PURPOSE: To investigate the relationship between the incidence of radiation-induced malformations and the extent of p53-dependent apoptosis. MATERIALS AND METHODS: Wild-type p53(+ / +) and heterozygous p53(+ / -) mice were exposed to X-rays at the mid-gestational period. The incidence of anomalies and prenatal deaths, the extent of apoptosis, and the levels of p53 protein were assessed. RESULTS: After X-irradiation with 2 Gy, the incidence of malformation (corrected for control levels) was 0 and 30%, respectively, for p53(+ / +) and p53(+ / -). After irradiation of p53(+ / +) foetuses with 3 Gy, the frequency (F) of apoptotic cells rapidly peaked at 80% at 4 h and fell close to the control level at 48 h. The relationship between F 4h after irradiation and dose (D) (1-3Gy) is accurately expressed by a single-hit equation, F= 1 -exp ( -(a + bD)¿, where the radiation-induced apoptosis rate, b, is 0.47 for the wild type and 0.22 for the heterozygous mice. The X-irradiated foetuses showed no increase in the levels of p53 protein. CONCLUSION: The higher susceptibility of irradiated p53(+ / -) foetuses to malformation is related to a twofold lower rate of apoptosis; competent removal by apoptosis of damaged cells from irradiated tissues is impaired dramatically if one of two wild-type p53 alleles is lost. The frequency of apoptotic cells in the wild type reached a maximum 4h after foetal irradiation with no measurable increase in the level of p53 protein, indicating that radiation-induced p53-mediated foetal apoptosis depends on non-transcriptional events.
PURPOSE: To investigate the relationship between the incidence of radiation-induced malformations and the extent of p53-dependent apoptosis. MATERIALS AND METHODS: Wild-type p53(+ / +) and heterozygous p53(+ / -) mice were exposed to X-rays at the mid-gestational period. The incidence of anomalies and prenatal deaths, the extent of apoptosis, and the levels of p53 protein were assessed. RESULTS: After X-irradiation with 2 Gy, the incidence of malformation (corrected for control levels) was 0 and 30%, respectively, for p53(+ / +) and p53(+ / -). After irradiation of p53(+ / +) foetuses with 3 Gy, the frequency (F) of apoptotic cells rapidly peaked at 80% at 4 h and fell close to the control level at 48 h. The relationship between F 4h after irradiation and dose (D) (1-3Gy) is accurately expressed by a single-hit equation, F= 1 -exp ( -(a + bD)¿, where the radiation-induced apoptosis rate, b, is 0.47 for the wild type and 0.22 for the heterozygous mice. The X-irradiated foetuses showed no increase in the levels of p53 protein. CONCLUSION: The higher susceptibility of irradiated p53(+ / -) foetuses to malformation is related to a twofold lower rate of apoptosis; competent removal by apoptosis of damaged cells from irradiated tissues is impaired dramatically if one of two wild-type p53 alleles is lost. The frequency of apoptotic cells in the wild type reached a maximum 4h after foetal irradiation with no measurable increase in the level of p53 protein, indicating that radiation-induced p53-mediated foetal apoptosis depends on non-transcriptional events.