Establishment and activity of the planning and acting network for low dose radiation research in Japan (PLANET): 2016-2023.

The Planning and Acting Network for Low Dose Radiation Research in Japan (PLANET) was established in 2017 in response to the need for an all-Japan network of experts. It serves as an academic platform to propose strategies and facilitate collaboration to improve quantitative estimation of health risks from ionizing radiation at low-doses and low-dose-rates. PLANET established Working Group 1 (Dose-Rate Effects in Animal Experiments) to consolidate findings from animal experiments on dose-rate effects in carcinogenesis. Considering international trends in this field as well as the situation in Japan, PLANET updated its priority research areas for Japanese low-dose radiation research in 2023 to include (i) characterization of low-dose and low-dose-rate radiation risk, (ii) factors to be considered for individualization of radiation risk, (iii) biological mechanisms of low-dose and low-dose-rate radiation effects and (iv) integration of epidemiology and biology. In this context, PLANET established Working Group 2 (Dose and Dose-Rate Mapping for Radiation Risk Studies) to identify the range of doses and dose rates at which observable effects on different endpoints have been reported; Working Group 3 (Species- and Organ-Specific Dose-Rate Effects) to consider the relevance of stem cell dynamics in radiation carcinogenesis of different species and organs; and Working Group 4 (Research Mapping for Radiation-Related Carcinogenesis) to sort out relevant studies, including those on non-mutagenic effects, and to identify priority research areas. These PLANET activities will be used to improve the risk assessment and to contribute to the revision of the next main recommendations of the International Commission on Radiological Protection.

Human-mouse comparison of the multistage nature of radiation carcinogenesis in a mathematical model.

Mouse models are vital for assessing risk from environmental carcinogens, including ionizing radiation, yet the interspecies difference in the dose response precludes direct application of experimental evidence to humans. Herein, we take a mathematical approach to delineate the mechanism underlying the human-mouse difference in radiation-related cancer risk. We used a multistage carcinogenesis model assuming a mutational action of radiation to analyze previous data on cancer mortality in the Japanese atomic bomb survivors and in lifespan mouse experiments. Theoretically, the model predicted that exposure will chronologically shift the age-related increase in cancer risk forward by a period corresponding to the time in which the spontaneous mutational process generates the same mutational burden as that the exposure generates. This model appropriately fitted both human and mouse data and suggested a linear dose response for the time shift. The effect per dose decreased with increasing age at exposure similarly between humans and mice on a per-lifespan basis (0.72- and 0.71-fold, respectively, for every tenth lifetime). The time shift per dose was larger by two orders of magnitude in humans (7.8 and 0.046 years per Gy for humans and mice, respectively, when exposed at ~35% of their lifetime). The difference was mostly explained by the two orders of magnitude difference in spontaneous somatic mutation rates between the species plus the species-independent radiation-induced mutation rate. Thus, the findings delineate the mechanism underlying the interspecies difference in radiation-associated cancer mortality and may lead to the use of experimental evidence for risk prediction in humans.

Rev1 overexpression accelerates N-methyl-N-nitrosourea (MNU)-induced thymic lymphoma by increasing mutagenesis.

