Are the sins of the father really passed on to the child? When it comes to a stress-filled lifestyle, Professor A. J. Hannan of the Florey Institute of Neuroscience and Mental Health at the University of Melbourne and colleagues, show that yes, they are. Chronic stress can alter sperm.
In their recent paper, the team revealed how a father’s stress before conception can impact his children’s mental health. Published in Molecular Psychiatry, the study showed that stress hormones disrupt specific molecules called long non-coding RNAs in sperm.1 These altered RNAs then affect the development and behavior of offspring, increasing their risk for anxiety and depression.
This study highlights how a father’s experiences can have a lasting impact on his children’s mental health.
Experiences can be inherited too
Scientists already knew that parents’ experiences can leave a mark on their offspring’s genes, influencing their traits – a phenomenon called epigenetic inheritance.2 Think of it like this: experiences can leave a mark on our genes that can be passed down to the next generation.
The research team had previously discovered that stress-related changes in certain molecules in sperm (small non-coding RNAs) could make male offspring more anxious.3 But this time, they focused on a different type of molecule called long non-coding RNAs (lncRNAs) to see if they also play a role in passing down the effects of stress.
“We published a study eight years ago showing that increased stress hormones caused changes to small non-coding RNAs in sperm of father mice, and changes in anxiety and social behavior in their offspring. We therefore wanted to study long non-coding RNAs and investigate whether these changes in sperm RNAs could contribute to changes in offspring brain and behavior,” explained Hannan in a recent press release.4
Essentially, RNA is a messenger that carries instructions from DNA to control the production of proteins, which are the building blocks of our bodies.5 Think of DNA as the master blueprint, and RNA as the detailed instructions that tell the body how to build specific parts. This study aimed to understand if stress alters these “instructions” in sperm, ultimately affecting the offspring’s brains.
While both small non-coding RNAs and long non-coding RNAs are types of RNA that don’t code for proteins, small non-coding RNAs are short and primarily regulate gene expression, acting like “on/off” switches.6,7 Long non-coding RNAs are longer and have more diverse roles, including influencing how DNA is structured and modifying other RNA molecules.7
From sperm to egg: how is stress transmitted?
To study the effects of stress, the researchers used two groups of male mice. One group was given corticosterone, a stress hormone, in their drinking water for four weeks to simulate chronic stress, while the other group received normal water.
After exposing the mice to the stress treatment, the researchers collected and analyzed their sperm to identify changes in long non-coding RNAs using a technique called CaptureSeq. To see if these changes had any effect, they injected the altered RNAs into fertilized mouse eggs and implanted these eggs into female mice to produce offspring.
The offspring were put through a series of tests to assess their behavior, including tests for anxiety, depression, social dominance, and even their attractiveness to potential mates. These tests included mazes, light-dark boxes, and observation of their interactions with other mice.
The light-dark box is a special two-compartment box: one side was brightly lit, while the other was dark. Mice naturally prefer the dark and feel anxious in bright light.1 By tracking how long the mice took to enter the light, how much time they spent there, and how often they ventured into the light, scientists could measure their anxiety levels.
The legacy: chronic stress alters sperm
Analyzing the sperm revealed that stress significantly changed the long non-coding RNA profile. Out of 7,552 long non-coding RNAs, 2,382 were different in the stressed mice, with 772 increased and 1,610 decreased. Importantly, these changes included alterations in specific long non-coding RNAs known to play a role in brain development.
Offspring injected with the altered long non-coding RNAs showed significant behavioral differences. The males displayed increased anxiety, spending more time in the light areas of the light-dark box test environment, and showed more signs of depression, becoming immobile more quickly in a swim test.
Interestingly, these offspring also grew larger than those conceived naturally, suggesting that these long non-coding RNAs can influence physical development.
“I was surprised that so many different large non-coding RNAs were altered by the increase in stress hormone levels,” Hannan stated in the press release.3 He continued, “these changes in offspring are relevant 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.”
References
- Hoffmann, L.B. et al. (2023) ‘Chronically high stress hormone levels dysregulate sperm long noncoding RNAS and their embryonic microinjection alters development and affective behaviours’, Molecular Psychiatry, 29(3), pp. 590–601. doi:10.1038/s41380-023-02350-2.
- Arzate-Mejía RG, Mansuy IM. Epigenetic Inheritance: Impact for Biology and Society-recent progress, current questions and future challenges. Environ Epigenet. 2022 Nov 5;8(1):dvac021. doi: 10.1093/eep/dvac021. PMID: 36589550; PMCID: PMC9790978.
- Short, A.K. et al. (2016) ‘Elevated paternal glucocorticoid exposure alters the small noncoding RNA profile in sperm and modifies anxiety and depressive phenotypes in the offspring’, Translational Psychiatry, 6(6). doi:10.1038/tp.2016.109.
- Dolan, E.W. (2024) Chronic stress can alter genetic material in sperm, leading to changes in offspring behavior, PsyPost. Available at: https://www.psypost.org/chronic-stress-can-alter-genetic-material-in-sperm-leading-to-changes-in-offspring-behavior/# (Accessed: 14 October 2024).
- Ribonucleic acid (RNA) (no date) Genome.gov. Available at: https://www.genome.gov/genetics-glossary/RNA-Ribonucleic-Acid (Accessed: 14 October 2024).
- Li X, Peng J, Yi C. The epitranscriptome of small non-coding RNAs. Noncoding RNA Res. 2021 Oct 26;6(4):167-173. doi: 10.1016/j.ncrna.2021.10.002. PMID: 34820590; PMCID: PMC8581453.
- Mattick, J.S. et al. (2023) ‘Long non-coding RNAS: Definitions, functions, challenges and recommendations’, Nature Reviews Molecular Cell Biology, 24(6), pp. 430–447. doi:10.1038/s41580-022-00566-8.