Stress in pregnancy passed down for generations
Scientists investigating pregnancies in four generations of rats show that inherited epigenetic effects of stress could affect pregnancies for generations.
To better understand problems during pregnancies today, we should look to the experiences of our ancestors, research published in the open access journal BMC Medicine suggests.
Researchers from the University of Lethbridge in Canada wanted to investigate how preterm births are influenced by stress.
Preterm birth is one of the leading causes of neonatal death and can lead to health problems later in life.
Scientists examined the length of pregnancies in rats because in general there is very little variation between them.
A first generation of rats were subjected to stress late in pregnancy. The following two generations were then split into two groups that were either stressed or not stressed. The daughters of stressed rats had shorter pregnancies than the daughters of those who had not been. Remarkably, the grand-daughters of stressed rats had shorter pregnancies, even if their mothers had not been stressed.
As well as shorter pregnancies, rats whose grandmothers and mothers experienced stress displayed higher glucose levels than the control group. In addition, rats whose grandmothers or mothers who were stressed weighed less.
"We show that stress across generations becomes powerful enough to shorten pregnancy length in rats and induce hallmark features of human preterm birth. A surprising finding was that mild to moderate stress during pregnancy had a compounding effect across generations. Thus, the effects of stress grew larger with each generation."
Gerlinde Alexandra Metz, PhD, Canadian Centre for Behavioural Neuroscience, University of Lethbridge, CA, senior author of the article.
Gerlinde Metz: "Previous epigenetic studies have mainly focused on inheritance of DNA methylation signatures. What we didn't know was whether microRNAs, which are important biomarkers of human disease, can be generated by experiences and inherited across generations. We have now shown that maternal stress can generate miRNA modifications with effects across several generations."
The researchers believe that these changes are due to epigenetics - the arrangement and expression of our genes. In most cases this refers to DNA methylation of the nucleotide base pairs. In this study the researchers believe the epigenetic changes are due to microRNA (miRNA) - non-coding RNA molecules that play a role in regulating gene expression.
Further work needs to be done to understand the mechanisms that generate these epigenetic signatures and how they are passed down from generation to generation. With more knowledge of these mechanisms it may be possible to predict and prevent preterm pregnancy but also other diseases.
Gerlinde Metz: "The findings have implications outside of pregnancy, in that they suggest the causes of many complex diseases could be rooted in the experiences of our ancestors. When we better understand the mechanisms of inherited epigenetic signatures, we can predict disease risk and potentially reduce the future risk of illness."
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.
Return to top of page