Recent research published in Molecular psychiatry The study shows that chronic stress can impact the genetic material of sperm and, therefore, the behavior of offspring. The study reveals that high levels of stress hormones disrupt long non-coding RNAs in sperm. When these altered RNAs are injected into fertilized eggs, they lead to developmental and behavioral changes linked to affective disorders such as anxiety and depression.
The researchers wanted to study how paternal stress before conception influences the behavior of future generations. Previous studies had shown that environmental factors encountered by parents can affect the behavior of their offspring, a phenomenon known as epigenetic inheritance. The team had previously found that stress-related changes in small noncoding RNAs in sperm could lead to increased anxiety-like behavior in male offspring. However, the role of long noncoding RNAs in this process remained unclear.
RNA, or ribonucleic acid, is a molecule essential for the coding, decoding, regulation, and expression of genes. It acts as a messenger that carries instructions from DNA to control protein synthesis.
Small noncoding RNAs are a class of RNA molecules, typically 20–30 nucleotides in length, that do not encode proteins but play a crucial role in regulating gene expression and maintaining genomic stability. In contrast, long noncoding RNAs are longer RNA molecules, more than 200 nucleotides in length, that are involved in various cellular processes, including chromatin remodeling, regulation of gene expression, and modification of other RNA molecules.
“We published a study 8 years ago (Short AK et al., 2016, Translational Psychiatry) showing that increased stress hormones caused changes in small non-coding RNAs in the sperm of father mice, and also changes in anxiety and social behavior in their offspring. So we wanted to look at long non-coding RNAs and see if these changes in sperm RNAs could contribute to changes in the brain and behavior of the offspring,” says study author Anthony Hannan of the Florey Institute of Neuroscience and Mental Health at the University of Melbourne.
The study was conducted on mice. The researchers used male mice of the C57BL/6 strain from two different facilities in Australia. These male mice were divided into two groups: the first group received corticosterone (a stress hormone) in their drinking water for four weeks to mimic chronic stress, while the control group received normal drinking water.
After treatment, sperm from the males was collected and analyzed using a technique called CaptureSeq to identify changes in long noncoding RNAs. To test the impact of these changes, the researchers injected long noncoding RNAs from the corticosterone-treated and control groups into fertilized mouse eggs. These eggs were then implanted into female mice to produce offspring.
Offspring underwent various behavioral tests to assess anxiety, depression, social dominance, and attractiveness. Tests included the elevated plus maze, light-dark box, social dominance tube test, mate choice test, and Porsolt swimming test.
The study found that corticosterone exposure led to significant changes in the sperm long noncoding RNA profile. Of 7,552 long noncoding RNAs, 2,382 were differentially expressed, with 772 upregulated and 1,610 downregulated. These changes included alterations in specific long noncoding RNAs known to be involved in neuronal differentiation.
“I was surprised to find that so many (over 2,000) different large non-coding RNAs were altered by increased stress hormone levels,” Hannan told PsyPost.
When the modified long noncoding RNAs were injected into fertilized eggs, the resulting offspring showed notable behavioral differences. Male offspring in the microinjection group spent more time in the light area of the light-dark box, suggesting increased anxiety-like behavior. They also displayed greater depressive-like behavior in the Porsolt swimming test, spending more time immobile than control offspring.
The study also found that microinjected offspring had increased body weight compared to naturally conceived mice, highlighting that the presence of additional long non-coding RNAs could impact physical growth in early adulthood.
“These results suggest that increased levels of stress hormones (modeling chronic stress) can cause major changes in long noncoding RNAs in sperm, and that these changes may contribute to altered behavior in offspring,” Hannan said. “These changes in offspring are linked to depression and anxiety disorders. We need to know whether these changes also occur in human sperm and whether they contribute to brain disorders in the next generation.”
The study provides compelling evidence linking paternal stress to behavioral changes in children, but it’s important to note that the research was conducted in mice. Human studies are needed to determine whether similar mechanisms are at play.
“The main problem is that our study was done in mice and we urgently need to know whether this also happens in human sperm,” Hannan noted. “But we know that human sperm contains a similar set of large noncoding RNAs. We also know that the RNA content of human sperm can be altered by environmental exposures, including stress.”
“We urgently want to understand the mechanisms involved, both before and after conception. While exploring these mechanisms in mouse models, we also want to continue human studies, including long-term cohort studies with detailed data on mothers, fathers and their children.”
Understanding these mechanisms could have important implications for human health, including understanding the inheritance of affective disorders such as anxiety and depression. This line of research also has broader implications for our understanding of evolution. The researchers suggest that such epigenetic inheritance mechanisms may be an adaptive response, allowing offspring to better cope with the environmental conditions their parents encountered.
“These types of studies of epigenetic inheritance have important implications for evolution,” Hannan said. “I propose that Darwinian evolution (which is very slow-moving and involves genetic mutations and natural selection over many generations) generated ‘Lamarckian mechanisms’ that allow information about changes in environmental exposures from fathers to be passed on to offspring in order to improve the adaptive capacity of the next generation.”
The study, “Chronic elevated levels of stress hormones dysregulate sperm long noncoding RNAs and their embryonic microinjection impairs development and affective behaviors,” was authored by L.B. Hoffmann, B. Li, Q. Zhao, W. Wei, L.J. Leighton, T.W. Bredy, T.Y. Pang, and A.J. Hannan.