Valproic acid (VPA), an antiepileptic and mood-stabilizing drug, is prescribed to women of reproductive age. VPA is associated with a 1-2% increase in neural tube defects in offspring following gestational exposure and results in epigenetic modifications induced by perturbations in transcription cofactors. Cbp and p300, two transcription cofactors, play key roles in embryonic neural development. p300 is a downstream target of Akt, a protein kinase B associated with cell survival and anti-apoptotic mechanisms, as part of the Akt-p300 axis. We examined the effects of in utero VPA exposure on Cbp, p300, and Akt in gestational day (GD)9, GD10 and GD13 CD-1 mouse embryos following a teratogenic maternal dose of 400 mg/kg. Embryos were collected at 0, 1, 3 and 6 hrs post-dosing on GD9, 24 hrs post-dosing on GD10 and on GD13. GD10 embryos were grouped according to the status of neural tube closure in control, closed and open groups. GD13 heads were grouped as control, exposed but non-exencephalic and exencephalic. Our data indicate that Cbp, p300 and Akt mRNA levels were downregulated at 1 and 3 hrs post-exposure in GD9 embryos while Cbp and p300 protein levels remained stable. Akt protein levels were significantly increased 1 hr post-exposure. No significant changes were observed in either mRNA or protein expression in embryos with closed or open neural tubes compared to the control group at GD10. Downregulated expression of Cbp, p300, and Akt may play a key role in VPA-induced neural tube defects considering their vitally important role in embryonic development.

中文翻译：

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Cbp，p300和Akt在丙戊酸诱导的CD-1小鼠胚胎神经管缺陷中的作用。

丙戊酸（VPA）是一种抗癫痫药和稳定情绪的药物，已向育龄妇女开出处方。VPA与妊娠暴露后代的神经管缺陷增加1-2％有关，并导致转录辅因子扰动引起表观遗传修饰。Cbp和p300，这两个转录辅助因子，在胚胎神经发育中起关键作用。p300是Akt的下游目标，Akt是与细胞存活和抗凋亡机制相关的蛋白激酶B，是Akt-p300轴的一部分。我们检查了胎儿致孕母体剂量为400 mg / kg后，子宫内VPA暴露对妊娠天（GD）9，GD10和GD13 CD-1小鼠胚胎中Cbp，p300和Akt的影响。在GD9给药后0、1、3和6小时，在GD10和GD13给药后24小时收集胚胎。GD10胚胎根据对照组，封闭组和开放组的神经管闭合状态进行分组。将GD13头分为对照组，裸露但非脑外和脑外。我们的数据表明，GD9胚胎在暴露后1和3小时Cbp，p300和Akt mRNA水平下调，而Cbp和p300蛋白水平保持稳定。暴露后1小时，Akt蛋白水平显着增加。与对照组相比，在GD10组中，封闭或开放神经管的胚胎中mRNA或蛋白质表达均未见明显变化。考虑到Cbp，p300和Akt的表达在胚胎发育中至关重要，它们的下调表达可能在VPA诱导的神经管缺陷中起关键作用。将GD13头分为对照组，裸露但非脑外和脑外。我们的数据表明，GD9胚胎在暴露后1和3小时Cbp，p300和Akt mRNA水平下调，而Cbp和p300蛋白水平保持稳定。暴露后1小时，Akt蛋白水平显着增加。与对照组相比，在GD10组中，封闭或开放神经管的胚胎中mRNA或蛋白质表达均未见明显变化。考虑到Cbp，p300和Akt的表达在胚胎发育中至关重要，它们的下调表达可能在VPA诱导的神经管缺陷中起关键作用。GD13头分为对照组，裸露但非脑外和脑外。我们的数据表明，GD9胚胎在暴露后1和3小时Cbp，p300和Akt mRNA水平下调，而Cbp和p300蛋白水平保持稳定。暴露后1小时，Akt蛋白水平显着增加。与GD10对照组相比，在封闭或开放神经管的胚胎中，mRNA或蛋白质表达均未见明显变化。考虑到Cbp，p300和Akt的表达在胚胎发育中至关重要，它们的下调表达可能在VPA诱导的神经管缺陷中起关键作用。在暴露后1和3小时，GD9胚胎中的p300和Akt mRNA水平被下调，而Cbp和p300蛋白水平保持稳定。暴露后1小时，Akt蛋白水平显着增加。与GD10对照组相比，在封闭或开放神经管的胚胎中，mRNA或蛋白质表达均未见明显变化。考虑到Cbp，p300和Akt的表达在胚胎发育中至关重要，它们的下调表达可能在VPA诱导的神经管缺陷中起关键作用。在暴露后1和3小时，GD9胚胎中的p300和Akt mRNA水平被下调，而Cbp和p300蛋白水平保持稳定。暴露后1小时，Akt蛋白水平显着增加。与GD10对照组相比，在封闭或开放神经管的胚胎中，mRNA或蛋白质表达均未见明显变化。考虑到Cbp，p300和Akt的表达在胚胎发育中至关重要，它们的下调表达可能在VPA诱导的神经管缺陷中起关键作用。