{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T01:33:33Z","timestamp":1792114413843,"version":"4.4.0"},"reference-count":44,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100002564","name":"Alternatives Research and Development Foundation","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100002564","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100005932","name":"Center for Alternatives to Animal Testing, Johns Hopkins Bloomberg School of Public Health","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/100005932","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Methusalem program","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Research Foundation Flanders","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Scientific Fund Willy Gepts","doi-asserted-by":"publisher","award":["NA"],"award-info":[{"award-number":["NA"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Over the past 75 years, fluorinated contaminants present in aquatic, dietary, and environmental matrices have increasingly raised scientific and public health concerns. Among these substances, ultrashort perfluoroalkyl substances (US-PFAS) demonstrate substantial environmental persistence and mobility, comparable to that of their long-chain counterparts. Reported human serum concentrations of individual US-PFAS reach up to 27.7 ng\/mL, substantially exceeding established thresholds for total PFAS levels. Nevertheless, data on human toxicity of US-PFAS remain limited. The present study aimed to investigate the impact of US-PFAS on cholestatic features and to elucidate the underlying mechanisms using an adverse outcome pathway network as a mechanistic compass. Human HepaRG liver cell cultures were exposed to 4 US-PFAS at various concentrations for 1 to 72 h. Transcriptomic profiles were assessed by RNA sequencing analysis. Functional alterations in early and key events associated with cholestatic pathology were evaluated using fluorescently labeled probes, while bile canaliculi dynamics were examined through in situ immunostaining and phase-contrast imaging. This revealed significant perturbations of molecular pathways involved in both early and late events relevant for cholestatic liver injury. US-PFAS did not significantly affect hepatocellular transporter activity or bile canalicular integrity at early time points (\u22646 h). In contrast, prolonged exposure (24\u201372 h) to several US-PFAS elicited hepatocellular stress responses, such as oxidative stress and endoplasmic reticulum stress, and promoted inflammatory cell adhesion. Collectively, these findings demonstrate that US-PFAS have the capacity to affect biliary homeostasis and trigger downstream cholestatic events, providing mechanistic insight relevant for hazard identification.<\/jats:p>","DOI":"10.1021\/acs.est.6c04152","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T19:02:09Z","timestamp":1786474929000},"page":"23134-23147","source":"Crossref","is-referenced-by-count":3,"title":["Ultrashort-Chain\nPer- and Polyfluoroalkyl Substances\nand Cholestasis:\n                    <i>In Vitro<\/i>\n                    Evidence of Liver Dysfunction\nfrom Emerging Environmental Contaminants"],"prefix":"10.1021","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6208-636X","authenticated-orcid":true,"given":"Amy","family":"Maerten","sequence":"first","affiliation":[{"name":"Vrije Universiteit Brussel , , ,","place":["Brussels, Belgium, 1090"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jette","family":"Ritz","sequence":"additional","affiliation":[{"name":"Vrije Universiteit Brussel , , ,","place":["Brussels, Belgium, 1090"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Devisscher","sequence":"additional","affiliation":[{"name":"Universiteit Gent , , ,","place":["Gent, Belgium, 9000"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathieu","family":"Vinken","sequence":"additional","affiliation":[{"name":"Vrije Universiteit Brussel , , ,","place":["Brussels, Belgium, 1090"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"2026083119444887600_cit1","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1093\/toxsci\/kfm128","article-title":"Perfluoroalkyl acids: A review of monitoring and toxicological findings","volume":"99","author":"Lau","year":"2007","journal-title":"Toxicol. 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Epidemiol."