Elevated zygotic let-7f-5p alters developmental trajectories and sex-specific somatic growth [Placenta]

Paternal preconception experiences shape offspring development and longitudinal health outcomes, including disease risk. Small non-coding RNA (sncRNA) are potential causal agents in the germline transmission of paternal exposures at conception. In a previous repeated sampling human cohort, we identified that sperm microRNA (miRNA), let-7f-5p (let-7f), was significantly increased in response to elevated prior perceived stress. To understand the potential role of sperm let-7f in the transmission of stress and its impact on development, we investigated outcomes produced by increasing zygote levels of this miRNA. We found alterations in gene expression at the blastocyst stage and at mid-gestation following zygotic microinjections. These changes were male-specific, and functional enrichment analyses revealed significant shifts in cellular developmental processes, metabolic functioning, neurodevelopment, and bone development. These sex-specific developmental differences persisted until adulthood, with let-7f males having greater somatic growth. Together, our findings demonstrate a clear role for sperm let-7f in shaping offspring trajectory.