{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T11:18:07Z","timestamp":1775042287553,"version":"3.50.1"},"reference-count":81,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000066","name":"National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["R01ES033625"],"award-info":[{"award-number":["R01ES033625"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Arch Toxicol"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Perfluorooctane sulfonate (PFOS) poses significant health and environmental risks due to its persistence and widespread use and has been linked to various adverse outcomes, such as liver toxicity. Although the molecular responses and toxicity effects of PFOS exposure have been extensively studied, considerable uncertainty remains regarding the causal mechanisms leading to PFOS-associated adverse effects. To help bridge this gap, we conducted CRISPR screens in HepG2\/C3A human liver cells exposed to IC\n                    <jats:sub>25<\/jats:sub>\n                    (170 \u00b5M) of PFOS to identify genes and pathways influencing PFOS-induced cytotoxicity. Using a genome-wide CRISPR knockout library targeting 18,819 genes, we identified 340 candidate genes that modulate PFOS-induced cytotoxicity when genetically disrupted (189 gene disruptions increased sensitivity and 151 gene disruptions increased resistance). From these candidate genes, we individually disrupted two candidate genes,\n                    <jats:italic>SLC6A9<\/jats:italic>\n                    which encodes the glycine transporter GlyT1, and\n                    <jats:italic>CPSF2<\/jats:italic>\n                    , and confirmed increased resistance to PFOS exposure. Further, molecular docking analysis predicts that PFOS directly binds to GlyT1 and functional inhibition of GlyT1 also increases resistance to PFOS exposure. Gene-Disease outcome association analysis using the Comparative Toxicogenomics Database (CTD) indicated an enrichment of candidate genes associated with cancer-related and liver disease phenotypes. KEGG and STRING enrichment analyses found over representation of several biological pathways including DNA damage response and cell cycle. Lastly, cross-species conservation analysis using the top two validated gene targets found that their pathways were highly conserved in several environmentally relevant species. These findings provide new mechanistic and functional insights into PFOS-induced cytotoxicity, highlight potential molecular targets for toxicity mitigation, and establish a foundation for cross-species toxicogenomic modeling of PFOS health effects.\n                  <\/jats:p>","DOI":"10.1007\/s00204-025-04294-8","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T01:59:10Z","timestamp":1769479150000},"page":"1391-1410","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of functional genetic components modulating toxicity response to PFOS using genome-wide CRISPR screens in HepG2\/C3A cells"],"prefix":"10.1007","volume":"100","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5706-9701","authenticated-orcid":false,"given":"Chanhee","family":"Kim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abderrahmane","family":"Tagmount","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaohan","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frances","family":"Wilson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danmeng","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David A.","family":"Ostrov","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William","family":"Brad Barbazuk","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rhonda","family":"Bacher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chris