Rev1 has two important functions in the translesion synthesis pathway, including dCMP transferase activity, and acts as a scaffolding protein for other polymerases involved in translesion synthesis. However, the role of Rev1 in mutagenesis and tumorigenesis in vivo remains unclear. We previously generated Rev1-overexpressing (Rev1-Tg) mice and reported that they exhibited a significantly increased incidence of intestinal adenoma and thymic lymphoma (TL) after N-methyl-N-nitrosourea (MNU) treatment. In this study, we investigated mutagenesis of MNU-induced TL tumorigenesis in wild-type (WT) and Rev1-Tg mice using diverse approaches, including whole-exome sequencing (WES). In Rev1-Tg TLs, the mutation frequency was higher than that in WT TL in most cases. However, no difference in the number of nonsynonymous mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) genes was observed, and mutations involved in Notch1 and MAPK signaling were similarly detected in both TLs. Mutational signature analysis of WT and Rev1-Tg TLs revealed cosine similarity with COSMIC mutational SBS5 (aging-related) and SBS11 (alkylation-related). Interestingly, the total number of mutations, but not the genotypes of WT and Rev1-Tg, was positively correlated with the relative contribution of SBS5 in individual TLs, suggesting that genetic instability could be accelerated in Rev1-Tg TLs. Finally, we demonstrated that preleukemic cells could be detected earlier in Rev1-Tg mice than in WT mice, following MNU treatment. In conclusion, Rev1 overexpression accelerates mutagenesis and increases the incidence of MNU-induced TL by shortening the latency period, which may be associated with more frequent DNA damage-induced genetic instability.

Combined effects of radiation and simulated microgravity on intestinal tumorigenesis in C3B6F1 ApcMin/+ mice.

Explorations of the Moon and Mars are planned as future manned space missions, during which humans will be exposed to both radiation and microgravity. We do not, however, know the health effects for such combined exposures. In a ground-based experiment, we evaluated the combined effects of radiation and simulated microgravity on tumorigenesis by performing X-irradiation and tail suspension in C3B6F1 ApcMin/+ mice, a well-established model for intestinal tumorigenesis. Mice were irradiated at 2 weeks of age and underwent tail suspension for 3 or 11 weeks using a special device that avoids damage to the tail. The tail suspension treatment significantly reduced the thymus weight after 3 weeks but not 11 weeks, suggesting a transient stress response. The combination of irradiation and tail suspension significantly increased the number of small intestinal tumors less than 2 mm in diameter as compared with either treatment alone. The combined treatment also increased the fraction of malignant tumors among all small intestinal tumors as compared with the radiation-only treatment. Thus, the C3B6F1 ApcMin/+ mouse is a useful model for assessing cancer risk in a simulated space environment, in which simulated microgravity accelerates tumor progression when combined with radiation exposure.

Ionizing radiation promotes, whereas calorie restriction suppresses, NASH and hepatocellular carcinoma in mice.

The pathological conditions of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH) are the major risk factors for hepatocellular carcinoma (HCC). Exposure to DNA-damaging agents such as ionizing radiation is another risk factor for HCC; calorie restriction (CR), however, effectively delays the onset of radiation-induced HCC. We investigated whether NASH is relevant to radiation-induced HCC and the cancer-preventing effect of CR. Eight-day-old male B6C3F1 mice were irradiated with 3.8 Gy of X-rays and then fed a standard diet or 30% CR diet from 49 days of age until necropsy, which was performed from 56 to 600 days with ~100-day intervals to assess both pathological changes and gene expression levels. We found that early-life exposure to radiation accelerated lipid accumulation and NASH-like histopathological changes in the liver, accompanied by accelerated development of HCC. CR ameliorated the changes in lipid metabolism in the liver and reversed the NASH-like pathology, which effectively delayed HCC development. Gene-expression profiling revealed the radiation-related activation and CR-related suppression of the peroxisome proliferator-activated receptor gamma/Cd36 pathway of transmembrane fatty-acid translocation before development of the NASH-like state. Thus, early-life exposure to radiation affects lipid metabolism and induces a steatoinflammatory microenvironment that favors HCC development. Therefore, targeting this pathway by CR (or measures that mimic CR) may be a promising strategy for preventing HCC caused by either radiation or other DNA-damaging agents.

Azithromycin induces read-through of the nonsense Apc allele and prevents intestinal tumorigenesis in C3B6F1 ApcMin/+ mice.

