Yao Youli, Robinson Alexandra M, Zucchi Fabiola C R, Robbins Jerrah C, Babenko Olena, Kovalchuk Olga, Kovalchuk Igor, Olson David M, Metz Gerlinde A S
BMC Med. 2014 Aug 7;12:121. doi: 10.1186/s12916-014-0121-6.
Chronic stress is considered to be one of many causes of human preterm birth (PTB), but no direct evidence has yet been provided. Here we show in rats that stress across generations has downstream effects on endocrine, metabolic and behavioural manifestations of PTB possibly via microRNA (miRNA) regulation.
Pregnant dams of the parental generation were exposed to stress from gestational days 12 to 18. Their pregnant daughters (F1) and grand-daughters (F2) either were stressed or remained as non-stressed controls. Gestational length, maternal gestational weight gain, blood glucose and plasma corticosterone levels, litter size and offspring weight gain from postnatal days 1 to 30 were recorded in each generation, including F3. Maternal behaviours were analysed for the first hour after completed parturition, and offspring sensorimotor development was recorded on postnatal day (P) 7. F0 through F2 maternal brain frontal cortex, uterus and placenta miRNA and gene expression patterns were used to identify stress-induced epigenetic regulatory pathways of maternal behaviour and pregnancy maintenance.
Progressively up to the F2 generation, stress gradually reduced gestational length, maternal weight gain and behavioural activity, and increased blood glucose levels. Reduced offspring growth and delayed behavioural development in the stress cohort was recognizable as early as P7, with the greatest effect in the F3 offspring of transgenerationally stressed mothers. Furthermore, stress altered miRNA expression patterns in the brain and uterus of F2 mothers, including the miR-200 family, which regulates pathways related to brain plasticity and parturition, respectively. Main miR-200 family target genes in the uterus, Stat5b, Zeb1 and Zeb2, were downregulated by multigenerational stress in the F1 generation. Zeb2 was also reduced in the stressed F2 generation, suggesting a causal mechanism for disturbed pregnancy maintenance. Additionally, stress increased placental miR-181a, a marker of human PTB.
The findings indicate that a family history of stress may program central and peripheral pathways regulating gestational length and maternal and newborn health outcomes in the maternal lineage. This new paradigm may model the origin of many human PTB causes.
慢性应激被认为是人类早产（PTB）的众多原因之一，但尚未有直接证据。在此，我们在大鼠中发现，跨代应激可能通过微小RNA（miRNA）调控对PTB的内分泌、代谢和行为表现产生下游影响。
亲代妊娠母鼠在妊娠第12至18天暴露于应激。它们的妊娠女儿（F1）和孙女（F2）要么接受应激，要么作为非应激对照。记录每一代（包括F3）的妊娠期长度、母体孕期体重增加、血糖和血浆皮质酮水平、窝仔数以及出生后1至30天的子代体重增加。在分娩完成后的第一小时分析母性行为，并在出生后第（P）7天记录子代感觉运动发育情况。利用F0至F2代母体大脑额叶皮质、子宫和胎盘的miRNA和基因表达模式来确定应激诱导的母性行为和妊娠维持的表观遗传调控途径。
直至F2代，应激逐渐缩短妊娠期长度、减少母体体重增加和行为活动，并升高血糖水平。应激组子代生长减缓及行为发育延迟早在P7时即可识别，在跨代应激母亲的F3代子代中影响最大。此外，应激改变了F2代母亲大脑和子宫中的miRNA表达模式，包括miR - 200家族，其分别调控与大脑可塑性和分娩相关的途径。子宫中主要的miR - 200家族靶基因Stat5b、Zeb1和Zeb2在F1代中因多代应激而下调。Zeb2在应激的F2代中也减少，提示妊娠维持受干扰的因果机制。此外，应激增加了胎盘miR - 181a，这是人类PTB的一个标志物。
研究结果表明，应激家族史可能会对母系中调节妊娠期长度以及母体和新生儿健康结局的中枢和外周途径进行编程。这一新模式可能为许多人类PTB病因的起源提供模型。
