Paternal Circadian Disruption Impairs Offspring Cognition via Sperm microRNAs

Apr 28, 2026Advanced science (Weinheim, Baden-Wurttemberg, Germany)

Disrupting Fathers' Body Clocks May Affect Offspring Thinking Through Changes in Sperm microRNAs

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Abstract

Male mice exposed to constant light resulted in memory dysfunction and impaired hippocampal synaptic plasticity in male offspring.

Paternal circadian rhythm disruption affected neural development and cognitive function in F1 male offspring, but not in females.
Changes in small RNA expression, particularly microRNAs, were observed in the sperm of male mice subjected to constant light.
Altered microRNA profiles were linked to changes in chromatin structure in spermatogonial stem cells, indicating a potential early origin of epigenetic changes.
In human sperm, miR-92a-3p was found to be upregulated following similar paternal circadian disruption.
Microinjection of altered small RNAs from disrupted sperm into zygotes replicated cognitive impairments in offspring, while inhibition of specific microRNAs partially reversed these effects.

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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.

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Paternal Circadian Disruption Impairs Offspring Cognition via Sperm microRNAs

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