Ancestral exposure to stress epigenetically programs preterm birth risk and adverse maternal and newborn outcomes

Abstract

BackgroundChronic 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.MethodsPregnant 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.ResultsProgressively 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.ConclusionsThe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-014-0121-6) contains supplementary material, which is available to authorized users.

Multigenerational prenatal stress increases the coherence of brain signaling among cortico–striatal–limbic circuits in adult rats

“…Our previous work showed that http multi-generational experience of recurrent PNS accumulates across generations and sensorimotor impairments in later generations exceed the effects of PNS in the first generation (Erikson et al, 2014;Yao et al, 2014). Contrary to such sensorimotor deficits, we propose that some essential cognitive functions may reveal adaptive changes of stress coping in multi-generational prenatal stressed (MGPNS) rats.…”

DNA methylation provides insight into intergenerational risk for preterm birth in African Americans

“…They linked their findings to epigenetic regulation of the placenta and other key tissues, providing a potential mechanism for inter-generational transmission of stress. 61 This study has a number of strengths and limitations. The primary limitation is the sample size, which is, in part, due to the fact that we restricted the design to only African Americans with spontaneous PTB prior to 34 weeks gestation and uncomplicated controls.…”

Kazanilmiş Epi̇geneti̇k Deği̇şi̇kli̇kleri̇n Kalitimi Ve Hastaliklara Yatkinliktaki̇ Rolü

“…Yao ve arkadaşları tarafından yapılan çalışmada, dişi fareye gebeliğin 12-18. günleri arasında kronik stres uygulanmasının F1, F2 ve F3 farelerde gebelik süresinde azalma, gebelik döneminde kilo alımı ve kan glukoz düzeyinde artış gözlenmiştir (21). Stres uygulaması ayrıca yavrularda büyüme geriliğine ve davranış bozukluklarına yol açarken, F2 annelerde beyin ve uterusta miR-200 ailesine ait miRNA'ların ifadelerinde değişiklikler saptanmıştır (21). Yapılan çalışmalarda, paternal stres sonucu sperm hücrelerinde oluşan epigenetik düzenlemelerin de sonraki jenerasyonlara aktarılarak yavrularda stres ile ilişkili fenotiplerin ortaya çıkmasına neden olduğu saptanmıştır (39).…”