Paternal SARS-CoV-2 infection impacts sperm small noncoding RNAs and increases anxiety in offspring in a sex-dependent manner

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Conflicts of Interest

Identified Weaknesses

Rating Explanation

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Paper Summary

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COVID Dads Make Anxious Mouse Babies (Maybe!), But Hold Your Horses, Human Dads!

This mouse study suggests that male SARS-CoV-2 infection can lead to increased anxiety-like behaviors in first-generation offspring and subtle changes in grand-offspring, mediated by alterations in sperm small noncoding RNAs. Microinjecting these altered sperm RNAs into oocytes partially replicated the anxiety phenotype. However, these findings are from an animal model and their direct relevance to humans requires further research.

Possible Conflicts of Interest

None identified

Identified Weaknesses

Animal Model (Mice)

The study was conducted on mice, and while a preclinical model, direct translation of these findings to human health and behavior is not guaranteed and requires significant further investigation.

Paternal Bodyweight Loss as a Confounding Factor

The infected male mice experienced significant bodyweight loss, which the authors acknowledge may have contributed to the observed intergenerational changes. This introduces a confounding factor not directly linked to the virus itself, but to its acute physiological effects.

Limited Transgenerational Effects (F2)

While F1 offspring showed clear anxiety phenotypes, the F2 (grand-offspring) only displayed 'limited differences' in early-life bodyweight and litter sizes, with no overt adult behavioral changes, suggesting the transgenerational effects may be minor or not fully captured.

Partial Phenocopying by Sperm RNA Microinjection

Microinjecting sperm RNAs from infected sires only partially reproduced the anxiety-like behavior in offspring, indicating that other biological mechanisms or factors might also be contributing to the observed F1 phenotypes.

Constraints of PC3 Animal Facility

The authors noted that due to size constraints within the PC3 facility, certain comprehensive behavioral tests (e.g., Morris water maze, Y-maze, elevated plus maze for F1/F2 natural cohorts) could not be performed, potentially limiting the detection of the full spectrum of phenotypic changes.

Rating Explanation

This is a well-conducted animal study using an established SARS-CoV-2 model, providing interesting findings on intergenerational effects via sperm RNA. However, its direct applicability to humans is a significant limitation due to the mouse model, and potential confounding factors like paternal bodyweight loss warrant caution. The transgenerational effects were also quite limited.

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