Threshold effect for teratogenic risk of radiation depends on dose-rate and p53-dependent apoptosis

Purpose : To obtain evidence that the p53 gene is indispensable for reducti on of high teratogenic risk of radiation at a high dose-rate to zero risk b y lowering the dose- rate. Materials and methods: Wild-type p53(+/+), heterozygous p53(+/-) and null p 53(-/-) mice were exposed to gamma -rays at high or low dose- rates during days 9.5-10.5 of gestation. The incidence of malformations and prenatal dea ths was studied. Frequencies of cells dying by apoptosis were measured duri ng or after protracted irradiation. Results: After irradiation with 2 Gy, the frequency of apoptotic cells incr eased to 20% for p53(+/+) mice and did not increase at all for p53(-/-) mic e. For p53(+/+) mice, 2 Gy gamma -rays induced 70% malformations when given at 1.06 Gy/min, but no malformations above the control when given at 1.2 m Gy/min. In contrast, after irradiation of p53(-/-) foetuses with 2 Gy at 1. 2 mGy/min, the incidence of malformations increased 12% above control level s. Conclusion : Foetal irradiation with 2 Gy at 1.2 mGy/min was not teratogeni c for p53( +/+) mice but teratogenic for p53(-/-) mice. This indicates that the p53 gene is indispensable for a threshold effect in the risk of radiat ion at low doses or dose- rates.