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

BMC Medicine

Research Article

Jerrah C Robbins¹  Fabiola CR Zucchi¹  Gerlinde AS Metz¹  Alexandra M Robinson¹  Olena Babenko²  Youli Yao²  Igor Kovalchuk³  Olga Kovalchuk³  David M Olson⁴ 

[1] Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, 4401 University Drive, T1K3M4, Lethbridge, AB, Canada;Canadian Centre for Behavioural Neuroscience, Department of Neuroscience, University of Lethbridge, 4401 University Drive, T1K3M4, Lethbridge, AB, Canada;Department of Biological Sciences, University of Lethbridge, 4401 University Drive, T1K3M4, Lethbridge, AB, Canada;Department of Biological Sciences, University of Lethbridge, 4401 University Drive, T1K3M4, Lethbridge, AB, Canada;Departments of Obstetrics & Gynecology, Pediatrics and Physiology, University of Alberta, 227 HMRC, T6G2S2, Edmonton, AB, Canada;

关键词: Preterm birth;    maternal stress;    prenatal stress;    transgenerational inheritance;    microRNA;    epigenetic regulation;    gestation;    maternal health;    behavioural development;    perinatal programming;    pregnancy;   

DOI  :  10.1186/s12916-014-0121-6

 received in 2014-01-10, accepted in 2014-07-01,  发布年份 2014

来源: Springer

【 摘 要 】

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.

【 授权许可】

Unknown   
© Yao et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article,unless otherwise stated.