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The adaptive response is an important phenomenon in radiobiology. A study of the conditions essential for the induction of an adaptive response is of critical importance to understanding the novel biological defense mechanisms against the hazardous effects of radiation. In our previous studies, the specific dose and timing of radiation for induction of an adaptive response were studied in ICR mouse fetuses. We found that exposure of the fetuses on embryonic day 11 to a priming dose of 0.3 Gy significantly suppressed prenatal death and malformation induced by a challenging dose of radiation on embryonic day 12. Since a significant dose-rate effect has been observed in a variety of radiobiological phenomena, the effect of dose rate on the effectiveness of induction of an adaptive response by a priming dose of 0.3 Gy administered to fetuses on embryonic day 11 was investigated over the range from 0.06 to 5.0 Gy/min. The occurrence of apoptosis in limb buds, incidences of prenatal death and digital defects, and postnatal mortality induced by a challenging dose of 3.5 Gy given at 1.8 Gy/min to the fetuses on embryonic day 12 were the biological end points examined. Unexpectedly, effective induction of an adaptive response was observed within two dose-rate ranges for the same dose of priming radiation, from 0.18 to 0.98 Gy/ min and from 3.5 to 4.6 Gy/min, for reduction of the detrimental effect induced by a challenging dose of 3.5 Gy. In contrast, when the priming irradiation was delivered at a dose rate outside these two ranges, no protective effect was observed, and at some dose rates elevation of detrimental effects was observed. In general, neither a normal nor a reverse dose- rate effect was found in the dose-rate range tested. These results clearly indicated that the dose rate at which the priming irradiation was delivered played a crucial role in the induction of an adaptive response. This paper provides the first evidence for the existence of two dose-rate ranges for the same dose of priming radiation to successfully induce an adaptive response in mouse fetuses.

The radioadaptive response and the bystander effect represent important phenomena in radiobiology that have an impact on novel biological response mechanisms and risk estimates. Micromass cultures of limb bud cells provide an in vitro cellular maturation system in which the progression of cell proliferation and differentiation parallels that in vivo. This paper presents for the first time evidence for the correlation and interaction in a micromass culture system between the radioadaptive response and the bystander effect. A radioadaptive response was induced in limb bud cells of embryonic day 11 ICR mice. Conditioning irradiation of the embryonic day 11 cells with 0.3 Gy resulted in a significant protective effect against the occurrence of apoptosis, inhibition of cell proliferation, and differentiation induced by a challenging dose of 5 Gy given the next day. Both protective and detrimental bystander effects were observed; namely, irradiating 50% of the embryonic day 11 cells with 0.3 Gy led to a successful induction of the protective effect, and irradiating 70% of the embryonic day 12 cells with 5 Gy produced a detrimental effect comparable to that seen when all the cells were irradiated. Further, the bystander effect was markedly decreased by pretreatment of the cells with an inhibitor to block the gap junction-mediated intercellular communication. These results indicate that the bystander effect plays an important role in both the induction of a protective effect by the conditioning dose and the detrimental effect of the challenge irradiation. Gap junction-mediated intercellular communication was suggested to be involved in the induction of the bystander effect.

We reported previously that a radiation-induced adaptive response existed in the late period of embryogenesis, and that radiation-induced apoptosis in the predigital regions was responsible for digital defects in embryonic ICR mice. To investigate the possible involvement of the Trp53 gene and radiation-induced apoptosis in radiation-induced adaptive responses in embryogenesis, the present study was conducted using Trp53 wild-type (Trp53(+/+)) and Trp53 heterozygous (Trp53(+/-)) embryonic mice of the C57BL/6 strain. The existence of a radioadaptive response in the Trp53(+/+) embryonic mice was demonstrated by irradiating the embryos with 5 or 30 cGy on embryonic day 11 prior to a challenging irradiation at 3 Gy on embryonic day 12. The two conditioning doses at 5 and 30 cGy significantly suppressed the induction of apoptosis by the challenging dose in the predigital regions of limb buds in the Trp53(+/+) embryonic mice, while no such effect was found in the Trp53(+/-) embryonic mice. These findings indicate that induction of a radioadaptive response in embryogenesis is related to Trp53 gene status and the occurrence of radiation-induced apoptosis.

We previously reported that a priming dose of 0.3 Gy on gestation day 11 significantly increased the rate of living fetuses and reduced the incidence of congenital malformations caused by exposure to 5 Gy X rays on gestation day 12 in ICR mice. In the present study, postnatal development of the live offspring was investigated using a set of developmental and behavioral parameters. The offspring of the mice irradiated with 0.3 Gy generally showed a delay in the appearance of most of the physiological markers, impaired acquisition of neonatal reflexes, and alteration of adult behavior. However, an increase in body weight in the females was observed 4 weeks postnatally. In the offspring primed with 0.3 Gy followed by a challenging dose of 5 Gy prenatally, a high postnatal mortality was found, and all the survivors had various radiation-induced detrimental effects. The results indicated that the priming dose was advantageous to survival itself, but was disadvantageous to the health of survivor. The results also suggested that studying the whole animal can show the extent of the effects of radiation, i.e. quality of life, in a way that cellular or molecular studies cannot.