{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T06:26:32Z","timestamp":1778739992071,"version":"3.51.4"},"reference-count":81,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T00:00:00Z","timestamp":1742342400000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P42ES031007"],"award-info":[{"award-number":["P42ES031007"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["T32ES007018"],"award-info":[{"award-number":["T32ES007018"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100023004","name":"Center for Environmental Health and Susceptibility, University of North Carolina at Chapel Hill","doi-asserted-by":"publisher","award":["P30ES010126"],"award-info":[{"award-number":["P30ES010126"]}],"id":[{"id":"10.13039\/100023004","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Environ and Mol Mutagen"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>Extracellular vesicles (EVs) are emitted from cells throughout the body and serve as signaling molecules that mediate disease development. Emerging evidence suggests that per\u2010 and polyfluoroalkyl substances (PFAS) impact EV release and content, influencing liver toxicity. Still, the upstream regulators of EV changes affected by PFAS exposure remain unclear. This study evaluated the hypothesis that PFAS exposures, individually and in a mixture, alter the expression of genes involved in EV regulation at concentrations comparable to genes involved in global biological response mechanisms. HepG2 liver cells were treated at multiple concentrations with individual PFOS, PFOA, or PFHxA, in addition to an equimolar PFAS mixture. Gene expression data were analyzed using three pipelines for concentration\u2010response modeling, with results compared against empirically derived datasets. Final benchmark concentration (BMC) modeling was conducted via Laplace model averaging in BMDExpress (v3). BMCs were derived at an individual gene level and across different gene sets, including Gene Ontology (GO) annotations as well as a custom EV regulation gene set. To determine relative PFAS contributions to the evaluated mixture, relative potency factors were calculated across resulting BMCs using PFOS as a standard reference chemical. Results demonstrated that PFAS exposures altered the expression of genes involved in EV regulation, particularly for genes overlapping with endoplasmic reticulum stress. EV regulatory gene changes occurred at similar BMCs as global gene set alterations, supporting concurrent regulation and the role of EVs in PFAS toxicology. This application of transcriptomics\u2010based BMC modeling further validates its utility in capturing both established and novel pathways of toxicity.<\/jats:p>","DOI":"10.1002\/em.70008","type":"journal-article","created":{"date-parts":[[2025,3,19]],"date-time":"2025-03-19T12:14:47Z","timestamp":1742386487000},"page":"99-121","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Extracellular Vesicle (<scp>EV<\/scp>) Mechanisms of Toxicity for Per and Polyfluoroalkyl Substances: Comparing Transcriptomic Points of Departure Across Global Versus <scp>EV<\/scp> Regulatory Gene Sets"],"prefix":"10.1002","volume":"66","author":[{"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":"Hadley","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":"Cynthia V.","family":"Rider","sequence":"additional","affiliation":[{"name":"Division of Translational Toxicology National Institute of Environmental Health Sciences  Research Triangle Park North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew W.","family":"Wheeler","sequence":"additional","affiliation":[{"name":"Biostatistics and Computational Biology Branch National Institute of Environmental Health Sciences  Research Triangle Park North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6294-3069","authenticated-orcid":false,"given":"Scott S.","family":"Auerbach","sequence":"additional","affiliation":[{"name":"Division of Translational Toxicology National Institute of Environmental Health Sciences  Research Triangle Park 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 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":"Curriculum in Toxicology and Environmental Medicine, School of Medicine, University of North Carolina  Chapel Hill North Carolina USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,3,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-016-0366-z"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfad044"},{"key":"e_1_2_10_4_1","unstructured":"Affymetrix.2015.\u201cMicroarray Normalization Using Signal Space Transformation With Probe Guanine Cytosine Count Correction [white paper].\u201d"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.langmuir.5b00095"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00442"},{"key":"e_1_2_10_7_1","unstructured":"Auerbach S. S.2022.\u201cBmdexpress\u20103.\u201d"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2024.124827"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tiv.2019.104700"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-021-00787-y"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2011.06.012"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1080\/21541248.2016.1264352"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envres.2016.07.027"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2015.04.010"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1021\/es062686m"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfad108"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/em.22522"},{"key":"e_1_2_10_18_1","unstructured":"Chang D. J.Cowden S.Davidson\u2010Fritz et\u00a0al.2024.\u201cScientific Studies Supporting Development of Transcriptomic Points of Departure for Epa Transcriptomic Assessment Products (etaps).\u201dUS Environmental Protection Agency. (EPA\/600\/X\u201023\/084)."