D.","family":"Vulpe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"4294_CR1","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1093\/toxsci\/kfad044","volume":"194","author":"GC Addicks","year":"2023","unstructured":"Addicks GC, Rowan-Carroll A, Reardon AJF et al (2023) Per- and polyfluoroalkyl substances (PFAS) in mixtures show additive effects on transcriptomic points of departure in human liver spheroids. Toxicol Sci 194:38\u201352. https:\/\/doi.org\/10.1093\/toxsci\/kfad044","journal-title":"Toxicol Sci"},{"key":"4294_CR3","doi-asserted-by":"publisher","first-page":"1414","DOI":"10.1124\/mol.60.6.1414","volume":"60","author":"BN Atkinson","year":"2001","unstructured":"Atkinson BN, Bell SC, De Vivo M et al (2001) ALX 5407: a potent, selective inhibitor of the hGlyT1 glycine transporter. Mol Pharmacol 60:1414\u20131420. https:\/\/doi.org\/10.1124\/mol.60.6.1414","journal-title":"Mol Pharmacol"},{"key":"4294_CR4","doi-asserted-by":"publisher","first-page":"4487","DOI":"10.1021\/acs.est.3c05974","volume":"58","author":"ER Azhagiya Singam","year":"2024","unstructured":"Azhagiya Singam ER, Durkin KA, Merrill L, M. A. et al (2024) Prediction of the interactions of a large number of per- and poly-fluoroalkyl substances with ten nuclear receptors. Environ Sci Technol 58:4487\u20134499. https:\/\/doi.org\/10.1021\/acs.est.3c05974","journal-title":"Environ Sci Technol"},{"key":"4294_CR5","doi-asserted-by":"publisher","first-page":"157255","DOI":"10.1016\/j.scitotenv.2022.157255","volume":"845","author":"DJ Beale","year":"2022","unstructured":"Beale DJ, Sinclair GM, Shah R et al (2022) A review of omics-based PFAS exposure studies reveals common biochemical response pathways. Sci Total Environ 845:157255. https:\/\/doi.org\/10.1016\/j.scitotenv.2022.157255","journal-title":"Sci Total Environ"},{"key":"4294_CR6","doi-asserted-by":"publisher","first-page":"394","DOI":"10.4254\/wjh.v6.i6.394","volume":"6","author":"F Bessone","year":"2014","unstructured":"Bessone F, Poles N, Roma MG (2014) Challenge of liver disease in systemic lupus erythematosus: clues for diagnosis and hints for pathogenesis. World J Hepatol 6:394\u2013409. https:\/\/doi.org\/10.4254\/wjh.v6.i6.394","journal-title":"World J Hepatol"},{"key":"4294_CR7","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.tox.2011.06.012","volume":"288","author":"JA Bjork","year":"2011","unstructured":"Bjork JA, Butenhoff JL, Wallace KB (2011) Multiplicity of nuclear receptor activation by PFOA and PFOS in primary human and rodent hepatocytes. Toxicology 288:8\u201317. https:\/\/doi.org\/10.1016\/j.tox.2011.06.012","journal-title":"Toxicology"},{"key":"4294_CR8","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1186\/s12940-022-00892-6","volume":"21","author":"MM Borghese","year":"2022","unstructured":"Borghese MM, Liang CL, Owen J et al (2022) Individual and mixture associations of perfluoroalkyl substances on liver function biomarkers in the Canadian Health Measures Survey. Environ Health 21:85. https:\/\/doi.org\/10.1186\/s12940-022-00892-6","journal-title":"Environ Health"},{"key":"4294_CR9","doi-asserted-by":"publisher","unstructured":"Butenhoff JL, Chang S-C, Olsen GW et al (2012) Chronic dietary toxicity and carcinogenicity study with potassium perfluorooctanesulfonate in Sprague Dawley rats. Toxicology 293:1\u201315. https:\/\/doi.org\/10.1016\/j.tox.2012.01.003","DOI":"10.1016\/j.tox.2012.01.003"},{"key":"4294_CR10","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1007\/s13181-011-0172-4","volume":"7","author":"DE Buttke","year":"2011","unstructured":"Buttke DE (2011) Toxicology, environmental