The high susceptibility of heterozygous p53(+/-) mice to malformation after foetal irradiation is related to sub-competent apoptosis

S. Nomoto, A. Ootsuyama, Y. Shioyama, M. Katsuki, S. Kondo, T. Norimura

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20 Citations (Scopus)

Abstract

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 4 h after irradiation and dose (D) (1-3 Gy) 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(+/-) foctuses 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 4 h 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.

Original languageEnglish
Pages (from-to)419-429
Number of pages11
JournalInternational Journal of Radiation Biology
Volume74
Issue number4
DOIs
Publication statusPublished - 1998

All Science Journal Classification (ASJC) codes

  • Radiological and Ultrasound Technology
  • Radiology Nuclear Medicine and imaging

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