Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD, 21201, United States.
Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD, 21201, United States.
Placenta. 2020 Oct;100:164-170. doi: 10.1016/j.placenta.2020.06.019. Epub 2020 Jul 12.
Despite a wealth of epidemiological evidence that cumulative parental lifetime stress experiences prior to conception are determinant of offspring developmental trajectories, there is a lack of insight on how these previous stress experiences are stored and communicated intergenerationally. Preconception experiences may impact offspring development through alterations in transcriptional regulation of the placenta, a major determinant of offspring growth and sex-specific developmental outcomes. We evaluated the lasting influence of maternal and paternal preconception stress (PCS) on the mid-gestation placenta and fetal brain, utilizing their transcriptomes as proximate readouts of intergenerational impact.
To assess the combined vs. dominant influence of maternal and paternal preconception environment on sex-specific fetal development, we compared transcriptional outcomes using a breeding scheme of one stressed parent, both stressed parents, or no stressed parents as controls.
Interestingly, offspring sex affected the directionality of transcriptional changes in response to PCS, where male tissues showed a predominant downregulation, and female tissues showed an upregulation. There was also an intriguing effect of parental sex on placental programming where paternal PCS drove more effects in female placentas, while maternal PCS produced more transcriptional changes in male placentas. However, in the fetal brain, maternal PCS produced overall more changes in gene expression than paternal PCS, supporting the idea that the intrauterine environment may have a larger overall influence on the developing brain than it does on shaping the placenta.
Preconception experiences drive changes in the placental and the fetal brain transcriptome at a critical developmental timepoint. While not determinant, these altered transcriptional states may underlie sex-biased risk or resilience to stressful experiences later in life.
尽管有大量的流行病学证据表明，父母在受孕前的终生压力经历会决定后代的发育轨迹，但对于这些先前的压力经历如何在代际间储存和传递，人们知之甚少。受孕前的经历可能会通过改变胎盘的转录调控来影响后代的发育，胎盘是决定后代生长和性别特异性发育结果的主要因素。我们利用胎盘和胎儿大脑的转录组作为代际影响的近似指标，评估了母体和父体受孕前压力（PCS）对中期胎盘和胎儿大脑的持久影响。
为了评估母体和父体受孕前环境对性别特异性胎儿发育的综合影响或主导影响，我们比较了采用一种压力父母、两种压力父母或无压力父母作为对照的繁殖方案下的转录结果。
有趣的是，后代的性别影响了对 PCS 反应的转录变化的方向性，其中雄性组织表现出主要下调，而雌性组织表现出上调。父体 PCS 对雌性胎盘有更多的编程作用，而母体 PCS 对雄性胎盘产生更多的转录变化，这也存在着父母性别对胎盘编程的有趣影响。然而，在胎儿大脑中，母体 PCS 引起的基因表达变化总体上比父体 PCS 更多，这支持了这样一种观点，即在宫内环境对发育中的大脑可能有比塑造胎盘更大的整体影响。
受孕前的经历在关键的发育时间点驱动了胎盘和胎儿大脑转录组的变化。虽然这些改变的转录状态不是决定性的，但它们可能是以后生活中对压力经历产生性别偏向的风险或恢复力的基础。
