Sometimes external events in a person’s life change their germline — the cellular information that’s passed on to their offspring. Those changes are called epigenetic changes.
Some studies suggest male mice’s sperm is affected by stress. Other studies have shown mouse parents can pass down increased sensitivity to stress to their offspring. But researchers haven’t been able to definitely prove if the sperm itself is the reason for these similarities in offspring or if other factors, like learned behavioral cues from the parents, are responsible.
New research, published Monday in The Journal of Neuroscience, suggests the sperm itself responsible for these changes — and the sperm of mice who are resilient to stress also pass that resiliency on to their offspring.
Further, the researchers determined the molecular changes in the mice’s sperm that cause the epigenetic changes to occur. These findings might help us better understand the complex factors involved in developing a mood disorder explains co-lead author Ashley Cunningham, a neuroscience Ph.D. student at the Icahn School of Medicine at Mount Sinai.
“Having a better understanding of what is contributing [to mood disorders] is important because this study suggests that it's not just the genes you inherit from your parents, but it can also be your parents' experiences that can impact your risk of developing mood disorders,” Cunningham tells Inverse.
How they did it — First, researchers sequenced the RNA in male mice’s sperm. They then exposed those mice to ten days of chronic social defeat stress, in which naive mice are exposed to aggressor mice. The scientists tracked their responses and evaluated stress levels.
Based on how the mice responded over the course of 10 days, the researchers sorted the mice into two groups:
- Mice who showed resiliency in the face of stress
- Mice who were susceptible to it
Then, the researchers sequenced the RNA in the male sperm again and compared the before and after changes.
What they found in the sperm — After sequencing the RNA, the team found stress changed 1,460 genes in susceptible mice but only 62 genes in resilient mice. These results reveal sperm transmits short-term environmental information to offspring through changes in the sperm.
Specifically, they found the changes in long noncoding RNA (IncRNA).
Co-lead author Ashley Cunningham is a neuroscience Ph.D. student at the Icahn School of Medicine at Mount Sinai. “One other study had looked at IncRNA, but our study is the first to sequence IncRNA both before and after the stressor and compare the two,” she tells Inverse.
What they found in the offspring — The offspring of stress-susceptible mice showed increased stress behaviors compared to the offspring of the resilient and control mice.
“... sperm plays a direct role in the transmission of stress responses.”
Cunningham says the researchers used natural mating as well as artificial insemination.
“Previous studies have found that if you allow a female to naturally mate with a male mouse that has gone through an environmental stressor, the female can sense that and they provide additional maternal care,” Cunningham says.
The researchers used siblings for natural mating and artificial insemination — the only difference was the means of insemination.
“The same pattern appeared in offspring conceived via artificial insemination, indicating sperm plays a direct role in the transmission of stress responses,” Cunningham says.
Why it matters — “Mood disorders are very complicated, Cunningham tells Inverse. “We understand some of the factors that contribute, like family history and genetics.”
What we don’t understand as well, Cunningham says, is how environmental stimuli like stress contribute to next-generation mood disorders. This study suggests the experiences of one’s parents might contribute.
“I think that's important when we're thinking about things like the Holocaust or slavery because those are generational traumas that we may not understand how they're impacting these large groups of communities.”
What it means for the future — As Cunningham says, mood disorders are complex. That makes them extremely difficult to effectively treat. What works for one person with a certain mood disorder often doesn’t work for someone else with the same disorder.
By better understanding the different factors that contribute to developing a mood disorder, we might be able to develop better treatments and ultimately even prevent them.
Abstract: Paternal stress can induce long-lasting changes in germ cells potentially propagating heritable changes across generations. To date, no studies have investigated differences in transmission patterns between stress-resilient and -susceptible mice. We tested the hypothesis that transcriptional alterations in sperm during chronic social defeat stress (CSDS) transmit increased susceptibility to stress phenotypes to the next generation. We demonstrate differences in offspring from stressed fathers that depend upon paternal category (resilient vs susceptible) and offspring sex. Importantly, artificial insemination reveals that sperm mediates some of the behavioral phenotypes seen in offspring. Using RNA-sequencing we report substantial and distinct changes in the transcriptomic profiles of sperm following CSDS in susceptible vs resilient fathers, with alterations in long noncoding RNAs (lncRNAs) predominating especially in susceptibility. Correlation analysis revealed that these alterations were accompanied by a loss of regulation of protein-coding genes by lncRNAs in sperm of susceptible males. We also identify several co-expression gene modules that are enriched in differentially expressed genes in sperm from either resilient or susceptible fathers. Taken together, these studies advance our understanding of intergenerational epigenetic transmission of behavioral experience.