Investigating the impact of paternal aging on murine sperm miRNA profiles and their potential link to autism spectrum disorder

Abstract

Background: Paternal aging has been consistently linked to an increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. While de novo mutations arising from paternal aging have been extensively studied, recent evidence has highlighted the role of epigenetic factors. We have previously revealed age-related DNA hypomethylation in mouse sperm and alterations in histone modifications during spermatogenesis. Objectives: This study aimed to investigate age-related alterations in the microRNA (miRNA) profile of mouse sperm and analyze the target genes regulated by differentially expressed miRNAs. Materials and Methods: Microarray analyses were conducted to identify differentially expressed miRNAs in sperm samples from mice at different ages: 3 months (3M), over 12M, and beyond 20M. The expression levels of genes potentially regulated by these miRNAs were also accessed. Comprehensive bioinformatic analyses were performed to unravel the intricate relationship between differentially expressed miRNAs and their target genes. Results: We identified 26 miRNAs exhibiting differential expression between the 3M and 20M, 34 miRNAs between the 12M and 20M, and 2 miRNAs between the 3M and 12M mice. Notably, the target genes regulated by these differentially expressed miRNAs were significantly associated with apoptosis and ferroptosis pathways. Some of these target genes were relevant to the nervous system and potentially involvement in ASD. Discussion: The findings suggest that aging induces alterations in the sperm miRNA profiles . Importantly, the target genes regulated by these differentially expressed miRNAs are associated with cell death and ASD, implying a potential link between paternal aging and an increased risk of neurodevelopmental disorders. Conclusion: The observed age-related changes in sperm miRNA profiles have the potential to impact sperm quality and subsequently affect offspring development. Further validation and through investigations are necessary to gain a comprehensive understanding of the precise effects of paternal aging on subsequent generations.

Dietary nutrients that potentially mitigate autism spectrum disorder and dietary recommendations for children and pregnant women

“…Current research indicates a clear correlation between advanced paternal age and an increased risk of offspring developing ASD, primarily mediated through reproductive influences leading to adverse birth outcomes (Kaltsas et al., 2023). Animal studies suggest that aging induces alterations in the microRNA profile of sperm, which is associated with neurodevelopmental disorders and may mean an increased incidence of ASD (Miyahara et al., 2023). Hence, strategies to prevent a decline in sperm quality may hold potential value in reducing the incidence of ASD.…”