Therapeutic strategies that promote read-through of a mutant gene have proved effective for certain non-neoplastic diseases. However, the efficacy of this approach is unproven regarding neoplastic diseases with germline nonsense mutations, including familial adenomatous polyposis. Here we examined the cancer-preventive efficacy of the macrolide antibiotic azithromycin, with a reported read-through effect, on intestinal tumorigenesis in C3B6F1 ApcMin/+ mice harboring a nonsense Apc mutation resulting in a truncated Apc protein. Mice were given drinking water lacking azithromycin or containing 0.0125-0.2 mg/mL azithromycin from 3 weeks of age. The small intestine and cecum were analyzed for pathological changes and alterations of intestinal flora. Azithromycin suppressed the number of tumors and the proportion of adenocarcinomas, with the most effective drinking-water concentration being 0.0125 mg/mL. Furthermore, azithromycin recovered the cellular level of full-length Apc, resulting in downregulation of ß-catenin and cyclin D1. Conversely, the effect of azithromycin on the diversity of the intestinal microbiota depended on the drinking-water concentration. These results suggest that the balance between azithromycin-mediate read-through of mutant Apc mRNA and antibacterial effects influences intestinal tumorigenesis. Thus, azithromycin is a potential anticancer agent for familial adenomatous polyposis patients harboring nonsense mutations.

Arsenite-induced Radiosensitization of Glioma Cells Is Dependent on p53 Deficiency.

BACKGROUND/AIM: Arsenite is a radiosensitizer of glioma cells both in vitro and in vivo; however, the underlying mechanism of action is unclear. Radiosensitizers specific for p53-deficient tumors are a promising adjunct to radiotherapy because, unlike normal cells, many tumor cells lack p53. Previously, we demonstrated that arsenite sensitizes the p53-deficient glioma cell line U87MG-E6 to X-rays. MATERIALS AND METHODS: Using flowcytometry, we expand these findings to p53-proficient U87MG cells exposed to heavy ion beams, including carbon and iron ions. RESULTS: Arsenite sensitized U87MG-E6, but not U87MG, cells to heavy ion beams and X-rays. Cell cycle analysis indicated that sensitization of U87MG-E6 was related to an increase in the percentage of cells in the late S/G2/M phases after combined treatment with arsenite, especially when carbon ion beams were used. Induction of γH2AX was significant in U87MG-E6, but not in U87MG, cells after irradiation with carbon ion beams plus arsenite. CONCLUSION: Arsenite sensitizes cells by increasing the percentage of cells in the late S/G2/M phases after irradiation, possibly via inhibition of DNA repair in the context of p53 deficiency. The findings provide information that may be useful for the development of advanced radiotherapy protocols.

Interstitial deletion of the Apc locus in ß-catenin-overexpressing cells is a signature of radiation-induced intestinal tumors in C3B6F1 ApcMin/+ mice†.

Recent studies have identified interstitial deletions in the cancer genome as a radiation-related mutational signature, although most of them do not fall on cancer driver genes. Pioneering studies in the field have indicated the presence of loss of heterozygosity (LOH) spanning Apc in a subset of sporadic and radiation-induced intestinal tumors of ApcMin/+ mice, albeit with a substantial subset in which LOH was not detected; whether copy number losses accompany such LOH has also been unclear. Herein, we analyzed intestinal tumors of C3B6F1 ApcMin/+ mice that were either left untreated or irradiated with 2 Gy of γ-rays. We observed intratumor mosaicism with respect to the nuclear/cytoplasmic accumulation of immunohistochemically detectable ß-catenin, which is a hallmark of Apc+ allele loss. An immunoguided laser microdissection approach enabled the detection of LOH involving the Apc+ allele in ß-catenin-overexpressing cells; in contrast, the LOH was not observed in the non-overexpressing cells. With this improvement, LOH involving Apc+ was detected in all 22 tumors analyzed, in contrast to what has been reported previously. The use of a formalin-free fixative facilitated the LOH and microarray-based DNA copy number analyses, enabling the classification of the aberrations as nondisjunction/mitotic recombination type or interstitial deletion type. Of note, the latter was observed only in radiation-induced tumors (nonirradiated, 0 of 8; irradiated, 11 of 14). Thus, an analysis considering intratumor heterogeneity identifies interstitial deletion involving the Apc+ allele as a causative radiation-related event in intestinal tumors of ApcMin/+ mice, providing an accurate approach for attributing individual tumors to radiation exposure.

