Hydroxyurea embryotoxicity is enhanced in P53-deficient mice

Hydroxyurea, a ribonucleotide reductase inhibitor, is a potent teratogen in mice, causing severe limb and skeletal defects. The exposure of gestation day nine murine embryos to hydroxyurea elicits an early embryonic stress response that involves activation of the P53 transcription factor. The impact of this P53 activation on the embryotoxicity of hydroxyurea- is not known. The goal of this study was to test the hypothesis that P53 acts to suppress hydroxyurea embryotoxicity. Trp53(+/-) timed pregnant mice were treated with saline or hydroxyurea (200 or 400 mg/kg) on gestation day nine; fetuses were examined for viability and external and skeletal malformations on gestation day eighteen. Neither the deletion of Trp53 nor hydroxyurea treatment significantly affected fetal growth although a trend towards a decrease in fetal weights was observed in Trp53(+/-) fetuses. However, hydroxyurea induced a significantly higher incidence of malformations and resorptions in Trp53(-/-)fetuses compared to their wildtype littermates. Thus, fetal P53 genotype is an important determinant of the effects of hydroxyurea on organogenesis-stage embryos.