Stressed fathers may end up with changes to their sperm that could affect behaviour in their offspring, research in mice has shown.

Previous work by the team found that male mice who were exposed to a mildly stressful event, such as being restrained, produced sperm that was richer in certain types of molecules called microRNAs.

Crucially, the higher levels of these microRNAs in the sperm seemed to result in offspring with a dampened response to stress. That, scientists have noted, could affect the mental health of offspring, since an inability to respond appropriately to stress has been linked to neuropsychiatric disorders such as PTSD and depression.

“The hypothalamus, the part of the brain that determines your stress response, has been wired differently,” said Tracy Bale, professor of neuroscience at the University of Maryland School of Medicine, who is presenting the new research at the meeting of the American Association for the Advancement of Science in Austin, Texas.

Now the researchers say they have unpicked what is going on through work in both mice and cultured cells – experiments known as “stress in the dish”.

The team say the new experiments, which have not yet been published, revealed that an uptick in stress hormones, known as glucocorticoids, triggers changes to proteins around DNA within cells lining tubules of the epididymis, a duct through which sperm passes on its way from the testes to the vas deferens.



These protein changes result in the cells producing far more of particular microRNA molecules. These are released in tiny sacs, called vesicles, that also contain molecules vital for encouraging sperm to mature. Sperm encounter the vesicles in the epididymis, with both ending up in semen.

“[The vesicles] interact with the sperm and then the sperm carry those differences to the egg at fertilisation,” said Bale, adding that microRNAs in the sperm appear to affect single-stranded genetic material stored in the egg , affecting development and resulting in offspring that are less reactive to stress.

While mice genetically modified to lack glucocorticoid receptors in a particular part of the epididymis were not found to have offspring with a dampened stress response, those with the receptors did. When cells from the lining of the epididymis of unmodified mice were bathed in the stress hormones, they produced vesicles with higher levels of the microRNAs, with further work revealing the changes to the proteins around the DNA.

“What it is telling us is that there is a point in the reproductive tract of the male that responds to changes in the environment – in this case it is stress, but other groups have looked at things like dietary challenge,” she added. “These effects … seem to be lasting in the father.”

The team also injected the microRNA molecules into adult mice and tracked where they went. The result showed that the molecules ended up in the testes, epididymis and brain.

Facebook Twitter Pinterest Post mortem results from both sets of modified mice revealed a difference in activity in a region of the brain that is involved in fear, panic and avoidance behaviours. Photograph: Alamy Stock Photo

But, Bale notes, it is not the case that the changes to proteins around the DNA of the cells lining the epididymis are being passed down from fathers to offspring. Rather, the changes trigger a particular effect in offspring. What’s more, these effects were not seen in later generations.



While the team are currently examining whether similar effects occur in humans, Bale says pilot studies have shown that changes in vesicles in men’s semen mirror that in their sperm, suggesting that, as in mice, the two interact.

MicroRNAs are also thought to play a role in psychiatric conditions, with new research presented by Paul Kenny, professor of neuroscience at the Icahn School of Medicine at Mount Sinai, suggesting that changes in levels of particular microRNA molecules could be linked to anxious or fearful behaviour.

Previous research from human postmortem tissues revealed that levels of a particular microRNA, known as microRNA-206, was associated with the degree to which the individuals had experienced symptoms of psychosis.

In the new work, Kenny and his team genetically modified mice so that they were unable to produce this microRNA, and compared their reactions to “normal” mice, when exposed to tasks requiring them to use their prefrontal cortex.

“[The modified mice] just didn’t engage with the task, they were much more likely to hide out in the corner,” said Kenny, adding that similar results were found when the production of microRNA-206 was prevented in just one type of neuron in the prefrontal cortex of mice – a type known to form crucial connections between other types of neuron, and which is thought to malfunction in humans with schizophrenia.



The team also found that mice unable to produce microRNA-206 showed signs that this set of neurons might not be working properly in the prefrontal cortex.

Post mortem results from both sets of modified mice shed further light on that matter, revealing a difference in activity in a region of the brain that is involved in fear, panic and avoidance behaviours, compared with “normal” mice.



The team say that, taken together, the findings hint at a possible mechanism by which the malfunctioning neurons could affect behaviour in those with psychiatric conditions.

.“I do suspect this microRNA might be part of the machineries that [influence] the control that the cortex exerts over these hindbrain anxiety and fear centres,” said Kenny. “[If] this microRNA isn’t working properly, maybe you are more or less likely to demonstrate fear or anxiety responses.”

Jonathan Mill, a professor of epigenetics at the University of Exeter who was not involved in the work, welcomed the research.

“MicroRNAs play a critical role in regulating gene expression in the brain during development,” he said, “and this study appears to suggest that miR-206 has an important role in controlling anxiety-related behaviour.””