Molecular and cellular basis of the dose-rate-dependent adverse effects of radiation exposure in animal models. Part I: Mammary gland and digestive tract.

While epidemiological data are available for the dose and dose-rate effectiveness factor (DDREF) for human populations, animal models have contributed significantly to providing quantitative data with mechanistic insights. The aim of the current review is to compile both the in vitro experiments with reference to the dose-rate effects of DNA damage and repair, and the animal studies, specific to rodents, with reference to the dose-rate effects of cancer development. In particular, the review focuses especially on the results pertaining to underlying biological mechanisms and discusses their possible involvement in the process of radiation-induced carcinogenesis. Because the concept of adverse outcome pathway (AOP) together with the key events has been considered as a clue to estimate radiation risks at low doses and low dose-rates, the review scrutinized the dose-rate dependency of the key events related to carcinogenesis, which enables us to unify the underlying critical mechanisms to establish a connection between animal experimental studies with human epidemiological studies.

Molecular and cellular basis of the dose-rate-dependent adverse effects of radiation exposure in animal models. Part II: Hematopoietic system, lung and liver.

While epidemiological data have greatly contributed to the estimation of the dose and dose-rate effectiveness factor (DDREF) for human populations, studies using animal models have made significant contributions to provide quantitative data with mechanistic insights. The current article aims at compiling the animal studies, specific to rodents, with reference to the dose-rate effects of cancer development. This review focuses specifically on the results that explain the biological mechanisms underlying dose-rate effects and their potential involvement in radiation-induced carcinogenic processes. Since the adverse outcome pathway (AOP) concept together with the key events holds promise for improving the estimation of radiation risk at low doses and low dose-rates, the review intends to scrutinize dose-rate dependency of the key events in animal models and to consider novel key events involved in the dose-rate effects, which enables identification of important underlying mechanisms for linking animal experimental and human epidemiological studies in a unified manner.

Calorie restriction alters the mechanisms of radiation-induced mouse thymic lymphomagenesis.

Calorie restriction (CR) suppresses not only spontaneous but also chemical- and radiation-induced carcinogenesis. Our previous study revealed that the cancer-preventive effect of CR is tissue dependent and that CR does not effectively prevent the development of thymic lymphoma (TL). We investigated the association between CR and the genomic alterations of resulting TLs to clarify the underlying resistance mechanism. TLs were obtained from previous and new experiments, in which B6C3F1 mice were exposed to radiation at 1 week of age and fed with a CR or standard (non-CR) diet from 7 weeks throughout their lifetimes. All available TLs were used for analysis of genomic DNA. In contrast to the TLs of the non-CR group, those of the CR group displayed suppression of copy-neutral loss of heterozygosity (LOH) involving relevant tumor suppressor genes (Cdkn2a, Ikzf1, Trp53, Pten), an event regarded as cell division-associated. However, CR did not affect interstitial deletions of those genes, which were observed in both groups. In addition, CR affected the mechanism of Ikzf1 inactivation in TLs: the non-CR group exhibited copy-neutral LOH with duplicated inactive alleles, whereas the CR group showed expression of dominant-negative isoforms accompanying a point mutation or an intragenic deletion. These results suggest that, even though CR reduces cell division-related genomic rearrangements by suppressing cell proliferation, tumors arise via diverse carcinogenic pathways including inactivation of tumor suppressors via interstitial deletions and other mutations. These findings provide a molecular basis for improved prevention strategies that overcome the CR resistance of lymphomagenesis.

Modifiers of radiation effects on breast cancer incidence revealed by a reanalysis of archival data of rat experiments.

