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

Kleeman, EA; Gubert, C; Reisinger, SN; Davidson, KC; Lu, D; Dayton, M; Mackiewicz, L; Masson, BA; Adithya, P; Garnham, AL; Stathatos, G; O&#39;Bryan, MK; RMuralitharan R; Marques, FZ; Li, S; Liao, H; McLaughlin, S; Keough, ET; Wheeler, MY; Kiridena, P; Doerflinger, M; Pellegrini, M; Hannan, AJ

Author(s): Kleeman, EA; Gubert, C; Reisinger, SN; Davidson, KC; Lu, D; Dayton, M; Mackiewicz, L; Masson, BA; Adithya, P; Garnham, AL; Stathatos, G; O'Bryan, MK; RMuralitharan R; Marques, FZ; Li, S; Liao, H; McLaughlin, S; Keough, ET; Wheeler, MY; Kiridena, P; Doerflinger, M; Pellegrini, M; Hannan, AJ;
Details: Publication Year 2025-10-11,Volume 16,Issue #1,Page 9045
Journal Title: Nature Communications
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.
Publisher: Springer Nature
Keywords: Animals; Male; *COVID-19/virology/genetics; *Spermatozoa/metabolism/virology; Female; Mice; *Anxiety/genetics/virology; *RNA, Small Untranslated/genetics/metabolism; *SARS-CoV-2; Hippocampus/metabolism; Disease Models, Animal; Sex Factors; Mice, Inbred C57BL; Humans
Research Division(s): Infection and Global Health; Bioinformatics and Computational Biology
PubMed ID: 41076487
Publisher's Version: https://doi.org/10.1038/s41467-025-64473-0
Open Access at Publisher's Site: https://doi.org/10.1038/s41467-025-64473-0
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-10-20 01:57:45

Last Modified: 2025-10-20 01:57:58