Sex-based differences in the lipidomic profile of circulating extracellular vesicles isolated from adolescents exposed to ethanol intoxication

Abstract Background Lipids represent essential components of extracellular vesicles (EVs), playing structural and regulatory functions during EV biogenesis, release, targeting, and cell uptake. Importantly, lipidic dysregulation has been linked to several disorders, including metabolic syndrome, inflammation, and neurological dysfunction. Our recent results demonstrated the involvement of plasma EV microRNAs as possible amplifiers and biomarkers of neuroinflammation and brain damage induced by ethanol intoxication during adolescence. Considering the possible role of EV lipids as regulatory molecules and biomarkers, we evaluated how acute ethanol intoxication differently affected the lipid composition of plasma EVs in male and female adolescents and explored the participation of the immune response. Methods Plasma EVs from humans, WT mice, and TLR4-KO mice were extracted. After the EVs lipids extraction and data acquisition by mass spectrometry, preprocessing and exploratory analyses were conducted. Experimental groups (ethanol and control groups of females and males) were compared from differential abundance analysis. Annotation of the lipids in their corresponding classes and a lipid set enrichment analysis were carried out to evaluate the biological function. Results We demonstrate for the first time that acute ethanol intoxication induces 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. All data and results generated have been made openly available on a web-based platform (http://bioinfo.cipf.es/sal). Conclusions Our 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.