health, and the one health concept. J Med Toxicol 7:329\u2013332. https:\/\/doi.org\/10.1007\/s13181-011-0172-4","journal-title":"J Med Toxicol"},{"key":"4294_CR12","doi-asserted-by":"publisher","first-page":"17039","DOI":"10.1021\/acs.est.2c04107","volume":"56","author":"X Cheng","year":"2022","unstructured":"Cheng X, Wei Y, Zhang Z, et al et al (2022) Plasma PFOA and PFOS levels, DNA methylation, and blood lipid levels: a pilot study. Environ Sci Technol 56:17039\u201317051. https:\/\/doi.org\/10.1021\/acs.est.2c04107","journal-title":"Environ Sci Technol"},{"key":"4294_CR13","doi-asserted-by":"publisher","first-page":"046001","DOI":"10.1289\/EHP10092","volume":"130","author":"E Costello","year":"2022","unstructured":"Costello E, Rock S, Stratakis N et al (2022) Exposure to per- and polyfluoroalkyl substances and markers of liver injury: a systematic review and meta-analysis. Environ Health Perspect 130:046001. https:\/\/doi.org\/10.1289\/EHP10092","journal-title":"Environ Health Perspect"},{"key":"4294_CR14","doi-asserted-by":"publisher","first-page":"338","DOI":"10.1007\/s00244-008-9194-6","volume":"56","author":"L Cui","year":"2009","unstructured":"Cui L, Zhou Q, Liao C et al (2009) Studies on the toxicological effects of PFOA and PFOS on rats using histological observation and chemical analysis. Arch Environ Contam Toxicol 56:338\u2013349. https:\/\/doi.org\/10.1007\/s00244-008-9194-6","journal-title":"Arch Environ Contam Toxicol"},{"key":"4294_CR15","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1016\/j.jhazmat.2015.06.031","volume":"299","author":"R Cui","year":"2015","unstructured":"Cui R, Zhang H, Guo X et al (2015) Proteomic analysis of cell proliferation in a human hepatic cell line (HL-7702) induced by perfluorooctane sulfonate using iTRAQ. J Hazard Mater 299:361\u2013370. https:\/\/doi.org\/10.1016\/j.jhazmat.2015.06.031","journal-title":"J Hazard Mater"},{"key":"4294_CR16","doi-asserted-by":"publisher","first-page":"105475","DOI":"10.1016\/j.tiv.2022.105475","volume":"85","author":"N Davidsen","year":"2022","unstructured":"Davidsen N, Ramh\u00f8j L, Kugathas I et al (2022) PFOS disrupts key developmental pathways during hiPSC-derived cardiomyocyte differentiation in vitro. Toxicol Vitro 85:105475. https:\/\/doi.org\/10.1016\/j.tiv.2022.105475","journal-title":"Toxicol Vitro"},{"key":"4294_CR17","doi-asserted-by":"publisher","first-page":"D1328","DOI":"10.1093\/nar\/gkae883","volume":"53","author":"AP Davis","year":"2025","unstructured":"Davis AP, Wiegers TC, Sciaky D et al (2025) Comparative toxicogenomics database\u2019s 20th anniversary: update 2025. Nucleic Acids Res 53:D1328\u2013D1334. https:\/\/doi.org\/10.1093\/nar\/gkae883","journal-title":"Nucleic Acids Res"},{"key":"4294_CR11","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1093\/jpp\/rgae051","volume":"76","author":"GA de Carvalho","year":"2024","unstructured":"de Carvalho GA, Tambwe PM, Nascimento LRC et al (2024) In silico evidence of bitopertin\u2019s broad interactions within the SLC6 transporter family. J Pharm Pharmacol 76:1199\u20131211. https:\/\/doi.org\/10.1093\/jpp\/rgae051","journal-title":"J Pharm Pharmacol"},{"key":"4294_CR18","doi-asserted-by":"publisher","first-page":"117003","DOI":"10.1289\/EHP11360","volume":"130","author":"P Deng","year":"2022","unstructured":"Deng P, Durham J, Liu J et al (2022) Metabolomic, lipidomic, transcriptomic, and metagenomic analyses in mice exposed to PFOS and fed soluble and insoluble dietary fibers. Environ Health Perspect 130:117003. https:\/\/doi.org\/10.1289\/EHP11360","journal-title":"Environ Health