in the two tissues at the high and low dose rates. The mutation induction rate in the liver did not show much change between the medium and low dose rates. Analysis of the molecular nature of the mutations indicated that 2- to 1,000-bp deletion mutations were specifically induced by radiation in both tissues after high- and low-dose-rate irradiation. The occurrence of deletion mutation without any sequence homology at the break point was elevated in spleen after high-dose-rate irradiation. The results indicate that the mutagenic effects of radiation in somatic tissues are dependent on dose rate and that there is some variability between tissues.