Approaches to incorporate extracellular vesicles into exposure science, toxicology, and public health research

Abstract

Extracellular vesicles (EVs) represent small, membrane-enclosed particles that are derived from parent cells and are secreted into the extracellular space. Once secreted, EVs can then travel and communicate with nearby or distant cells. Due to their inherent stability and biocompatibility, these particles can effectively transfer RNAs, proteins, and chemicals/metabolites from parent cells to target cells, impacting cellular and pathological processes. EVs have been shown to respond to disease-causing agents and impact target cells. Given that disease-causing agents span environmental contaminants, pathogens, social stressors, drugs, and other agents, the translation of EV methods into public health is now a critical research gap. This paper reviews approaches to translate EVs into exposure science, toxicology, and public health applications, highlighting blood as an example due to its common use within clinical, epidemiological, and toxicological studies. Approaches are reviewed surrounding the isolation and characterization of EVs and molecular markers that can be used to inform EV cell-of-origin. Molecular cargo contained within EVs are then discussed, including an original analysis of blood EV data from Vesiclepedia. Methods to evaluate functional consequences and target tissues of EVs are also reviewed. Lastly, the expanded integration of these approaches into future public health applications is discussed, including the use of EVs as promising biomarkers of exposure, effect, and disease. IMPACT STATEMENT: Extracellular vesicles (EVs) represent small, cell-derived structures consisting of molecules that can serve as biomarkers of exposure, effect, and disease. This review lays a novel foundation for integrating EVs, a rapidly advancing molecular biological tool, into the field of public health research including epidemiological, toxicological, and clinical investigations. This article represents an important advancement in public health and exposure science as it is among the first to translate EVs into this field.

Keywords: Health Studies, Epidemiology, Exposomics, New Approach Methodologies (NAMs), Biomonitoring.

Figure 1.. Mechanisms of EV biogenesis, resulting in three defined classes of EVs (i.e., exosomes, microvesicles, and apoptotic bodies) with overlapping ranges in size, composition, and function.

Note that dying-cell-derived EVs can be generated through any of the below mechanisms.

Figure 2.. The most common proteins that have been measured in EVs circulating in human blood and their related biological functions.

The illustrated proteins include those that have been identified in 10 or more publications aggregated from the Vesiclepedia database. Molecules were further visualized according to functional categories based on Gene Ontology Biological Processes obtained from the Universal Protein Resource Knowledgebase [92]. Abbreviations: A2M, alpha-2-macroglobulin; ALB, albumin; ANXA5, annexin A5; APOB, apolipoprotein B; C1QC, complement C1q subcomponent subunit C; C3, complement C3; C4BPA, c4b-binding protein alpha chain; CD5L, CD5 antigen-like; FGA, fibrinogen alpha chain; FGB, fibrinogen beta chain; FGG, fibrinogen gamma chain; FN1, fibronectin; GP1BA, platelet glycoprotein 1b alpha chain; HP, haptoglobin; HPR, haptoglobin-related protein; ITGB3, integrin beta-3; KRT2, kertain, type II cytoskeletal 2 epidermal; LGALS3BP, Galectin-3-binding protein; PECAM1, platelet endothelial cell adhesion molecule; SERPINA1, alpha-1-antitrypsin.

Figure 3.. The most common lipids, mRNAs, and miRNAs and that have been measured in EVs circulating in human blood.

The illustrated molecules include those that have been identified across the highest number of publications aggregated from the Vesiclepedia database.

Figure 4.. Overview of example utilities of EV research in environmental science, toxicology, and public health applications.

Shown here are example approaches to integrate EVs within human cohort evaluations, resulting in applications to better understand disease etiology, biomarkers of disease, and solutions to better protect public health.