Perspect"},{"key":"4294_CR19","doi-asserted-by":"publisher","first-page":"2229","DOI":"10.1042\/BST20210323","volume":"49","author":"Z Dominski","year":"2021","unstructured":"Dominski Z, Tong L (2021) U7 deciphered: the mechanism that forms the unusual 3\u2032 end of metazoan replication-dependent histone mRNAs. Biochem Soc Trans 49:2229\u20132240. https:\/\/doi.org\/10.1042\/BST20210323","journal-title":"Biochem Soc Trans"},{"key":"4294_CR20","doi-asserted-by":"publisher","first-page":"105726","DOI":"10.1016\/j.yrtph.2024.105726","volume":"154","author":"NL Drury","year":"2024","unstructured":"Drury NL, Prueitt RL, Beck BD (2024) Commentary: Understanding IARC\u2019s PFOA and PFOS carcinogenicity assessments. Regul Toxicol Pharmacol 154:105726. https:\/\/doi.org\/10.1016\/j.yrtph.2024.105726","journal-title":"Regul Toxicol Pharmacol"},{"key":"4294_CR21","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/s12940-022-00958-5","volume":"22","author":"V Ehrlich","year":"2023","unstructured":"Ehrlich V, Bil W, Vandebriel R et al (2023) Consideration of pathways for immunotoxicity of per- and polyfluoroalkyl substances (PFAS). Environ Health 22:19. https:\/\/doi.org\/10.1186\/s12940-022-00958-5","journal-title":"Environ Health"},{"key":"4294_CR22","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfaf066","author":"FA Ekuban","year":"2025","unstructured":"Ekuban FA, Gripshover TC, Ames P et al (2025) Perfluorooctane sulfonate exposure and alcohol-associated liver disease severity in a mouse chronic-binge ethanol feeding model. Toxicol Sci. https:\/\/doi.org\/10.1093\/toxsci\/kfaf066","journal-title":"Toxicol Sci"},{"key":"4294_CR23","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1016\/j.stemcr.2020.08.003","volume":"15","author":"CB Eldridge","year":"2020","unstructured":"Eldridge CB, Allen FJ, Crisp A et al (2020) A p53-dependent checkpoint induced upon DNA damage alters cell fate during HiPSC differentiation. Stem Cell Rep 15:827\u2013835. https:\/\/doi.org\/10.1016\/j.stemcr.2020.08.003","journal-title":"Stem Cell Rep"},{"key":"4294_CR24","doi-asserted-by":"publisher","first-page":"116136","DOI":"10.1016\/j.taap.2022.116136","volume":"449","author":"N Evans","year":"2022","unstructured":"Evans N, Conley JM, Cardon M et al (2022) In vitro activity of a panel of per- and polyfluoroalkyl substances (PFAS), fatty acids, and pharmaceuticals in peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, and estrogen receptor assays. Toxicol Appl Pharmacol 449:116136. https:\/\/doi.org\/10.1016\/j.taap.2022.116136","journal-title":"Toxicol Appl Pharmacol"},{"key":"4294_CR25","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1002\/etc.4890","volume":"40","author":"SE Fenton","year":"2021","unstructured":"Fenton SE, Ducatman A, Boobis A et al (2021) Per- and polyfluoroalkyl substance toxicity and human health review: current state of knowledge and strategies for informing future research. Environ Toxicol Chem 40:606\u2013630. https:\/\/doi.org\/10.1002\/etc.4890","journal-title":"Environ Toxicol Chem"},{"key":"4294_CR26","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1016\/j.addr.2017.01.005","volume":"116","author":"B George","year":"2017","unstructured":"George B, You D, Joy MS et al (2017) Xenobiotic transporters and kidney injury. Adv Drug Deliv Rev 116:73\u201391. https:\/\/doi.org\/10.1016\/j.addr.2017.01.005","journal-title":"Adv Drug Deliv Rev"},{"key":"4294_CR28","doi-asserted-by":"publisher","unstructured":"G\u00f6ckener B, Weber T, R\u00fcdel H et al (2020) Human biomonitoring of per- and polyfluoroalkyl substances in German blood plasma samples from 1982 to 2019. Environ Int 