Four thousand 8-week-old SPF B6C3F1 mice (2000 of each sex) were divided into four groups, one nonirradiated (control) and three irradiated. The irradiated groups were exposed to (137)Cs gamma rays at dose rates of 21, 1.1 and 0.05 mGy day(-1) for approximately 400 days with total doses equivalent to 8000, 400 and 20 mGy, respectively. All mice were kept until natural death, and pathological examination was performed to determine the cause of death. Neoplasms accounted for >86.7% of all deaths. Compared to the nonirradiated controls, the frequency of myeloid leukemia in males, soft tissue neoplasms and malignant granulosa cell tumors in females, and hemangiosarcoma in both sexes exposed to 21 mGy day(-1) were significantly increased. The number of multiple primary neoplasms per mouse was significantly increased in mice irradiated at 21 mGy day(-1). Significant increases in body weights were observed from 32 to 60 weeks of age in males and females exposed to 1.1 mGy day(-1) and 21 mGy day(-1), respectively. Our results suggest that life shortening (Tanaka et al., Radiat. Res. 160, 376-379, 2003) in mice continuously exposed to low-dose-rate gamma rays is due to early death from a variety of neoplasms and not from increased incidence of specific neoplasms.
Chronological changes in the chromosome aberration rates of splenocytes from specific-pathogen-free (SPF) mice after continuous and long-term exposure to low-dose-rate gamma rays were studied. Incidences of dicentrics plus centric rings (Dic+Rc), detected by conventional Giemsa staining, and dicentric chromosomes, detected by fluorescence in situ hybridization (Dic by FISH) using a centromere probe, showed an essentially linear increase up to a total accumulated dose of 8000 mGy after irradiation for about 400 days at a low dose rate of 20 mGy/day. For comparison, acute high-dose-rate and medium-dose-rate irradiation were performed. The values of the alpha coefficients in the linear regression lines for these unstable-type aberrations decreased as the dose rates were lowered from medium dose rates (200 and 400 mGy/day) to low dose rates (1 and 20 mGy/day). The dose and dose-rate effectiveness factor (DDREF), estimated by the ratio of calculated incidences using the best-fit regression lines at a high dose rate (890 mGy/min) and low dose rate (20 mGy/day), was 4.5 for Dic by FISH and 5.2 for Dic+Rc, respectively, at the same dose of 100 mGy, while different DDREFs were obtained for different accumulated doses. This is the first study to provide information regarding the effects of long-term exposure to low-dose-rate radiation on chromosomes.
Measuring global gene expression using cDNA or oligonucleotide microarrays is an effective approach to understanding the complex mechanisms of the effects of radiation. However, few studies have been carried out that investigate gene expression in vivo after prolonged exposure to low-dose-rate radiation. In this study, C57BL/6J mice were continuously irradiated with gamma-rays for 485 days at dose-rates of 0.032-13 microGy/min. Gene expression profiles in the kidney and testis from irradiated and unirradiated mice were analyzed, and differentially expressed genes were identified. A combination of pathway analysis and hierarchical clustering of differentially expressed genes revealed that expression of genes involved in mitochondrial oxidative phosphorylation was elevated in the kidney after irradiation at the dose-rates of 0.65 microGy/min and 13 microGy/min. Expression of cell cycle-associated genes was not profoundly modulated in the kidney, in contrast to the response to acute irradiation, suggesting a threshold in the dose-rate for modulation of the expression of cell cycle-related genes in vivo following exposure to radiation. We demonstrated that changes to the gene expression profile in the testis were largely different from those in the kidney. The Gene Ontology categories "DNA metabolism", "response to DNA damage" and "DNA replication" overlapped significantly with the clusters of genes whose expression decreased with an increase in the dose-rate to the testis. These observations provide a fundamental insight into the organ-specific responses to low-dose-rate radiation.
Paclitaxel (Taxol), a yew-derived antimitotic agent which binds to microtubules, can mimic certain effects of lipopolysaccharide (LPS) on macrophages from LPS responder mouse strains. The production of nitric oxide (NO) by the peritoneal macrophages of LPS responder C3H/HeN mice stimulated with taxol or LPS was partially, but not completely, suppressed by microtubule-disrupting agents, such as colchicine, podophyllotoxin, vinblastine, and nocodazole, but not by lumicolchicine, an inactive derivative of colchicine. Inducible NO synthase protein expression induced by taxol and LPS in the macrophages was also suppressed by colchicine, but colchicine did not suppress the transcription of iNOS mRNA in the macrophages after stimulation with taxol or LPS. These findings suggest that microtubules function in the posttranscriptional processes of iNOS protein expression rather than in the transcriptional process of iNOS mRNA and the synthetic process of NO molecules.
Changes in gene expression profiles in mouse liver induced by long-term low-dose-rate γ irradiation were examined by microarray analysis. Three groups of male C57BL/6J mice were exposed to whole-body radiation at dose rates of 17-20 mGy/day, 0.86-1.0 mGy/day or 0.042-0.050 mGy/day for 401-485 days with cumulative doses of approximately 8 Gy, 0.4 Gy or 0.02 Gy, respectively. The gene expression levels in the livers of six animals from each exposure group were compared individually with that of pooled sham-irradiated animals. Some genes revealed a large variation in expression levels among individuals within each group, and the number of genes showing common changes in individuals from each group was limited: 20 and 11 genes showed more than 1.5-fold modulation with 17-20 mGy/day and 0.86-1.0 mGy/day, respectively. Three genes showed more than 1.5-fold modulation even at the lowest dose-rate of 0.04-0.05 mGy/day. Most of these genes were down-regulated. RT-PCR analysis confirmed the expression profiles of the majority of these genes. The results indicate that a few genes are modulated in response to very low-dose-rate irradiation. The functional analysis suggests that these genes may influence many processes, including obesity and tumorigenesis.
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