Yuko Hoshi

Suppression of carcinogenic processes in mice by chronic low dose rate gamma-irradiation

Effects of low dose rate radiation on the process of carcinogenesis induced by a chemical carcinogen were examined. ICR female mice, 35 or 36 mice for each group, were kept and exposed to 137 Cs gamma-rays in the long- term low dose rate irradiation facility at the Central Research Institute of Electric Power Industry at a dose rate of 0.3, 0.96, or 2.5 mGy/h. Thirty-five days later, the mice were injected in the groin with 0.5 mg of 20-methylcholanthrene (MC) dissolved in olive oil, and irradiation was continued. Tumours started to appear 2 months after MC injection. Cumulative tumour incidences after 216 days following MC injection were 94% in the mice irradiated at 0.3 mGy/h, 76% at 0.95 mGy/h, 89% at 0.30 mGy/h, and 94% in non-irradiated control mice. The difference between the tumour incidence in the control mice and that in the mice irradiated at 0.95 mGy/h was statistically significant. These results indicate the suppressive effect of low dose rate irradiation on the process of tumour induction initiated by MC with an optimum dose rate of approximately 1 mGy/h.

Induction of thioredoxin in human lymphocytes with low-dose ionizing radiation

Induction of the expression of the thioredoxin (TRX) gene, producing a key protein in regulating cellular functions through redox reaction as well as being a radioprotector, was followed after ionizing irradiation of lymphocytes from human donors. The TRX mRNA level increased to a peak, 5.7-fold higher than the control at maximum, 6 h after irradiation, and then decreased. The optimum radiation dose for enhancement of induction of the TRX mRNA was 0.25 Gy. The TRX protein also increased to a peak, a 3-fold increase at maximum, with the same timing as that for TRX mRNA.

Quantitative Analysis of Biological Responses to Ionizing Radiation, Including Dose, Irradiation Time, and Dose Rate

Abstract Magae, J., Hoshi, Y., Furukawa, C., Kawakami, Y. and Ogata, H. Quantitative Analysis of Biological Responses to Ionizing Radiation, Including Dose, Irradiation Time, and Dose Rate. Radiat. Res. 160, 543–548 (2003). Because biological responses to radiation are complex processes that depend on both irradiation time and total dose, consideration of both dose and dose rate is necessary to predict the risk from long-term irradiations at low dose rates. Here we mathematically and statistically analyzed the quantitative relationships between dose, dose rate and irradiation time using micronucleus formation and inhibition of proliferation of human osteosarcoma cells as indicators of biological response. While the dose–response curves did not change with exposure times of less than 20 h, at a given dose, both biological responses clearly were reduced as exposure time increased to more than 8 days. These responses became dependent on dose rate rather than on total dose when cells were irradiated for 20 to 27 days. Mathematical analysis demonstrates that the relationship between effective dose and dose rate is well described by an exponential function when the logarithm of effective dose is plotted as a function of the logarithm of dose rate. These results suggest that our model, the modified exponential (ME) model, can be applied to predict the risk from exposure to low-dose/low-dose-rate radiation.

Ionizing Radiation Leads to the Replacement and de novo Production of Colonic Lgr5+ Stem Cells

Tissue stem cells have self-renewal capability throughout their whole life, which is high enough to lead to the accumulation of DNA damage in a stem cell pool. Whether radiation-induced damage accumulates in tissue stem cells remains unknown, but could be investigated if the fate of tissue stem cells could be followed after irradiation. To realize this goal, we used an Lgr5-dependent lineage tracing system that allows the conditional in vivo labeling of Lgr5+ intestinal stem cells and their progeny. We found that radiation induced loss of Lgr5+ stem cells in the colon, but not in the duodenum. Interestingly, the loss of colonic Lgr5+ cells was compensated by de novo production of Lgr5+ cells, which increased after irradiation. These findings show that ionizing radiation effectively stimulates the turnover of colonic Lgr5+ stem cells, implying that radiation-induced damage does not accumulate in the colonic Lgr5+ stem cells by this mechanism.

Simultaneous quantitative analysis of prostaglandins and thromboxane after low-dose X irradiation

The appearance of prostaglandins and thromboxane in mouse serum after X irradiation was observed by simultaneous quantitative analysis using gas chromatography/mass spectrometry/selected ion monitoring with stable isotope dilution methods. Mice of two strains (C57BL/CN Jcl and BALB/c) showed similar responses to X irradiation. In C57BL/6N Jcl mice, 0.2 Gy irradiation elicited a significant increase in generation of prostanoids: Immediately after irradiation, the 6-keto PGF1 alpha:TXB2 ratio and the level of PGE2 increased, after 20 min 6-keto PGF1 alpha and PGE2 increased, and after 4 h PGE1 and PGE2 increased. In BALB/c mice, generation of prostanoids was increased significantly immediately after irradiation (6-keto PGF1 alpha, 6-keto PGF1 alpha:TXB2 ratio, PGE2), and the increase was maintained from 20 min to 4 h (PGE1, PGE2) after 0.2 Gy irradiation. In C57BL/6N Jcl mice, a significant increase in production of 9alpha,11beta-PGF2 was observed at 20 min after irradiation. In BALB/c mice, a significant increase in 9alpha,11beta-PGF2 was seen immediately after irradiation and was maintained for 20 min. In C57BL/6N Jcl mice, the level of 8-epi PGF2 alpha was clearly increased 4 h after 4 Gy irradiation. A slight and slow increase was also seen after 0.2 Gy irradiation. In BALB/c mice, 8-epi PGF2 alpha was increased significantly at 20 min and 4 h after 4 Gy irradiation. These results show that 0.2 Gy irradiation stimulates production of prostanoids related to the inflammatory response in mice.

Suppressive effect of long-term low-dose rate gamma-irradiation on chemical carcinogenesis in mice

Abstract Female ICR mice, 6 weeks old, 35 in each group, were exposed to gamma-rays from a 137Cs source in the long-term low-dose rate irradiation facility at the Central Research Institute of Electric Power Industry (CRIEPI). The dose rate was 2.6 (A), 0.96 (B), or 0.30 mGy/h (C). Thirty-five days later, the mice were injected in the groin with 0.5 mg of methylcholanthrene (MC) dissolved in olive oil and irradiation was continued. Cumulative tumor incidences after 216 days following MC injection were 89% in group A, 76% in group B, and 94% in group C. The one in the non-irradiated control group was 94%. The difference in the tumor incidence between the control and position B was statistically significant, indicating the suppressive effect of the low-dose rate irradiation on the process of MC-induced carcinogenesis with an optimum dose rate around 1 mGy/h.