Extracellular vesicles in toxicological studies: key roles in communication between environmental stress and adverse outcomes.

External stressors, especially environmental toxicants can disturb biological homeostasis and thus lead to adverse health effects. However, there is limited understanding of how cells directly exposed to stressors transmit the signals to cells indirectly in contact with stressors. Extracellular vesicles (EVs) are receiving increasing attention as signal transductors between various types of cells in organisms. Cargo in EVs, including RNAs, proteins, lipids, and other signal molecules can be transferred between cells and become critical determining factors of intercellular communication. EVs can be a powerful mediator of environmental stimuli. It has been shown that external stressors reshape the secretion of EVs, modify the composition of EVs, and thus influence the mediating function of EVs. These abnormal EVs can lead to dysfunction of recipient cells, and even the pathogenesis of diseases. In this review, we first summarized current knowledge about the responses of EVs to external stimuli, including chemicals and chemical mixtures. Then we explained how these altered EVs regulate signal pathways in recipient cells, thus mediating physio-pathological responses in detail. The most up-to-date evidence from molecular, cellular, animal and human levels was synthesized to systematically address the mediating roles of EVs. EVs can be regarded as a bridge to link external stressors and internal response. Further toxicological and molecular epidemiological studies are expected to provide further insight into the roles of EVs in toxicology. The gaps in the engulfment of toxicants into EVs are listed as the priority to be solved in future studies.