},{"key":"2026083119444887600_cit5","doi-asserted-by":"publisher","first-page":"180975","DOI":"10.1016\/j.scitotenv.2025.180975","article-title":"Effects of per- and\npolyfluoroalkyl substances on molecular\ninitiating events of cholestatic liver injury","volume":"1008","author":"Maerten","year":"2025","journal-title":"Sci. Total Environ."},{"key":"2026083119444887600_cit6","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2021.e08272","article-title":"Hexafluoropropylene\noxide dimer acid (GenX) exposure induces apoptosis in HepG2 cells","volume":"7","author":"Yoo","year":"2021","journal-title":"Heliyon"},{"key":"2026083119444887600_cit7","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1021\/acs.chemrestox.3c00342","article-title":"GenX disturbs the indicators\nof hepatic lipid metabolism aven at\nenvironmental concentration in drinking water via PPAR\u03b1 signaling\npathways","volume":"37","author":"Shi","year":"2024","journal-title":"Chem. Res. Toxicol."},{"key":"2026083119444887600_cit8","doi-asserted-by":"publisher","first-page":"6133","DOI":"10.1021\/acs.est.1c02471","article-title":"Exposure to\nGenX and its novel analogs disrupts hepatic bile acid metabolism in\nmale mice","volume":"56","author":"Guo","year":"2022","journal-title":"Environ. Sci. Technol."},{"key":"2026083119444887600_cit9","doi-asserted-by":"publisher","first-page":"115001","DOI":"10.1016\/j.ecoenv.2023.115001","article-title":"Perfluorooctanoic\nacid (PFOA) and\nhexafluoropropylene oxide-dimer acid (GenX): Hepatic stress and bile\nacid metabolism with different pathways","volume":"259","author":"Yoo","year":"2023","journal-title":"Ecotoxicol.\nEnviron. 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Total Environ."},{"key":"2026083119444887600_cit14","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1177\/0192623320905803","article-title":"Assessment of the\nmode of action underlying the effects\nof GenX in mouse liver and implications for assessing human health\nrisks","volume":"48","author":"Chappell","year":"2020","journal-title":"Toxicol. 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Res."},{"key":"2026083119444887600_cit17","doi-asserted-by":"publisher","first-page":"15782","DOI":"10.1021\/acs.est.2c06715","article-title":"Elevated levels\nof ultrashort- and\nshort-chain perfluoroalkyl acids in US homes and people","volume":"57","author":"Zheng","year":"2023","journal-title":"Environ. Sci. Technol."},{"key":"2026083119444887600_cit18","doi-asserted-by":"publisher","first-page":"21393","DOI":"10.1021\/acs.est.4c04453","article-title":"Environmental occurrence\nand biotic concentrations of ultrashort-chain perfluoroalkyl acids:\noverlooked global organofluorine contaminants","volume":"58","author":"Zhi","year":"2024","journal-title":"Environ. Sci. 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G.\n          ORD Human Health Toxicity Value for Perfluoropropanoic\nAcid (CASRN 422-64-0|DTXSID8059970), 2023. https:\/\/pubmed.ncbi.nlm.nih.gov\/38442220\/ (accessed November 10, 2025)."},{"key":"2026083119444887600_cit24","doi-asserted-by":"publisher","first-page":"104465","DOI":"10.1016\/j.jbi.2023.104465","article-title":"Optimization of an\nadverse outcome pathway network on chemical-induced cholestasis using\nan artificial intelligence-assisted data collection and confidence\nlevel quantification approach","volume":"145","author":"van Ertvelde","year":"2023","journal-title":"J. Biomed. 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Toxicol."},{"key":"2026083119444887600_cit32","doi-asserted-by":"publisher","first-page":"3381","DOI":"10.1007\/s00204-024-03814-2","article-title":"In vitro screening\nof understudied PFAS with a focus\non lipid metabolism disruption","volume":"98","author":"Kashobwe","year":"2024","journal-title":"Arch. Toxicol."},{"key":"2026083119444887600_cit33","doi-asserted-by":"publisher","first-page":"153312","DOI":"10.1016\/j.tox.2022.153312","article-title":"Investigating the cytotoxicity of\nper- and polyfluoroalkyl\nsubstances in HepG2 cells: A structure-activity relationship approach","volume":"480","author":"Amstutz","year":"2022","journal-title":"Toxicology"},{"key":"2026083119444887600_cit34","doi-asserted-by":"publisher","first-page":"573","DOI":"10.1093\/toxsci\/kfv155","article-title":"Cellular accumulation\nand toxic effects of bile acids in cyclosporine A-treated HepaRG hepatocytes","volume":"147","author":"Sharanek","year":"2015","journal-title":"Toxicol. Sci."