父亲昼夜节律紊乱通过精子microRNA损害后代认知功能的研究

Abstract

A father's lifestyle can impact offspring's health. However, it is unclear whether and how paternal circadian rhythm disruption affects offspring neural development and cognitive function. Here, we show that male mice exposed to constant light (LL-F0) led to memory dysfunction and impaired hippocampal synaptic plasticity in male, but not female, F1 offspring (LL-F1). Paternal circadian disruption altered expression profiles of small RNAs, especially microRNAs (miRNAs), in mouse sperm. These miRNA changes were associated with chromatin accessible regions in spermatogonial stem cells, pointing to an early germline origin of the disrupted epigenetic state. In human sperm, we identified and validated upregulation of miR-92a-3p. Microinjection of total small RNAs from LL-F0 sperm or synthetic miR-92a-3p/miR-25-3p into zygotes was sufficient to phenocopy offspring cognitive impairment, whereas inhibition of these miRNAs in zygotes partially reversed the phenotype. These findings support a role for sperm-borne miRNAs in the intergenerational transmission of neurobehavioral deficits induced by paternal circadian disruption.