Cancer risk after exposure to ionizing radiation can vary between individuals and populations, but the impact of factors governing those variations is not well understood. We previously conducted a series of carcinogenesis experiments using a rat model of breast cancer, in which 1654 rats born in 2002-2012 were exposed to γ rays at various doses and ages with or without non-radiation factors including high-fat diet, parity and chemical carcinogens. We herein reanalyze the incidence data from these archival experiments to clarify the effect of age at exposure, attained age, radiation dose and non-radiation factors (i.e. fat, parity, chemicals and birth cohorts) on radiation-related mammary cancer incidence. The analysis used excess relative risk (ERR) and excess absolute risk (EAR) models as well as generalized interaction models. Age-at-exposure dependence displayed a peak of susceptibility at puberty in both the ERR and EAR models. Attained age decreased ERR and increased EAR per unit radiation dose. The dose response was concordant with a linear model. Dietary fat exhibited a supra-multiplicative interaction, chemicals represented a multiplicative interaction, and parity and birth cohorts displayed interactions that did not significantly depart from additivity or multiplicativity. Treated as one entity, the four non-radiation factors gave a multiplicative interaction, but separation of the four factors significantly improved the fit of the model. Thus, the present study supports age and dose dependence observed in epidemiology, indicates heterogenous interactions between radiation and various non-radiation factors, and suggests the potential use of more flexible interaction modeling in radiological protection.

Lung-Cancer Risk in Mice after Exposure to Gamma Rays, Carbon Ions or Neutrons: Egfr Pathway Activation and Frequent Nuclear Abnormality.

Lung is one of the high-risk organs for radiation-induced carcinogenesis, but the risk of secondary lung-cancer development after particle-beam therapy and the underlying mechanism(s) remain to be elucidated. To investigate the effects of particle-beam radiation on adjacent normal tissues during cancer therapy, 7-week-old male and female B6C3F1 mice were irradiated with 0.2-4 Gy of gamma rays (for comparison), carbon ions (290 MeV/u, linear energy transfer 13 keV/µm), or fast neutrons (0.05-1 Gy, mean energy, ∼2 MeV), and lung-tumor development was assessed by histopathology. Mice irradiated with ≥2 Gy of carbon ions or ≥0.2 Gy of neutrons developed lung adenocarcinoma (AC) significantly sooner than did non-irradiated mice. The relative biological effectiveness values for carbon ions for lung AC development were 1.07 for male mice and 2.59 for females, and the corresponding values for neutrons were 4.63 and 4.57. Genomic analysis of lung ACs revealed alterations in genes involved in Egfr signaling. Hyperphosphorylation of Erk and a frequent nuclear abnormality (i.e., nuclear groove) were observed in lung ACs of mice irradiated with carbon ions or neutrons compared with ACs from non-irradiated or gamma-ray-irradiated groups. Our data indicate that the induction of lung AC by carbon ions occurred at a rate similar to that for gamma rays in males and approximately 2-to 3-fold greater than that for gamma rays in females. In contrast, the effect of neutrons on lung AC development was approximately 4- to 5-fold greater than that of gamma rays. Our results provide valuable information concerning risk assessment of radiation-induced lung tumors after particle-beam therapy and increase our understanding of the molecular basis of tumor development.

DOSE-RATE EFFECT OF RADIATION ON RAT MAMMARY CARCINOGENESIS AND AN EMERGING ROLE FOR STEM CELL BIOLOGY.

The uncertain cancer risk of protracted radiation exposure at low dose rates is an important issue in radiological protection. Tissue stem/progenitor cells are a supposed origin of cancer and may contribute to the dose-rate effect on carcinogenesis. The authors have shown that female rats subjected to continuous whole body γ irradiation as juveniles or young adults have a notably reduced incidence of mammary cancer as compared with those irradiated acutely. Experiments using the mammosphere formation assay suggested the presence of radioresistant progenitor cells. Cell sorting indicated that basal progenitor cells in rat mammary gland were more resistant than luminal progenitors to killing by acute radiation, especially at high doses. Thus, the evidence indicates a cell-type-dependent inactivation of mammary cells that manifests only at high acute doses, implying a link to the observed dose-rate effect on carcinogenesis.

