Altered sperm tsRNAs in aged male contribute to anxiety‐like behavior in offspring

Abstract

Parental age at first pregnancy is increasing worldwide. The offspring of aged father has been associated with higher risk of several neuropsychiatric disorders, such as schizophrenia and autism, but the underlying mechanism remains elusive. Here we report that advanced paternal age in mice alters the profile of transfer RNA-derived small RNAs (tsRNAs). Injection of sperm tsRNAs from aged male mice into zygotes induced anxiety-like behaviors in F1 males. RNA sequencing of the cerebral cortex and hippocampus of those F1 male mice altered the gene expression of dopaminergic synapse and neurotrophin. tsRNAs from aged male mice injection also altered the neuropsychiatry-related gene expression in two-cell and blastocyst stage embryos. More importantly, the sperm tsRNA profile changes significantly during aging in human. The up-regulated sperm tsRNA target genes were involved in neurogenesis and nervous system development. These results suggest that aging-related changes of sperm tsRNA may contribute to the intergenerational transmission of behavioral traits.