A mild respiratory infection in male mice is enough to induce lasting changes in their sperm, leading to offspring that exhibit heightened anxiety and altered brain development, a new study has found. The research demonstrates for the first time that a paternal SARS-CoV-2 infection before conception can have behavioral consequences for the next generation, suggesting that the virus can leave a subtle imprint on the molecular instructions passed from father to child.
The findings, published in Nature Communications, reveal that the virus causes inflammation in the male reproductive system and modifies crucial RNA molecules within sperm. These altered molecules appear to reshape how genes are expressed in the brains of the resulting offspring, particularly in the hippocampus, a region vital for regulating emotion and memory. While the study was conducted in a specialized mouse model, it opens up new avenues of inquiry into whether the COVID-19 pandemic could have multigenerational health impacts in humans, extending far beyond the initial respiratory illness.
An Inheritance Beyond DNA
The study centers on the concept of epigenetic inheritance, a process where a parent’s experiences and environmental exposures can influence their offspring without changing the underlying DNA sequence. Factors like diet, stress, and now viral infections can leave molecular marks on sperm and eggs. These marks, often on RNA molecules, can act as a set of instructions that fine-tune how an offspring’s genes are turned on or off during development.
Researchers at the Florey Institute of Neuroscience and Mental Health were building on previous work that showed paternal lifestyle factors could affect brain development in their young. According to lead researcher Professor Anthony Hannan, the father’s experiences can change the information carried in sperm, specifically the small RNA molecules that guide the growth of the embryo. The team hypothesized that a significant biological event like a SARS-CoV-2 infection could similarly encode new information into the sperm, with lasting effects on the next generation’s neurological health.
Tracing the Viral Footprint
To test their hypothesis, the scientists designed a carefully controlled experiment using mice as a model system. The work required a specific type of mouse genetically engineered to have the human ACE2 receptor, the protein that the SARS-CoV-2 virus uses to enter and infect cells. This modification allowed the mice to contract the virus in a way that mimics a human infection.
Impact on the Fathers
Adult male mice were infected with the virus and monitored. The infection triggered a significant immune response and inflammation within the testes, an organ typically protected from such activity. Researchers observed direct damage to the male reproductive system, including a notable drop in both sperm count and motility. Microscopic examination revealed damage to the seminiferous tubules, the precise structures where sperm are produced. This confirmed that even a mild, non-lethal infection could have clear physiological consequences on the paternal reproductive organs, setting the stage for potential changes to the sperm themselves.
Studying the Next Generation
After the infected male mice had fully recovered for several weeks, they were mated with healthy, uninfected females. The scientific team then conducted a series of behavioral tests on the resulting litters of pups to assess their anxiety levels and cognitive function. They compared these offspring to a control group of pups sired by males that had not been exposed to the virus. Following the behavioral assessments, the researchers analyzed the brain tissue of the offspring to identify any molecular or genetic differences that could explain their observations.
A Legacy of Anxiety
The results of the behavioral tests were consistent and clear: offspring sired by COVID-recovered fathers displayed significantly more anxiety-like behaviors compared to the control group. According to Dr. Elizabeth Kleeman, the study’s first author, this behavioral shift was observed in all offspring from infected fathers. This finding provided the first direct evidence linking a paternal respiratory virus infection to behavioral changes in the next generation.
When the team examined the brains of these mice, they discovered corresponding changes in gene activity. The most significant alterations were found in the hippocampus, a brain structure central to learning, memory, and emotional regulation. Interestingly, these changes in gene expression were especially pronounced in female offspring. Co-senior author Dr. Carolina Gubert explained that these disruptions in the hippocampus could be the biological basis for the increased anxiety observed in the offspring, passed down through epigenetic inheritance that ultimately alters brain development.
How Sperm Carries the Message
The central mechanism for this transmission appears to be small, non-coding RNA molecules contained within the sperm. Unlike DNA, which provides the permanent genetic blueprint, these RNA molecules are more malleable and can be changed by environmental factors. They act as regulatory switches, influencing which genes are activated and when, particularly during the critical early stages of embryonic development.
The study found that the SARS-CoV-2 infection altered the profile of these RNA molecules in the fathers’ sperm. Some of the affected RNA molecules are known to be involved in regulating genes that are essential for the proper formation and function of the brain. In essence, the viral infection in the father rewrote some of the short-term instructions carried by his sperm. When this sperm fertilized an egg, it passed along these modified instructions, which in turn influenced how the resulting offspring’s brain was wired, predisposing it to anxiety.
Human Relevance and Future Work
While the findings are compelling, the researchers emphasize that they come with important caveats. The experiments were conducted in mice, whose immune and reproductive systems differ from those of humans. Furthermore, the mice were exposed to high viral loads to ensure infection. It remains unknown whether the same transgenerational effects occur in people after a typical COVID-19 infection. More research is necessary to bridge the gap between these animal model findings and their potential implications for human public health.
Despite these limitations, the study offers a crucial proof of principle. It shows that a paternal viral infection can have subtle, lasting consequences that echo into the next generation. Professor Hannan noted that if these results translate to humans, the COVID-19 pandemic could have long-lasting effects on millions of children worldwide. The research underscores the complex and interconnected nature of health, where a single infection might not only affect the individual who falls ill but also cast a long shadow over the well-being of their descendants.