},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.128868"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2022.107631"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2024.1374791"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1289\/EHP10092"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00244-008-9194-6"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2016.12.007"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538-7836.2011.04557.x"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/etc.4890"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envint.2019.105358"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S291956"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.2147\/IJN.S310357"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-021-00730-1"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41370-023-00545-x"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-017-2595-9"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gene.2017.04.024"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2021.721507"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2022.166484"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1196831"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfac097"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1289\/EHP12980"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2016.10.019"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfy220"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2014.05.004"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0013066"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2021.151003"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2017.08.014"},{"issue":"10","key":"e_1_2_10_45_1","first-page":"2808","article-title":"Extracellular Vesicles as Therapeutic and Diagnostic Tools for Chronic Liver Diseases","volume":"11","author":"Leszczynska A.","year":"2023","journal-title":"Biomedicine"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijerph120606098"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2023.1103141"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2023.122138"},{"key":"e_1_2_10_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s10020-023-00731-5"},{"key":"e_1_2_10_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-12991-z"},{"key":"e_1_2_10_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.yrtph.2019.01.019"},{"key":"e_1_2_10_52_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfac127"},{"key":"e_1_2_10_53_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.est.8b06017"},{"key":"e_1_2_10_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41576-024-00767-1"},{"key":"e_1_2_10_55_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201701291RR"},{"key":"e_1_2_10_56_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb3112"},{"key":"e_1_2_10_57_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1200448109"},{"key":"e_1_2_10_58_1","unstructured":"Network.2023.\u201cNorth Carolina PFAS Testing Network.\u201dhttps:\/\/ncpfastnetwork.com\/."},{"key":"e_1_2_10_59_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfy176"},{"key":"e_1_2_10_60_1","unstructured":"NTP.2018.\u201cNTP Research Report on National Toxicology Program Approach to Genomic Dose\u2010Response Modeling: Research Report 5.\u201dDurham (NC)."},{"key":"e_1_2_10_61_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.envpol.2020.114182"},{"key":"e_1_2_10_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2000"},{"key":"e_1_2_10_63_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2023.169861"},{"key":"e_1_2_10_64_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-013118-111902"},{"key":"e_1_2_10_65_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfab102"},{"key":"e_1_2_10_66_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-77097-9"},{"key":"e_1_2_10_67_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2020.115204"},{"key":"e_1_2_10_68_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41370-023-00593-3"},{"key":"e_1_2_10_69_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41370-018-0094-1"},{"key":"e_1_2_10_70_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202003505"},{"key":"e_1_2_10_71_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2012.03.010"},{"key":"e_1_2_10_72_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ecoenv.2020.110253"},{"key":"e_1_2_10_73_1","doi-asserted-by":"publisher","DOI":"10.3390\/toxics10050265"},{"key":"e_1_2_10_74_1","doi-asserted-by":"publisher","DOI":"10.1111\/risa.13537"},{"key":"e_1_2_10_75_1","doi-asserted-by":"publisher","DOI":"10.1002\/env.2728"},{"key":"e_1_2_10_76_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.comtox.2022.100259"},{"key":"e_1_2_10_77_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2013.12.002"},{"key":"e_1_2_10_78_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.955419"},{"key":"e_1_2_10_79_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-015-1913-6"},{"key":"e_1_2_10_80_1","doi-asserted-by":"publisher","DOI":"10.3390\/pharmaceutics15092365"},{"key":"e_1_2_10_81_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.est.1c03979"},{"key":"e_1_2_10_82_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpubh.2018.00261"}],"container-title":["Environmental and Molecular Mutagenesis"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/em.70008","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,11]],"date-time":"2025-04-11T08:27:51Z","timestamp":1744360071000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/em.70008"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3]]},"references-count":81,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2025,3]]}},"alternative-id":["10.1002\/em.70008"],"URL":"https:\/\/doi.org\/10.1002\/em.70008","archive":["Portico"],"relation":{},"ISSN":["0893-6692","1098-2280"],"issn-type":[{"value":"0893-6692","type":"print"},{"value":"1098-2280","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3]]},"assertion":[{"value":"2024-11-26","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-19","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}