Prenatal Maternal Stress in Rats Alters the Epigenetic and Transcriptomic Landscape of the Maternal-Fetal Interface Across Four Generations [miRNA]

Prenatal maternal stress (PNMS) determines lifetime mental and physical health. Here, we show in rats that PNMS has consequences for placental function and fetal brain development across four generations (F0-F3). Using a systems biology approach, comprehensive DNA methylation (DNAm), miRNA, and mRNA profiling revealed a moderate impact of PNMS in the F1 generation, but drastic changes in F2 and F3 generations, suggesting compounding effects of PNMS with each successive generation. Both maternal and placental miRNA gene targets included de novo DNA methyltransferases, indicating robust PNMS-induced disruption in the complex epigenetic regulatory network between miRNAs and DNAm. Transgenerational programming mainly involved genes and biological pathways associated with neurological and psychiatric diseases which were linked to maternal-fetal crosstalk facilitated by the placenta. The highly correlated placenta-brain profiles support the use of placenta as a noninvasive biomarker resource to predict pathological changes in the neonatal brain. The transgenerational persistence of critical DNAm, miRNA and mRNA signatures may explain familial non-genetic disease risks.产前母体应激（Prenatal Maternal Stress，PNMS）可决定个体终身的心理与生理健康状况。本研究以大鼠为实验对象，证实产前母体应激会对四代（F0至F3）子代的胎盘功能与胎儿脑发育产生影响。研究采用系统生物学方法，通过全面的DNA甲基化（DNA methylation，DNAm）、微小RNA（microRNA，miRNA）以及信使RNA（messenger RNA，mRNA）谱分析发现，产前母体应激对F1代仅产生轻度影响，但在F2代与F3代中则引发剧烈变化，提示产前母体应激的效应会随子代传代次数增加而不断复合累积。母体与胎盘来源的微小RNA靶基因均包含从头DNA甲基转移酶（de novo DNA methyltransferases），这表明产前母体应激可强烈干扰微小RNA与DNA甲基化之间复杂的表观遗传调控网络。跨代编程所涉及的基因与生物学通路主要与神经系统及精神疾病相关，而这些通路与胎盘介导的母胎串扰存在关联。胎盘与脑组织的谱学特征高度相关，这支持将胎盘作为无创生物标志物来源，用以预测新生儿脑组织的病理变化。关键的DNA甲基化、微小RNA以及信使RNA特征可跨代持续存在，这或可解释家族性非遗传性疾病的发病风险。