},{"key":"2026083119444887600_cit35","doi-asserted-by":"publisher","first-page":"115424","DOI":"10.1016\/j.envres.2023.115424","article-title":"Short-chain per- and\npolyfluoralkyl substances (PFAS) effects on oxidative stress biomarkers\nin human liver, kidney, muscle, and microglia cell lines","volume":"223","author":"Solan","year":"2023","journal-title":"Environ. Res."},{"key":"2026083119444887600_cit36","doi-asserted-by":"publisher","first-page":"108820","DOI":"10.1016\/j.envint.2024.108820","article-title":"Metabolic\nand phenotypic changes induced by PFAS exposure in two human hepatocyte\ncell models","volume":"190","author":"Alijagic","year":"2024","journal-title":"Environ. Int."},{"key":"2026083119444887600_cit37","doi-asserted-by":"publisher","first-page":"2501","DOI":"10.1038\/s41467-022-30238-2","article-title":"Stress-induced protein disaggregation in the endoplasmic\nreticulum catalysed by BiP","volume":"13","author":"Melo","year":"2022","journal-title":"Nat. Commun."},{"key":"2026083119444887600_cit38","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1111\/cei.13140","article-title":"Synergistic\neffect of interleukin-17 and tumour necrosis factor-\u03b1 on inflammatory\nresponse in hepatocytes through interleukin-6-dependent and independent\npathways","volume":"193","author":"Beringer","year":"2018","journal-title":"Clin. Exp. Immunol."},{"key":"2026083119444887600_cit39","doi-asserted-by":"publisher","first-page":"100241","DOI":"10.1016\/j.mcpro.2022.100241","article-title":"Interval-based secretomics unravels\nacute-phase response in hepatocyte model systems","volume":"21","author":"Knecht","year":"2022","journal-title":"Mol. Cell. Proteomics"},{"key":"2026083119444887600_cit40","doi-asserted-by":"publisher","first-page":"110337","DOI":"10.1016\/j.envint.2026.110337","article-title":"PFAS exposure\nmodulates mitochondrial susceptibility in steatotic hepatocytes","volume":"213","author":"Barbosa","year":"2026","journal-title":"Environ. Int."},{"key":"2026083119444887600_cit41","doi-asserted-by":"publisher","first-page":"109763","DOI":"10.1016\/j.envint.2025.109763","article-title":"Assessing\nthe impact of perfluoroalkyl\nsubstances on liver health: a comprehensive study using multi-donor\nhuman liver spheroids","volume":"203","author":"Golden-Mason","year":"2025","journal-title":"Environ. Int."},{"key":"2026083119444887600_cit42","doi-asserted-by":"publisher","DOI":"10.1002\/aws2.1243","article-title":"Practical implications\nof perfluoroalkyl\nsubstances adsorption on bottle materials: Isotherms","volume":"3","author":"Kleiner","year":"2021","journal-title":"AWWA Water Sci."},{"key":"2026083119444887600_cit43","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1007\/978-1-0716-4003-6_12","article-title":"Adverse outcome pathways mechanistically\ndescribing\nhepatotoxicity","volume":"2834","author":"Callewaert","year":"2025","journal-title":"Methods Mol. Biol."},{"key":"2026083119444887600_cit44","doi-asserted-by":"publisher","first-page":"153814","DOI":"10.1016\/j.tox.2024.153814","article-title":"A quantitative\nweight-of-evidence method for confidence\nassessment of adverse outcome pathway networks: A case study on chemical-induced\nliver steatosis","volume":"505","author":"Verhoeven","year":"2024","journal-title":"Toxicology"}],"container-title":["Environmental Science &amp;\nTechnology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/acs.est.6c04152","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/esthag\/article-pdf\/60\/33\/23134\/66501379\/acs.est.6c04152.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/esthag\/article-pdf\/60\/33\/23134\/66501379\/acs.est.6c04152.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T23:44:56Z","timestamp":1788219896000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/esthag\/article\/60\/33\/23134\/5252844\/Ultrashort-Chain-Per-and-Polyfluoroalkyl"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,11]]},"references-count":44,"journal-issue":{"issue":"33","published-online":{"date-parts":[[2026,8,11]]},"published-print":{"date-parts":[[2026,8,25]]}},"URL":"https:\/\/doi.org\/10.1021\/acs.est.6c04152","relation":{},"ISSN":["0013-936X","1520-5851"],"issn-type":[{"value":"0013-936X","type":"print"},{"value":"1520-5851","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,11]]}}}