Brca1L63X /+ rat is a novel model of human BRCA1 deficiency displaying susceptibility to radiation-induced mammary cancer.

Women who are heterozygous for deleterious BRCA1 germline mutations harbor a high risk of hereditary breast cancer. Previous Brca1-heterozygous animal models do not recapitulate the breast cancer phenotype, and thus all currently used knockout models adopt conditional, mammary-specific homozygous Brca1 loss or addition of Trp53 deficiency. Herein, we report the creation and characterization of a novel Brca1 mutant rat model harboring the germline L63X mutation, which mimics a founder mutation in Japan, through CRISPR-Cas9-based genome editing. Homozygotes (Brca1L63X/L63X ) were embryonic lethal, whereas heterozygotes (Brca1L63X/+ ) showed apparently normal development. Without carcinogen exposure, heterozygotes developed mammary carcinoma at a comparable incidence rate with their wild-type (WT) littermates during their lifetime. Intraperitoneal injection of 1-methyl-1-nitrosourea (25 or 50 mg/kg) at 7 weeks of age induced mammary carcinogenesis at comparable levels among the heterozygotes and their littermates. After exposure to ionizing radiation (0.1-2 Gy) at 7 weeks of age, the heterozygotes, but not WT littermates, displayed dose-dependent mammary carcinogenesis with 0.8 Gy-1 excess in hazard ratio during their middle age; the relative susceptibility of the heterozygotes was more prominent when rats were irradiated at 3 weeks of age. The heterozygotes had tumors with a lower estrogen receptor α immunopositivity and no evidence of somatic mutations of the WT allele. The Brca1L63X/+ rats thus offer the first single-mutation, heterozygous model of BRCA1-associated breast cancer, especially with exposure to a DNA break-inducing carcinogen. This implies that such carcinogens are causative and a key to breast cancer prevention in individuals who carry high-risk BRCA1 mutations.

Impacts of psychological stress on high dose-rate radiation acute effects in a mouse experimental model.

Psychological stress affects health. Radiation workers in the medical field or astronauts living in space have possible risks of exposure to radiation, and psychological stress is considered to be easily induced in them due to activities performed in small areas or stress conditions. The impact of psychological stress on the effects of radiation was evaluated in senescence-accelerated mouse prone 10 (SAMP10) mice and ddY mice using a confrontational housing model, which makes dominant and subordinate mice in a cage live together without severe quarrel. Mice of ddY and SAMP10 have been previously demonstrated to be influenced in terms of acute and late effects, respectively, under psychological stress by this model. In SAMP10 mice, irradiation with 4 Gy induced the death of irradiated mice under psychological stress. In ddY mice, irradiation with 5 Gy X-rays alone had almost no effect on the mouse survival, but irradiation in conditions of psychological stress promoted acute death of irradiated mice. In addition, hypocellular bone marrow was also observed histopathologically in irradiated ddY mice under stress. Psychological stress may promote damage caused by radiation through modulation of radio-sensitivity in bone marrow in mice. This model would be useful for evaluation of modulation of radiation-induced various effects by psychological stress.

Copenhagen Rats Display Dominantly Inherited Yet Non-uniform Resistance to Spontaneous, Radiation-induced, and Chemically-induced Mammary Carcinogenesis.

