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Nat Commun
. 2025 Oct 11;16(1):9045.
doi: 10.1038/s41467-025-64473-0. Paternal SARS-CoV-2 infection impacts sperm small noncoding RNAs and increases anxiety in offspring in a sex-dependent manner
Elizabeth A Kleeman 1 2 , Carolina Gubert # 3 , Sonali N Reisinger # 1 , Kathryn C Davidson 4 5 , Da Lu 1 2 , Merle Dayton 4 , Liana Mackiewicz 4 , Bethany A Masson 1 2 , Pranav Adithya 1 2 , Alexandra L Garnham 4 5 , Gemma Stathatos 6 , Moira K O'Bryan 6 , Rikeish R Muralitharan 7 8 , Francine Z Marques 7 8 9 , Shanshan Li 1 , Huan Liao 1 , Shae McLaughlin 1 , Emmet T Keough 1 , Michelle Y Wheeler 1 , Pamudika Kiridena 1 2 , Marcel Doerflinger 4 5 , Marc Pellegrini 4 5 , Anthony J Hannan 10 11 12
Affiliations
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.
. 2025 Oct 11;16(1):9045.
doi: 10.1038/s41467-025-64473-0. Paternal SARS-CoV-2 infection impacts sperm small noncoding RNAs and increases anxiety in offspring in a sex-dependent manner
Elizabeth A Kleeman 1 2 , Carolina Gubert # 3 , Sonali N Reisinger # 1 , Kathryn C Davidson 4 5 , Da Lu 1 2 , Merle Dayton 4 , Liana Mackiewicz 4 , Bethany A Masson 1 2 , Pranav Adithya 1 2 , Alexandra L Garnham 4 5 , Gemma Stathatos 6 , Moira K O'Bryan 6 , Rikeish R Muralitharan 7 8 , Francine Z Marques 7 8 9 , Shanshan Li 1 , Huan Liao 1 , Shae McLaughlin 1 , Emmet T Keough 1 , Michelle Y Wheeler 1 , Pamudika Kiridena 1 2 , Marcel Doerflinger 4 5 , Marc Pellegrini 4 5 , Anthony J Hannan 10 11 12
Affiliations
- PMID: 41076487
- PMCID: PMC12515249
- DOI: 10.1038/s41467-025-64473-0
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.