Reproductive tract extracellular vesicles are sufficient to transmit intergenerational stress and program neurodevelopment

We report reproductive tract extracellular vesicles (EVs) transmit information regarding stress in the paternal environment to sperm, ultimately altering fetal development. Using intracytoplasmic sperm injection, we found that sperm incubated with EVs collected from stress-treated epididymal epithelial cells produced offspring with altered neurodevelopment and adult stress reactivity. Proteomic and transcriptomic assessment of these EVs showed dramatic changes in protein and miRNA content long after stress treatment had ended. Overall design: Examination of 1) impact of chronic stress on mouse sperm microRNA content over time (1 vs 12 weeks post-stress), 2) impact of corticostrone on secreted EV microRNA content from DC2 cells over time (1, 4, 8 days post-treatment), 3) impact of intracytoplasmic sperm injection with sperm incubated with control or corticosterone-treated EVs on mouse E12.5 brain and 4) E12.5 placentas, 5) impact of perceived stress dynamic on human sperm over 6 months