BACKGROUND/AIM: Genetic and environmental factors interact to dictate the risk of cancer, and animal models are expected to provide avenues for identifying such interactions. The aim of the study was to clarify the genetic susceptibility of Copenhagen rats to spontaneous, radiation-induced, and chemically-induced mammary carcinogenesis. MATERIALS AND METHODS: Female Copenhagen and Sprague- Dawley rats and their F1 hybrids were subjected at age 7 weeks to γ-irradiation or intraperitoneal injection with 1-methyl-1-nitrosourea or were not treated, and palpable mammary tumours were diagnosed histologically. Data were pooled with previous data acquired for both nontreated and irradiated Sprague-Dawley rats. RESULTS: Radiation and 1-methyl-1-nitrosourea both significantly increased the incidence of mammary cancer in all strains. Copenhagen and F1 rats displayed a significantly lower incidence than Sprague-Dawley rats in all groups, with relatively higher incidence after irradiation. F1 rats exhibited significantly higher mammary cancer incidence than Copenhagen rats in the nontreated, but not the treated, groups. The interaction of the strain and exposure effects was suggested to be quasi-multiplicative. CONCLUSION: Copenhagen rats display non-uniform resistance to spontaneous, radiation-induced, and chemically-induced mammary carcinogenesis with dominant inheritance over Sprague-Dawley rats.

Genomic profile of radiation-induced early-onset mouse B-cell lymphoma recapitulates features of Philadelphia chromosome-like acute lymphoblastic leukemia in humans.

Epidemiological studies have revealed a radiation-related increase in the risk of developing acute lymphoblastic leukemia (ALL). Our recent study revealed early induction and increased risk of precursor B-cell (pB) lymphomas in mice after radiation exposure. However, the genomic landscape of radiation-induced B-cell lymphomas remains unclear. To identify the relevant genetic alterations in mice, whole-exome sequencing was performed on both early-onset and late-onset B-cell lymphomas that developed spontaneously or after gamma-irradiation. In addition to multiple driver mutations, the data revealed that interstitial deletion of chromosome 4, including Pax5, and missense mutations in Jak3 are unique genomic alterations in radiation-induced, early-onset B-cell lymphomas. RNA sequencing revealed a pB-cell-type gene-expression profile with no involvement of known fusion genes for human ALLs in the early-onset B-cell lymphomas. Activation of Jak3/Stat5 signaling in early-onset B-cell lymphomas was validated using western capillary electrophoresis. Those features were similar to those of Philadelphia chromosome-like ALL. Our data suggest a critical role for Pax5 loss-of-function mutations in initiating B-cell leukemogenesis coupled with activation of Jak3/Stat5 signaling as a basis for the rapid development of radiation-induced pB-ALL. These molecular signatures for radiation-induced cancers will inform both risk assessment and potential targeted therapies for pB-ALL.

Environmental Enrichment Increases Radiation-induced Apoptosis Not Spontaneous Apoptosis in Mouse Intestinal Crypt Cells.

BACKGROUND/AIM: An enriched environment (EE) modifies apoptotic cell death and promotes cell proliferation in the central nervous system (CNS) in mice. However, few studies have examined the effects of an EE on apoptosis in non-CNS organs in model orgamisms. In addition, the intestinal tract is one of organs at high-risk of carcinogenesis after radiation exposure. Herein we evaluated the effects of an EE on spontaneous and radiation-induced apoptosis in intestinal crypt cells of mice. MATERIALS AND METHODS: Juvenile (3-week-old) and adult (11-week-old) male B6C3F1 mice were housed in a standard environment or EE for 8 weeks and then were whole-body irradiated with 2 Gy X-rays. Apoptosis in the small intestine and colon was analyzed with antibody against cleaved caspase 3. RESULTS: The EE significantly reduced body weight; adipose tissue weight; and serum levels of total cholesterol, triglyceride, leptin, and insulin. Although EE did not change the spontaneous apoptotic index without irradiation, it significantly increased the index after irradiation in the colonic crypt. The apoptotic index in the small intestinal crypt showed similar patterns. CONCLUSION: An EE enhances radiation-induced apoptosis of stem/progenitor cells in the small intestine and colon without affecting spontaneous apoptosis. An EE may thus reduce the risk of cancer in the intestinal tract after radiation exposure such as radiotherapy.