Seminal Extracellular Vesicles as Molecular Modulators of Male Reproductive Function

Extracellular vesicles (sEVs) contained in seminal plasma (SP) maintain, in concert with free SP-components (proteins, hormones, cytokines, metabolites and antioxidants) under an endocrine umbrella the functional in vivo homeostasis of ejaculated spermatozoa. The sEVs define a generic mixture of nanovesicles delivered by male epithelial cells, from the testis to the accessory glands, where their lipid membrane encloses and protects a load of proteins, nucleic acids, enzymes, and lipids. This cargo can, following molecular uploading to target cells, dynamically interplay with spermatozoa allowing membrane remodelling pre-fertilization. It can also interact with the lining epithelia of the female internal reproductive tract to induce gene expression changes, modifying ovulation timing and the female immune system leading to tolerate paternal epitopes. This review critically summarizes experimental evidence of the function of the sEVs on fertility, for their primary relevance as diagnostic and fertility biomarkers envisioning possible use of molecular components to select breeding sires, as well as for eventual additives to improve sperm cryosurvival or refine reproductive strategies, including in vitro ARTs. Since methodological stringency is a priority, particular attention is given to sEVs isolation, characterization and experimentation, bound with eventual risks of nanoplastic contamination, keeping view of the delicate balance between SP- and sEVs-molecules and their concerted effects on male fertility.