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

Summary Parental preconception experiences shape offspring development and longitudinal health outcomes, including disease risk. In a longitudinal human cohort, we previously identified sperm let-7f-5p (let-7f) as significantly increased in response to elevated prior perceived stress. As microRNAs (miRNAs) are causal agents in the germline transmission of prior paternal experience, we investigated developmental outcomes altered by increased let-7f using mouse zygote microinjection. Let-7f embryos developed at a faster rate until stalling at the morula stage, resulting in reduced blastocyst survival. Blastocyst and fetal RNA sequencing revealed significant differences in gene expression enriched for metabolic and growth pathways, effects that were limited to male offspring. Sex-specific developmental differences persisted into adulthood, with significantly increased body weight and bone length in let-7f males. These results demonstrate that increased let-7f shapes embryo development and male fetal and adult growth, advancing our understanding of how parental experiences may facilitate offspring developmental plasticity.