Ethanol-induced sex-based differences in the extracellular vesicles lipidome.

Lipids represent essential components of extracellular vesicles (EVs), playing structural and regulatory functions. Importantly, lipidic dysregulation has been linked to several inflammatory and neurological disorders. Thus, exosome lipidomics is emerging as an innovative field for discovering novel lipid species with biomedical applications. Likewise, EVs isolated from adolescents exposed to alcohol intoxication demonstrated a sex-based difference in their microRNA profiles. Accordingly, we applied a lipidomics computational strategy using R language programming in order to examine how acute ethanol intoxication affects the lipid composition of plasma EVs, differently by sex in adolescents and the involvement of the immune response. After an exploratory analysis experimental groups (ethanol and control groups of females and males) were compared with a differential abundance analysis. Annotation of the lipids in their corresponding classes and class enrichment were carried out to evaluate the biological function. This strategy was performed in human subjects and WT and TLR4-KO mice. The latter to explore the role of the toll-like receptor 4 (TLR4) in the response. We identified a higher enrichment of specific EV lipid species in human female adolescents (e.g., PA, LPC, unsaturated FA and FAHFA) than in males (e.g., PI). These lipid species participate in the formation, release, and uptake of EVs and the activation of the immune response; therefore, results suggest that female adolescents who binge drink alcohol also display increased levels of EV biogenesis and neuroinflammatory spread than males. Our findings also support the potential use of EV-enriched lipids as biomarkers of ethanol-induced neuroinflammation during adolescence.</p