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 reduction of high teratogenic risk of radiation at a high dose-rate to zero risk by lowering the dose- rate. Materials and methods: Wild-type p53(+/+), heterozygous p53(+/-) and null p53(-/-) 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 deaths was studied. Frequencies of cells dying by apoptosis were measured during or after protracted irradiation. Results: After irradiation with 2 Gy, the frequency of apoptotic cells increased to 20% for p53(+/+) mice and did not increase at all for p53(-/-) mice. 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 mGy/min. In contrast, after irradiation of p53(-/-) foetuses with 2 Gy at 1.2 mGy/min, the incidence of malformations increased 12% above control levels. Conclusion : Foetal irradiation with 2 Gy at 1.2 mGy/min was not teratogenic for p53( +/+) mice but teratogenic for p53(-/-) mice. This indicates that the p53 gene is indispensable for a threshold effect in the risk of radiation at low doses or dose- rates.