145:106123. https:\/\/doi.org\/10.1016\/j.envint.2020.106123","DOI":"10.1016\/j.envint.2020.106123"},{"key":"4294_CR29","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s13059-021-02268-4","volume":"22","author":"E Gon\u00e7alves","year":"2021","unstructured":"Gon\u00e7alves E, Thomas M, Behan FM et al (2021) Minimal genome-wide human CRISPR-Cas9 library. Genome Biol 22:40. https:\/\/doi.org\/10.1186\/s13059-021-02268-4","journal-title":"Genome Biol"},{"key":"4294_CR30","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1113\/jphysiol.2009.186262","volume":"588","author":"A Howard","year":"2010","unstructured":"Howard A, Tahir I, Javed S et al (2010) Glycine transporter GLYT1 is essential for glycine-mediated protection of human intestinal epithelial cells against oxidative damage. J Physiol 588:995\u20131009. https:\/\/doi.org\/10.1113\/jphysiol.2009.186262","journal-title":"J Physiol"},{"key":"4294_CR31","doi-asserted-by":"publisher","DOI":"10.1007\/s40726-023-00269-4","author":"S India-Aldana","year":"2023","unstructured":"India-Aldana S, Yao M, Midya V et al (2023) PFAS exposures and the human metabolome: a systematic review of epidemiological studies. Curr Pollution Rep. https:\/\/doi.org\/10.1007\/s40726-023-00269-4","journal-title":"Curr Pollution Rep"},{"key":"4294_CR32","doi-asserted-by":"publisher","first-page":"113431","DOI":"10.1016\/j.envres.2022.113431","volume":"212","author":"L Jane","year":"2022","unstructured":"Jane L, Espartero L, Yamada M, Ford J et al (2022) Health-related toxicity of emerging per- and polyfluoroalkyl substances: comparison to legacy PFOS and PFOA. Environ Res 212:113431. https:\/\/doi.org\/10.1016\/j.envres.2022.113431","journal-title":"Environ Res"},{"key":"4294_CR33","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1177\/07482337241277259","volume":"40","author":"C Jiajing","year":"2024","unstructured":"Jiajing C, Shuqi Y, Haoyan M et al (2024) Perfluorooctane sulfonate causes damage to L-02 cells via Wnt\/\u03b2-catenin signal path and Endoplasmic reticulum stress pathway. Toxicol Ind Health 40:653\u2013666. https:\/\/doi.org\/10.1177\/07482337241277259","journal-title":"Toxicol Ind Health"},{"key":"4294_CR34","doi-asserted-by":"publisher","first-page":"828","DOI":"10.1038\/nprot.2017.016","volume":"12","author":"J Joung","year":"2017","unstructured":"Joung J, Konermann S, Gootenberg JS et al (2017) Genome-scale CRISPR-Cas9 knockout and transcriptional activation screening. Nat Protoc 12:828\u2013863. https:\/\/doi.org\/10.1038\/nprot.2017.016","journal-title":"Nat Protoc"},{"key":"4294_CR35","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","volume":"596","author":"J Jumper","year":"2021","unstructured":"Jumper J, Evans R, Pritzel A et al (2021) Highly accurate protein structure prediction with alphafold. Nature 596:583\u2013589. https:\/\/doi.org\/10.1038\/s41586-021-03819-2","journal-title":"Nature"},{"key":"4294_CR36","doi-asserted-by":"publisher","first-page":"116929","DOI":"10.1016\/j.envpol.2021.116929","volume":"279","author":"S Kim","year":"2021","unstructured":"Kim S, Thapar I, Brooks BW (2021) Epigenetic changes by per- and polyfluoroalkyl substances (PFAS). Environ Pollut 279:116929. https:\/\/doi.org\/10.1016\/j.envpol.2021.116929","journal-title":"Environ Pollut"},{"key":"4294_CR37","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1080\/10915810252825975","volume":"21","author":"CD Klaassen","year":"2002","unstructured":"Klaassen CD (2002) Xenobiotic transporters: another protective mechanism for chemicals. Int J Toxicol 21:7\u201312. https:\/\/doi.org\/10.1080\/10915810252825975","journal-title":"Int J Toxicol"},{"key":"4294_CR38","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1007\/s13273-018-0019-z","volume":"14","author":"J-K