The high susceptibility of heterozygous p53(+/-) mice to malformation after foetal irradiation is related to sub-competent apoptosis.
OBJECTIVE
To investigate the relationship between the incidence of radiation-induced malformations and the extent of p53-dependent apoptosis.


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.


CONCLUSIONS
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.
Nomoto
S
S
Department of Radiation Biology and Health, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan.
Ootsuyama
A
A
Shioyama
Y
Y
Katsuki
M
M
Kondo
S
S
Norimura
T
T
D000483:Alleles; D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D004307:Dose-Response Relationship, Radiation; D005313:Fetal Death; D005333:Fetus / Q000473:pathology / Q000528:radiation effects*; D016158:Genes, p53 / Q000235:genetics*; D005865:Gestational Age; D006579:Heterozygote; D007700:Kinetics; D051379:Mice; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D012333:RNA, Messenger / Q000378:metabolism; D011836:Radiation Tolerance / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014965:X-Rays / Q000009:adverse effects
D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2