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Numerous PFAS co-occur across sources of drinking water, including areas in North Carolina (NC) where some detected concentrations are above the Environmental Protection Agency\u2019s health advisory levels. Although evidence demonstrates that PFAS exposure induces harmful effects in the liver, the involvement of extracellular vesicles (EVs) as potential mediators of these effects has yet to be evaluated. This study set out to evaluate the hypothesis that PFAS mixtures induce dose-dependent release of EVs from liver cells, with exposures causing differential loading of microRNAs (miRNAs) and PFAS chemical signatures. To test this hypothesis, a defined PFAS mixture was prioritized utilizing data collected by the NC PFAS Testing Network. This mixture contained 3 substances, perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), and perfluorohexanoic acid (PFHxA), selected based upon co-occurrence patterns and the inclusion of both short-chain (PFHxA) and long-chain (PFOA and PFOS) substances. HepG2 liver cells were exposed to equimolar PFAS, and secreted EVs were isolated from conditioned media and characterized for count and molecular content. Exposures induced a dose-dependent release of EVs carrying miRNAs that were differentially loaded upon exposure. These altered miRNA signatures were predicted to target mRNA pathways involved in hepatic fibrosis and cancer. Chemical concentrations of PFOS, PFOA, and PFHxA were also detected in both parent HepG2 cells and their released EVs, specifically within a 15-fold range after normalizing for protein content. This study therefore established EVs as novel biological responders and measurable endpoints for evaluating PFAS-induced toxicity.<\/jats:p>","DOI":"10.1093\/toxsci\/kfad108","type":"journal-article","created":{"date-parts":[[2023,10,17]],"date-time":"2023-10-17T08:48:25Z","timestamp":1697532505000},"page":"155-169","source":"Crossref","is-referenced-by-count":14,"title":["Extracellular vesicles altered by a per- and polyfluoroalkyl substance mixture:<i>in vitro<\/i>dose-dependent release, chemical content, and microRNA signatures involved in liver health"],"prefix":"10.1093","volume":"197","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2753-0082","authenticated-orcid":false,"given":"Celeste K","family":"Carberry","sequence":"first","affiliation":[{"name":"The Institute for Environmental Health Solutions, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA"},{"name":"Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacqueline","family":"Bangma","sequence":"additional","affiliation":[{"name":"Center for Environmental Measurement and Modeling, Office of Research and Development, U.S. Environmental Protection Agency , Research Triangle Park, North Carolina 27711, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Koval","sequence":"additional","affiliation":[{"name":"The Institute for Environmental Health Solutions, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA"},{"name":"Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Deepak","family":"Keshava","sequence":"additional","affiliation":[{"name":"The Institute for Environmental Health Solutions, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hadley J","family":"Hartwell","sequence":"additional","affiliation":[{"name":"The Institute for Environmental Health Solutions, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA"},{"name":"Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"Sokolsky","sequence":"additional","affiliation":[{"name":"Center for Nanotechnology in Drug Delivery, University of North Carolina , Chapel Hill, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca C","family":"Fry","sequence":"additional","affiliation":[{"name":"The Institute for Environmental Health Solutions, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA"},{"name":"Department of Environmental Sciences and Engineering, Gillings School of Global Public Health, The University of North Carolina at Chapel Hill , Chapel Hill, North Carolina, USA"},{"name":"School of Medicine, Curriculum in Toxicology and Environmental Medicine, University of North Carolina , Chapel Hill, North Carolina, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2882-5042","authenticated-orcid":false,"given":"Julia E","family":"Rager","sequence":"additional","affiliation":[{"name":"The Institute for Environmental Health Solutions, Gillings 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