Radiation hormesis: Stimulatory effects of low doses ionizing radiation

Low to small doses of ionizing radiation conditionally show stimulatory effects in various cells and organisms, contrasting with detrimental effects induced at high doses. Radiation hormesis is defined as biopositive health effects, such as augmentation of growth and survival, enhancement of immune response, suppression of mutagenesis, and increase in resistance to damages induced by subsequent high dose exposure. Accumulating data on molecular, cellular, and organism levels demonstrate a variety of hormetic phenomena produced by low dose radiation. Living organisms have been exposed to low doses radiation since the early period of evolution, therefore, radiation hormesis may be established at least in part as a defense mechanism, and thus has important implications for health and diseases. In this review, data of radiation hormesis were presented with special emphasis on the responses of organisms. Recent studies also show potential application of low dose radiation for intervention of diseases. Research on radiation hormesis will indisputably contribute to elucidate aging processes

Radiation Hormesis: Stimulatory Effects of Low Doses Ionizing Radiation

High doses of ionizing radiation (HDR) induce a variety of harmfuleffects. However, low-doses radiation (LDR) can conditionally result instimulatory effects in various cells and organisms. Radiation hormesis isdefined as biopositive effects, such as augmentation of growth and survival,enhancement of immune response, suppression of mutagenesis and increase inresistance to the effects of further HDR. Adaptive response refers toLDR-induced resistance to the subsequent HDR. Radioadaptive responsemanifests a wide cross-resistance against oxidative damage from otherstresses. In this presentation, first we would like to introduce briefly thedose effect relationship of ionizing radiation and then review theexperimental, epidemiological and clinical data of radiation hormesis, withspecial emphasis on the studies conducted with whole-body irradiation.Second, we present our data clearly demonstrating radiation hormesis in thewhole body irradiated animals. Living organisms have always lived in thepresence of LDR. Radiation hormesis may be established at least in partevolutionarily as a cellular defense mechanism and thus have importantbiological significance and implications for health and disease. Researchon radiation hormesis will indisputably contribute to elucidate agingprocess.第7回アジア・オセアニア国際老年学会

Phosphatidylserine induces apoptosis in CHO cells without mitochondrial dysfunction in a manner dependent on caspases other than caspases-1, -3, -8 and -9.

Treatment of Chinese hamster ovary K1 cells with phosphatidylserine (PS) caused typical　apoptosis with distinct morphological and biochemical features in a dose- and time-dependent manner. However, unlike camptothecin-induced apoptosis, changes in mitochondrial transmembranepotential were not observed. In addition, cytochrome c release did not occur in PS-induced apoptosis. A pan caspase inhibitor, Z-VAD, significantly inhibited the apoptosis, but inhibitors of caspase-1, -3, -8 and -9 did not. Activities of caspase-1, -3, -8 and -9 were increased bytreatment of the cells with camptothecin, but not with PS. These results suggest that PS-induced apoptosis occurs without the collapse of mitochondrial transmembrane potential and without the release of cytochrome c, in a manner independent of caspase-1, -3, -8 and -9

Effects of Pre-exposure on the Survival and Hematological Changes in the Lethally Irradiated C57BL Mice

Exposing mice to 0.5 Gy 2 weeks before lethal (around LD50/30) whole-body irradiation has been reported to induce marked radio-resistance and to rescue them from "bone marrow death." It is widely accepted that cause of the death after dose around LD50/30 is mainly mediated by hematological failure. In order to elucidate the mechanism underlying the adaptive response, we examined effects of 0.5 Gy pre-exposure on the survival and hematological changes in C57BL mice irradiated with 6.5 Gy X-rays. The pre-exposure 2 weeks before the challenging dose enhanced survival to 77% at day 30, whereas without exposure, the survival decreased to 20 % at day 20 and 0% at day 26 after 6.5 Gy. Hematopoietic progenitor CFU-GM in the pre-irradiated mice began to recover around day 20 and then increased markedly. However, peripheral blood cell counts depleted to reach a nadir at day 20, regardless of the pre-irradiation, in spite of marked difference in the survival between the pre-irradiated and non-pre-irradiated mice. These cell counts in the pre-exposed mice recovered at day 30. We found that OK432, a bio-response modifier, could further enhance the survival of pre-exposed mice to 97%, when administrated 2 days before 0.5 Gy. The OK432 administrated mice also survived without recovery of the peripheral blood cell counts at day 20. These results manifest that the lethally irradiated mice are rescued by pre-exposure without recovery of hematological failure at least by day 20. Furthermore, we have observed long-term effect of pre-exposure for 1 year. More than half of the survivor of the pre-irradiated mice and the OK432 injected mice survived 1 year, even though they showed a variety of abnormalities.低線量放射線の生物影響に関する国際シンポジウ

Radioadaptive Response and Radiation-Induced Teratogenesis in the Late Period of Organogenesis in Mice: Involvement of p53-Dependent Apoptosis.

