Stress affects us in so many ways, and not just our own bodies either: those of our children and even grandchildren can ultimately feel its lingering effects. Slowly unraveling this intriguing yet poorly understood field of research, a new study has now detailed how stress can change sperm in such a way that it ultimately affects the stress response of offspring, altering gene expression patterns in a region of the brain. The work has been published in Proceedings of the National Academy of Sciences.
DNA may be our hereditary material, but how we end up with the traits that we do is not quite so black and white. For starters, we know that the environment can also influence our characteristics, and then of course there is epigenetics: the kind of bridge between the two, whereby the environment can alter the way in which genes are expressed without changing the actual sequence of DNA itself.
This phenomenon is what the current study was interested in. The group, based at the University of Pennsylvania, previously demonstrated that male mice subjected to stressful situations prior to siring young produced offspring with a diminished stress response. When they examined the males’ sperm, they discovered an increase in production of nine small molecules called miRNAs. Unlike RNA, or more specifically messenger RNA (mRNA), which serves as a blueprint for the production of proteins, miRNAs do not “code” for proteins, but rather alter the expression of proteins by “silencing” strands of coding RNA, chopping them up or destabilizing them.
“Just showing that the levels were different doesn’t make it relevant or interesting,” lead researcher Tracy Bale said in a statement. “We wanted to find out whether they were having a causal role.”
To explore this idea, the researchers subjected mouse zygotes (early embryos) to three different conditions prior to implantation in an unstressed surrogate mother: one group was injected with these nine miRNAs, a second received just a single miRNA, and the third received control injections. When the resulting offspring grew to adulthood, they were subjected to stress tests and analyzed further.
As anticipated, the offspring exposed to heightened levels of the nine miRNAs demonstrated altered responses to stressful situations. After being briefly restrained, the animals demonstrated dampened levels of the stress hormone cortisol compared to mice in the other two groups. Going a little deeper, the researchers were able to demonstrate that these animals had altered expression of hundreds of genes in a brain region known to be involved in stress regulation, the paraventricular nucleus of the hypothalamus.
So we know that miRNAs target stretches of mRNA, but what specifically could be going on in this situation to exert these effects? To find out, the team repeated the first stages of the experiment, but this time around they looked at the resulting levels of maternal mRNA stored in the zygotes, which only exists in the egg for a brief window during development. They found that the sperm miRNAs functioned to deplete these mRNA stores, degrading, among others, those strands involved in the remodeling of DNA and its associated molecules. Ultimately, this leads to a reprogramming of gene expression in the hypothalamus of the offspring, dysregulating their stress response.
While interesting, this doesn’t necessarily reflect what goes on in humans. That said, the researchers would like to continue this work by looking at miRNA levels in humans and examining whether they also vary in response to stress.