Morio Yonezawa

Two types of X-ray-induced radioresistance in mice: presence of 4 dose ranges with distinct biological effects.

Preirradiation with 0.05 Gy of X rays 2 months before a second exposure to a mid-lethal dose significantly enhanced the survival rate in both female and male ICR strain mice. The radioresistance was observed between 2-2.5 months after exposure to 0.05 Gy. It did not appear within 1.5 months, and disappeared after 3 months. This radioresistance was induced only by whole-body preirradiation (not by partial irradiation of the head or the trunk). On the other hand, preirradiation with 0.30 Gy as well as 0.50 Gy resulted in radioresistance 2 weeks later, but not 2 months later. The radioresistance was induced by whole-body preirradiation or partial preirradiation of the trunk. No radioresistance was evident after exposure of intermediate preirradiation doses of 0.15 and 0.20 Gy administered before 2 months and 2-5 weeks, respectively. The present and previous results show that the biological effects of ionizing radiation may be distinguished with the following four radiation dose ranges; (1) below 0.025 Gy: no radioresistance after 2 months; (2) 0.05-0.10 Gy: significant radioresistance after 2-2.5 months; (3) 0.20 Gy: no radioresistance after 2-5 weeks; and (4) 0.30-0.50 Gy or more: significant radioresistance after 2 weeks. These results conflict with previous findings of the biological effects of ionizing radiation in which the radiation hazard increases in relation to increasing accumulated doses. Some stimulation, in addition to adaptation, by low dose irradiation may have occurred.

Radiation response of apoptosis in C57BL/6N mouse spleen after whole-body irradiation.

Purpose : Primary conditioning low dose irradiation suppresses the molecular responses against secondary challenge high dose irradiation; this phenomenon has been termed the radioadaptive response. The mechanism of the radioadaptive response is not yet clear. This study was undertaken to elucidate the radiation response of apoptosis in mouse spleen after whole-body irradiation. Materials and methods : The induction of apoptosis was analysed in the spleens of C57BL/6N mice after chronic irradiation with γ-rays at 1.5 Gy (0.001 Gy/min for 25 h) followed by challenge irradiation with X-rays at 3.0Gy (1 Gy/min). Results : Accumulation of p53 and Bax, and the induction of apoptosis were observed dose-dependently in mouse spleen 12 h after acute irradiation at a high dose-rate. However, it was found that there was significant suppression of the accumulation of p53 and Bax, and induction of apoptosis 12 h after challenge irradiation at 3.0Gy at a high dose-rate following chronic preirradiation at 1.5Gy at a low dose-rate. In addition, the combination of pre-irradiation at 1.5Gy at a high dose-rate and challenge irradiation at 3.0Gy at a high dose-rate could not suppress the accumulation of p53 and Bax or the induction of apoptosis. Conclusions : Chronic pre-irradiation at a low dose-rate suppressed Bax-mediated apoptosis. These findings suggest that the radioadaptive response in mouse spleen may be due to a suppression of p53-mediated apoptosis.

Increase in Endogenous Spleen Colonies without Recovery of Blood Cell Counts in Radioadaptive Survival Response in C57BL/6 Mice

Abstract Yonezawa, M., Horie, K., Kondo, H. and Kubo, K. Increase in Endogenous Spleen Colonies without Recovery of Blood Cell Counts in Radioadaptive Survival Response in C57BL/6 Mice. Radiat. Res. 161, 161–167 (2004). The radioadaptive survival response induced by a conditioning exposure to 0.45 Gy and measured as an increase in 30-day survival after mid-lethal X irradiation was studied in C57BL/6N mice. The acquired radioresistance appeared on day 9 after the conditioning exposure, reached a maximum on days 12–14, and disappeared on day 21. The conditioning exposure 14 days prior to the challenge exposure increased the number of endogenous spleen colonies (CFU-S) on days 12–13 after the exposure to 5 Gy. On day 12 after irradiation, the conditioning exposure also increased the number of endogenous CFU-S to about five times that seen in animals exposed to 4.25–6.75 Gy without preirradiation. The effect of the interval between the preirradiation and the challenge irradiation on the increase in endogenous CFU-S was also examined. A significant increase in endogenous CFU-S was observed when the interval was 14 days, but not 9 days. This result corresponded to the increase in survival observed on day 14 after the challenge irradiation. Radiation-inducted resistance to radiation-induced lethality in mice appears to be closely related to the marked recovery of endogenous CFU-S in the surviving hematopoietic stem cells that acquired radioresistance by preirradiation. Preirradiation enhanced the recovery of the numbers of erythrocytes, leukocytes and thrombocytes very slightly in mice exposed to a sublethal dose of 5 Gy, a dose that does not cause bone marrow death. There appears to be no correlation between the marked increase in endogenous CFU-S and the slight increase or no increase in peripheral blood cells induced by the radioadaptive response. The possible contribution by some factor, such as Il4 or Il11, that has been reported to protect irradiated animals without stimulating hematopoiesis is discussed.

Suppression of X-ray-induced apoptosis by low dose pre-irradiation in the spleen of C57BL/6 mice

Abstract Pre-irradiation with 0.45 Gy of X-rays inhibited p53 accumulation determined by a Western blotting analysis in the spleen of C57BL/6 mice 5 h after challenging exposure to 3.0 Gy. Immuno-histochemical analyses showed that the pre-irradiation decreased p53, Bax as well as apoptosis positive cell accumulation in the spleen on day 7 after 3.0 Gy. Recovery of spleen weight as well as endogenous CFUs after challenging exposure to 5.0 Gy was also stimulated by the pre-irradiation. These situations might favor recovery of hematopoietic function from radiation-induced acute injury, and might contribute to a decrease in bone-marrow death rate.

Activation of host-defense mechanism induced by exposure to a low dose of radiation: an approach to accumulate evidence on the interaction between the whole body and radiation

We found that the effect of a small dose of irradiation on the whole body exists at certain dose level windows which induce delayed radio-protective effects on an animal after a fixed time span depending on its dose levels. The striking increase of survivals against the second mid-lethal irradiation was observed in mice pre-irradiated with 5 cGy eight weeks before, or pre-irradiated with 50 cGy two weeks before. Thymocyte apoptosis was increased six hours after 5 or 50 cGy pre-irradiation. While in spleen plaqueforming cell counts with SRBC immunisation increased at the very time when mice manifested the optimal increase in survival, namely two weeks after 50 cGy pre-irradiation or eight weeks after 5 cGy pre-irradiation. Stress inducing treatment (e.g. administration of a heavy metal salt or irradiation at higher dose etc.) seems to act within a few days stimulating more events at the biochemical level. However, the low-dose irradiation seems to act more at the immune level influencing the cooperation between immune system components in the whole body.

Small dose pre-irradiation induced radioresistance and longevity after challenging irradiation in splenectomized C57BL/6 mice

Abstract Pre-irradiation with 0.45 Gy of X-rays significantly decreased bone marrow death rate after challenging high-dose exposure to 6.75 Gy in splenectomized mice. However, the increment of the 30-day survival rate was smaller compared with that of the intact animals. The life span after day 30 of the control and pre-irradiated groups of mice was observed. The median survival time was 121 days for the control and 182 days for the pre-irradiated group. Statistical analyses by generalized Wilcoxons rank sum test and log rank test showed that the pre-irradiation significantly elongated the life span of the high-dose irradiated mice.