Stress is something that we’re all too familiar with, but its impact across generations has remained controversial. The distinction between intergenerational effect and transgenerational inheritance is particularly important to understand the differences between a direct effect on exposed gametes or indirect transmission to unexposed gametes. However, the molecular mechanisms behind both phenomena have received much less attention.
Previously, the lab of Tracy Bale at the University of Pennsylvania created a mouse model to examine the effects of paternal stress on offspring. They exposed fathers to 6 weeks of chronic stress before breeding and identified transcriptomic changes in the paraventricular nucleus (PVN) of the hypothalamic-pituitary-adrenal (HPA) axis, a key brain circuit behind the stress response. Interestingly, when they examined the sperm of these fathers, they found that 9 miRNAs were upregulated, suggesting that lifetime experience affecting the HPA axis can reprogram the germ line.
Now, in their latest study, they examine what happens when these nine miRNAs are transmitted to the next generation. Here’s what went down:
- They used single-cell microinjection to deliver all nine miRNAs to wild-type zygotes.
- The multi-miRNA injection recreated an altered stress response phenotype that was “nearly identical” to that resulting from paternal exposure to chronic stress, whereas the injection of buffer or one miRNA alone did not.
- The expression of extracellular matrix and collagen genes was low in the PVN of adult offspring, suggesting altered blood-brain barrier permeability.
- None of the injected miRNAs showed differential expression in the adult PVN.
- Focusing on the mechanism of transmission, the authors used single-cell technology on the early zygotes and found that the injected miRNAs degrade stored maternal transcripts.
- The degraded target maternal transcripts included Ube3a and Sirt1, two important factors behind chromatin remodeling and neurodevelopmental disorders.
These findings confirm earlier work by the group of Isabelle Mansuy, who showed that the injection of total RNA from the sperm of stressed fathers into wild type oocytes recreates miRNA alterations and a stressed phenotype until the F2 generation. Interestingly, in Mansuy’s study, the miRNA markers analyzed disappeared in the F3 generation but altered behaviour remained, suggesting that the mechanisms of transmission may later involve other epigenetic systems.
Learn more about how stress travels across generations in PNAS, October 2015