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

Elizabeth A. Kleeman, Carolina Gubert (), Sonali N. Reisinger, Kathryn C. Davidson, Da Lu, Merle Dayton, Liana Mackiewicz, Bethany A. Masson, Pranav Adithya, Alexandra L. Garnham, Gemma Stathatos, Moira K. O’Bryan, Rikeish R. Muralitharan, Francine Z. Marques, Shanshan Li, Huan Liao, Shae McLaughlin, Emmet T. Keough, Michelle Y. Wheeler, Pamudika Kiridena, Marcel Doerflinger, Marc Pellegrini and Anthony J. Hannan ()
Additional contact information
Elizabeth A. Kleeman: Parkville
Carolina Gubert: Parkville
Sonali N. Reisinger: Parkville
Kathryn C. Davidson: Parkville
Da Lu: Parkville
Merle Dayton: Parkville
Liana Mackiewicz: Parkville
Bethany A. Masson: Parkville
Pranav Adithya: Parkville
Alexandra L. Garnham: Parkville
Gemma Stathatos: Parkville
Moira K. O’Bryan: Parkville
Rikeish R. Muralitharan: Monash University
Francine Z. Marques: Monash University
Shanshan Li: Parkville
Huan Liao: Parkville
Shae McLaughlin: Parkville
Emmet T. Keough: Parkville
Michelle Y. Wheeler: Parkville
Pamudika Kiridena: Parkville
Marcel Doerflinger: Parkville
Marc Pellegrini: Parkville
Anthony J. Hannan: Parkville

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract Given that the SARS-CoV-2 virus, and the COVID-19 pandemic, constitutes a major environmental challenge faced by billions of people worldwide, we investigated whether paternal pre-conceptual SARS-CoV-2 infection has impacts on sperm RNA content, and intergenerational (F1) and transgenerational (F2) effects on offspring phenotypes. Using an established mouse-adapted SARS-CoV-2 (P21) preclinical model, we infected adult male mice with the virus, or performed a mock control infection, and bred them with naïve female mice four weeks later, when males were no longer infectious. Here we show that offspring of infected sires display increased anxiety-like behaviors. Additionally, the F1 offspring have significant transcriptomic changes in their hippocampus. Various sperm small noncoding RNAs, including PIWI-interacting RNAs, transfer-derived RNAs and microRNAs, are differentially altered by prior paternal SARS-CoV-2 infection. Microinjection of RNA from the sperm of SARS-CoV-2 infected males into fertilized oocytes leads to a phenotype resembling that of the naturally born F1 offspring, supporting the interpretation that sperm RNAs are contributing to the outcomes of our paternal SARS-CoV-2 model. Therefore, this study provides evidence that paternal SARS-CoV-2 infection impacts sperm and affects offspring phenotypes. These findings have public-health implications and inform further research in males affected by COVID-19, and their offspring.

Date: 2025
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DOI: 10.1038/s41467-025-64473-0

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