GENERAL INTRODUCTION In the past 5 years, a series of study was done at National Institute of Radiological Sciences to investigate the effects of radiation on the embryogenesis in mice with an emphasis on mechanisms involved in the radiation-induced adaptive response and the role of radiation-induced apoptosis played in teratogenesis in the late period of organogenesis. \nMATERIALS AND METHODS Animals: The pregnant ICR mice bearing p53(+/+) fetuses and pregnant C57BL/6 mice bearing p53(+/+), p53(+/-) and p53(-/-) fetuses were used. X-Irradiation: The animals were exposed to whole-body irradiation at room temperature with an X-ray machine, operated at 200 kVp and 20 mA, using a 0.5 mm Al + 0.5 mm Cu filter. For investigation on induction of limb defects, 1-5 Gy at 1.8 Gy/min was given on E11. For induction of radioadaptation, the priming dose of 0.05-0.50 Gy and challenging dose of 3 or 5 Gy were given on E11 and E12, respectively. The priming and challenging irradiation dose rates were 34 cGy/min and 1.8 Gy/min, respectively. Biological Endpoints: In both limb teratogenesis and induction of radioadaptation study, the dams were sacrificed by cervical dislocation. Fetuses were removed by cesarean section. The limb buds were obtained 4-6 h after irradiation, and apoptotic cells in the predigital regions were identified by the routine hematoxylin eosin staining method and quantified microscopically. The number of living fetuses and the percentage of living malformed fetuses in total living fetuses were scored on E18. \nRESULTS Radiation, via induction of apoptosis in a dose-dependent way, selectively killed the cells in the predigital regions of limb buds where the cells were undergoing differentiation. Radiation-induced apoptosis hardly occurred in the cells in the preinterdigital regions where cells had stopped DNA synthesis and were scheduled to go spontaneous apoptosis. Radiation-inducted apoptosis was responsible for both digital defects and the severity of limb teratogenesis in ICR p53(+/+) mice [1]. In C57BL/6 mice, susceptibility to radiation-induced apoptosis in the predigital regions and digital defects depended on both p53 gene dose and radiation dosage, namely, p53 wild-type (p53(+/+)) mice appeared the most sensitive, p53 heterozygous type (p53(+/-)) mice were intermediate, and p53 knockout (p53(-/-)) mice showed the most resistant. Therefore, it was concluded that prenatal radiation-induced limb defects were mediated by p53-dependent apoptosis [2]. In ICR p53(+/+) mice, prior to a challenging dose of 5.0 Gy on E12, a priming dose of 0.30 Gy on E11 significantly increased the number of the living fetuses per dam and decreased that of the external gross malformations among living fetuses on E19. The adapted dams could give some living births unexpectively, but the pups showed a high postnatal mortality, and the survivors suffered from various detrimental effects such as growth retardation and behavioral alterations. These indicated the existence of a radiation-induced adaptive response reducing prenatal death and limb defects induced by a challenging dose radiation in the late period of embryogenesis in mice [3,4]. For C57BL/6 mice, prior to a challenging dose of 3.0 Gy, the adaptive response could be induced with a priming dose at 0.05 or 0.30 Gy on E11, but this was only among the animals with p53(+/+) gene status. From these results, it was demonstrated that the adaptive response in embryogenesis was related to radiation-induced apoptosis and that induction of the radioadaptation required the involvement of p53 gene [5,6].\nREFERENCES1. B. Wang, K. Fujita, K. Watanabe, C. Ohhira, T. Odaka, I. Hayata , H. Mitani, H. Ohyama, T. Yamada and A. Shima, Radiation-induced apoptosis and limb bud teratogenesis in embryonic mice. Radiat. Res. 151, 63-68(1999).2. B. Wang, H. Ohyama, K. Haginoya, T. Odaka, T. Yamada and I. Hayata, Prenatal radiation-induced limb defects mediated by Trp53-dependent apoptosis in mice. Radiat. Res. 154, 673-679(2000).3. B. Wang, H. Ohyama, M. Nose, H. Itsukaichi, T. Nakajima , O. Yukawa, T. Odaka , K. Tanaka, E. Kojima, T. Yamada and I. Hayata, Adaptive response in embryogenesis: I. Dose and timing of radiation for reduction of prenatal death and congenital malformation during the late period of organogenesis. Radiat. Res. 150, 120-122(1998).4. B. Wang, K. Haginoya, H. Ohyama , M. Nose, H. Itsukaichi, T. Nakajima , O. Yukawa, T. Odaka , T. Yamada and I. Hayata, Adaptive response in embryogenesis: II. Postnatal developmental retardation in the prenatally irradiated mice. Radiat. Res. 152, 119-123(1999).5. B. Wang, H. Ohyama , K. Haginoya, T. Odaka , H. Itsukaichi, O. Yukawa, T. Yamada and I. Hayata, Adaptive response in embryogenesis: III. Relationship to radiation-induced apoptosis and Trp53 gene status. Radiat. Res. 154, 277-282(2000).6. B. Wang, Involvement of p53-dependent apoptosis in radiation teratogenesis and in the radioadaptive response in the late period of organogenesis of mice. J. Radiat. Res. 42, 1-10(2001).International Symposium on Biological Effects of Low Dose Radiation: Molecular Mechanisms for Radiation-induced Cellular Response and Cancer Development