Ancestral exposure to stress epigenetically programs preterm birth risk and adverse maternal and newborn outcomes
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Date
2014
Authors
Yao, Youli
Robinson, Alexandra M.
Zucchi, Fabiola C. R.
Robbins, Jerrah C.
Babenko, Olena M.
Kovalchuk, Olga
Kovalchuk, Igor
Olson, David M.
Metz, Gerlinde A. S.
Journal Title
Journal ISSN
Volume Title
Publisher
BioMed Central
Abstract
Abstract
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
Description
Sherpa Romeo green journal: open access
Keywords
Preterm birth , Maternal stress , Prenatal stress , Transgenerational inheritance , MicroRNA , Epigenetic regulation , Gestation , Maternal health , Behavioural development , Perinatal programming , Pregnancy
Citation
Yao, Y., Robinson, A.M., Zucchi, F.C.R., Robbins, J.C., Babenko, O., Kovalchuk, O., ...Metz, G.A.S. (2014). Ancestral exposure to stress epigenetically programs preterm birth risk and adverse maternal and newborn outcomes. BMC Medicine, 12 (121), 1-12. doi:10.1186/s12916-014-0121-6