Lee","year":"2018","unstructured":"Lee J-K, Lee S, Choi Y-A et al (2018) Perfluorooctane sulfonate exacerbates mast cell-mediated allergic inflammation by the release of Histamine. Mol Cell Toxicol 14:173\u2013181. https:\/\/doi.org\/10.1007\/s13273-018-0019-z","journal-title":"Mol Cell Toxicol"},{"key":"4294_CR41","doi-asserted-by":"publisher","first-page":"554","DOI":"10.1186\/s13059-014-0554-4","volume":"15","author":"W Li","year":"2014","unstructured":"Li W, Xu H, Xiao T et al (2014) MAGeCK enables robust identification of essential genes from genome-scale CRISPR\/Cas9 knockout screens. Genome Biol 15:554. https:\/\/doi.org\/10.1186\/s13059-014-0554-4","journal-title":"Genome Biol"},{"key":"4294_CR39","doi-asserted-by":"publisher","first-page":"124030","DOI":"10.1016\/j.envpol.2024.124030","volume":"350","author":"F Li","year":"2024","unstructured":"Li F, Yang R, Lu L et al (2024) Comparative steroidogenic effects of hexafluoropropylene oxide trimer acid (HFPO-TA) and perfluorooctanoic acid (PFOA): regulation of histone modifications. Environ Pollut 350:124030. https:\/\/doi.org\/10.1016\/j.envpol.2024.124030","journal-title":"Environ Pollut"},{"key":"4294_CR40","doi-asserted-by":"publisher","first-page":"7920","DOI":"10.1038\/s41598-025-92678-2","volume":"15","author":"H Li","year":"2025","unstructured":"Li H, Yu B, Yuan Y et al (2025) Integrated computational analysis of molecular mechanisms underlying perfluorooctane sulfonic acid induced thyroid toxicity. Sci Rep 15:7920. https:\/\/doi.org\/10.1038\/s41598-025-92678-2","journal-title":"Sci Rep"},{"key":"4294_CR42","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1002\/jat.4383","volume":"43","author":"J Ling","year":"2023","unstructured":"Ling J, Hua L, Qin Y et al (2023) Perfluorooctane sulfonate promotes hepatic lipid accumulation and steatosis in high-fat diet mice through AMP-activated protein kinase\/acetyl-CoA carboxylase (AMPK\/ACC) pathway. J Appl Toxicol 43:312\u2013322. https:\/\/doi.org\/10.1002\/jat.4383","journal-title":"J Appl Toxicol"},{"key":"4294_CR44","doi-asserted-by":"publisher","unstructured":"Liu L, Manley JL (2024) Modulation of diverse biological processes by CPSF, the master regulator of mRNA 3\u2032 ends. RNA 30:1122\u20131140. https:\/\/doi.org\/10.1261\/rna.080108.124","DOI":"10.1261\/rna.080108.124"},{"key":"4294_CR43","doi-asserted-by":"publisher","first-page":"806","DOI":"10.1016\/j.envpol.2016.04.089","volume":"214","author":"G Liu","year":"2016","unstructured":"Liu G, Zhang S, Yang K et al (2016) Toxicity of perfluorooctane sulfonate and perfluorooctanoic acid to Escherichia coli: membrane disruption, oxidative stress, and DNA damage induced cell inactivation and\/or death. Environ Pollut 214:806\u2013815. https:\/\/doi.org\/10.1016\/j.envpol.2016.04.089","journal-title":"Environ Pollut"},{"key":"4294_CR47","doi-asserted-by":"publisher","first-page":"3137","DOI":"10.1007\/s00204-020-02808-0","volume":"94","author":"J Louisse","year":"2020","unstructured":"Louisse J, Rijkers D, Stoopen G et al (2020) Perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorononanoic acid (PFNA) increase triglyceride levels and decrease cholesterogenic gene expression in human HepaRG liver cells. Arch Toxicol 94:3137\u20133155. https:\/\/doi.org\/10.1007\/s00204-020-02808-0","journal-title":"Arch Toxicol"},{"key":"4294_CR45","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1007\/s00204-023-03450-2","volume":"97","author":"J Louisse","year":"2023","unstructured":"Louisse J, Fragki S, Rijkers D et al (2023) Determination of in vitro hepatotoxic potencies of a series of perfluoroalkyl substances (PFASs) based on gene expression changes in HepaRG liver cells. Arch Toxicol 97:1113\u20131131. https:\/\/doi.org\/10.1007\/s00204-023-03450-2","journal-title":"Arch Toxicol"},{"key":"4294_CR46","doi-asserted-by":"publisher","unstructured":"Louisse J, Pedroni L, van den Heuvel JJMW et al (2024) In vitro and in silico characterization of the transport of selected perfluoroalkyl carboxylic acids and perfluoroalkyl sulfonic acids by human organic anion transporter 1 (OAT1), OAT2 and OAT3. Toxicology 509:153961. https:\/\/doi.org\/10.1016\/j.tox.2024.153961","DOI":"10.1016\/j.tox.2024.153961"},{"key":"4294_CR48","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1038\/84298","volume":"2","author":"CR Mackay","year":"2001","unstructured":"Mackay CR (2001) Chemokines: immunology\u2019s high impact factors. Nat Immunol 2:95\u2013101. https:\/\/doi.org\/10.1038\/84298","journal-title":"Nat Immunol"},{"key":"4294_CR49","doi-asserted-by":"publisher","first-page":"115250","DOI":"10.1016\/j.taap.2020.115250","volume":"408","author":"E Marques","year":"2020","unstructured":"Marques E, Pfohl M, Auclair A et al (2020) Perfluorooctanesulfonic acid (PFOS) administration shifts the hepatic proteome and augments dietary outcomes related to hepatic steatosis in mice. Toxicol Appl Pharmcol 408:115250. https:\/\/doi.org\/10.1016\/j.taap.2020.115250","journal-title":"Toxicol Appl Pharmcol"},{"key":"4294_CR50","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1016\/B978-0-12-800249-0.00005-6","volume":"121","author":"K Mayes","year":"2014","unstructured":"Mayes K, Qiu Z, Alhazmi A et al (2014) ATP-dependent chromatin remodeling complexes as novel targets for cancer therapy. Adv Cancer Res 121:183\u2013233. https:\/\/doi.org\/10.1016\/B978-0-12-800249-0.00005-6","journal-title":"Adv Cancer Res"},{"key":"4294_CR51","doi-asserted-by":"publisher","first-page":"398","DOI":"10.1093\/toxsci\/kfq322","volume":"119","author":"SH O\u2019Shea","year":"2011","unstructured":"O\u2019Shea SH, Schwarz J, Kosyk O et al (2011) In vitro screening for population variability in chemical toxicity. Toxicol Sci 119:398\u2013407. https:\/\/doi.org\/10.1093\/toxsci\/kfq322","journal-title":"Toxicol Sci"},{"key":"4294_CR52","doi-asserted-by":"publisher","first-page":"113980","DOI":"10.1016\/j.ecoenv.2022.113980","volume":"244","author":"C Otero-Sabio","year":"2022","unstructured":"Otero-Sabio C, Giacomello M, Centelleghe C et al (2022) Cell cycle alterations due to perfluoroalkyl substances PFOS, PFOA, PFBS, PFBA and the new PFAS C6O4 on bottlenose Dolphin (Tursiops truncatus) skin cell. Ecotoxicol Environ Saf 244:113980. https:\/\/doi.org\/10.1016\/j.ecoenv.2022.113980","journal-title":"Ecotoxicol Environ Saf"},{"key":"4294_CR53","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1093\/toxsci\/kfaf101","volume":"207","author":"R Owen","year":"2025","unstructured":"Owen R, de Macedo G, Nerlich J et al (2025) Perfluorooctanesulfonic acid (PFOS) antagonizes gamma-aminobutyric acid (GABA) receptors in larval zebrafish and mammalian models. Toxicol Sci 207:449\u2013466. https:\/\/doi.org\/10.1093\/toxsci\/kfaf101","journal-title":"Toxicol Sci"},{"key":"4294_CR54","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1016\/j.envint.2013.06.004","volume":"59","author":"F P\u00e9rez","year":"2013","unstructured":"P\u00e9rez F, Nadal M, Navarro-Ortega A et al (2013) Accumulation of perfluoroalkyl substances in human tissues. Environ Int 59:354\u2013362. https:\/\/doi.org\/10.1016\/j.envint.2013.06.004","journal-title":"Environ Int"},{"key":"4294_CR55","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1093\/toxsci\/kfaa172","volume":"180","author":"M