Stressed dads affect offspring brain development through sperm microRNA

Public Release: 19-Oct-2015
Penn: Stressed dads affect offspring brain development through sperm microRNA
University of Pennsylvania

More and more, scientists have realized that DNA is not the only way that a parent can pass on traits to their offspring. Events experienced by a parent over a lifetime can also have an impact.

Now University of Pennsylvania researchers have shown at the molecular level how experiencing stress changes a male mouse's sperm in such a way that it affects his offspring's response to stress. This change is imparted epigenetically, or through a means other than the DNA code, by molecules called microRNAs, or miRs.

The work, led by Tracy L. Bale, professor of neuroscience in Penn's School of Veterinary Medicine and Perelman School of Medicine, provides important clues for understanding how a father's life experiences may affect his children's brain development and mental health through a purely biological and not behavioral means.

"It's remarkable to me that seemingly mild stress to a male mouse would trigger this massive change in microRNA response and that that would get wired into the course of his offspring's development," Bale said.

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In earlier research, Bale's lab had shown that male mice that were stressed, prior to being bred, by such means as changing cages or exposing them to a predator odor of fox urine, had offspring with a dampened response to stress. When they compared sperm from the stressed fathers to their unstressed counterparts, they found increased expression of nine miRs in the stressed animals. Unlike some other types of RNA, miRs do not code for a protein; instead, they serve to silence or degrade specific messenger RNAs, preventing them from being translated into proteins.

"Just showing that the levels were different doesn't make it relevant or interesting," Bale said. "We wanted to find out whether they were having a causal role."

To find out, the team microinjected the nine miRs into mouse zygotes, which were then implanted into normal female mice who carried them as surrogates. They also included control groups in which zygotes received either a sham injection or an injection of a single miR. When the offspring became adults, the researchers examined their response to stress, just as they had done in their 2013 study.

"The results mapped right onto what we had shown before," Bale said.

When subjected to a mild stress, in this case, being restrained briefly, the offspring that arose from the zygotes that received the multi-miR injections had lower cortisone levels compared to offspring in the control groups. The mice in the multi-miR injection group also had significant changes in the expression of hundreds of genes in the paraventricular nucleus, a brain region involved in directing stress regulation, suggesting wide-spread changes in early neurodevelopment.

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They also hope to study the role of miRs in humans to discern whether some may vary in response to stress in a similar way as in mice.

The work was supported by the National Institute of Mental Health.
[I expect this effect will be shown in other species, including humans, because it is a way to quickly improve the offspring's responses to a particular environment.]