Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Reprod Toxicol. 2018 Oct;81:28-33. doi: 10.1016/j.reprotox.2018.06.011. Epub 2018 Jun 22.
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.
羟脲，一种核苷酸还原酶抑制剂，在小鼠中是一种强有力的致畸物，导致严重的肢体和骨骼缺陷。将怀孕第 9 天的鼠胚胎暴露于羟脲中会引发早期胚胎应激反应，涉及 P53 转录因子的激活。这种 P53 激活对羟脲致胚胎毒性的影响尚不清楚。本研究的目的是检验 P53 抑制羟脲胚胎毒性的假说。Trp53 定时怀孕的小鼠在妊娠第 9 天接受生理盐水或羟脲（200 或 400mg/kg）治疗；在妊娠第 18 天检查胎儿的活力以及外部和骨骼畸形。尽管在 Trp53 胎儿中观察到胎儿体重有下降的趋势，但 Trp53 的缺失或羟脲处理均未显著影响胎儿生长。然而，与野生型同窝仔相比，羟脲在 Trp53 胎儿中引起更高的畸形和吸收发生率。因此，胎儿 P53 基因型是羟脲对器官发生期胚胎影响的重要决定因素。