Pfohl","year":"2021","unstructured":"Pfohl M, Marques E, Auclair A et al (2021) An omics approach to unraveling the Paradoxical effect of diet on perfluorooctanesulfonic acid (PFOS) and perfluorononanoic acid (PFNA)-induced hepatic steatosis. Toxicol Sci 180:277\u2013294. https:\/\/doi.org\/10.1093\/toxsci\/kfaa172","journal-title":"Toxicol Sci"},{"key":"4294_CR56","doi-asserted-by":"publisher","first-page":"108197","DOI":"10.1016\/j.envint.2023.108197","volume":"180","author":"J Rhee","year":"2023","unstructured":"Rhee J, Chang VC, Cheng I et al (2023) Serum concentrations of per- and polyfluoroalkyl substances and risk of renal cell carcinoma in the multiethnic cohort study. Environ Int 180:108197. https:\/\/doi.org\/10.1016\/j.envint.2023.108197","journal-title":"Environ Int"},{"key":"4294_CR57","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1002\/etc.5600","volume":"42","author":"C Rivetti","year":"2023","unstructured":"Rivetti C, Houghton J, Basili D et al (2023) Genes-to-pathways species conservation analysis: enabling the exploration of conservation of biological pathways and processes across species. Environ Toxicol Chem 42:1152\u20131166. https:\/\/doi.org\/10.1002\/etc.5600","journal-title":"Environ Toxicol Chem"},{"key":"4294_CR58","doi-asserted-by":"crossref","unstructured":"Rockett JC (2002) Use of genomic data in risk assessment. Genome Biol 3:reports4011.1\u2013reports4011.3","DOI":"10.1186\/gb-2002-3-4-reports4011"},{"key":"4294_CR59","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1093\/toxsci\/kfab039","volume":"181","author":"A Rowan-Carroll","year":"2021","unstructured":"Rowan-Carroll A, Reardon A, Leingartner K et al (2021) High-Throughput transcriptomic analysis of human primary hepatocyte spheroids exposed to per- and polyfluoroalkyl substances as a platform for relative potency characterization. Toxicol Sci 181:199\u2013214. https:\/\/doi.org\/10.1093\/toxsci\/kfab039","journal-title":"Toxicol Sci"},{"key":"4294_CR60","doi-asserted-by":"publisher","first-page":"366","DOI":"10.1093\/toxsci\/kfaa071","volume":"176","author":"M Russo","year":"2020","unstructured":"Russo M, Sobh A, Zhang P et al (2020) Functional pathway identification with CRISPR\/Cas9 Genome-wide gene disruption in human dopaminergic neuronal cells following chronic treatment with dieldrin. Toxicol Sci 176:366\u2013381. https:\/\/doi.org\/10.1093\/toxsci\/kfaa071","journal-title":"Toxicol Sci"},{"key":"4294_CR61","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1038\/s41370-018-0060-y","volume":"29","author":"S Salihovic","year":"2019","unstructured":"Salihovic S, Fall T, Ganna A et al (2019) Identification of metabolic profiles associated with human exposure to perfluoroalkyl substances. J Expo Sci Environ Epidemiol 29:196\u2013205. https:\/\/doi.org\/10.1038\/s41370-018-0060-y","journal-title":"J Expo Sci Environ Epidemiol"},{"key":"4294_CR62","doi-asserted-by":"publisher","DOI":"10.3389\/fenvs.2024.1303705","author":"S Sauv\u00e9","year":"2024","unstructured":"Sauv\u00e9 S (2024) Toxicology, environmental chemistry, ecotoxicology, and one health: definitions and paths for future research. Front Environ Sci. https:\/\/doi.org\/10.3389\/fenvs.2024.1303705","journal-title":"Front EnvironSci"},{"key":"4294_CR63","doi-asserted-by":"publisher","first-page":"168573","DOI":"10.1016\/j.scitotenv.2023.168573","volume":"912","author":"P Schumann","year":"2024","unstructured":"Schumann P, Rivetti C, Houghton J et al (2024) Combination of computational new approach methodologies for enhancing evidence of biological pathway conservation across species. Sci Total Environ 912:168573. https:\/\/doi.org\/10.1016\/j.scitotenv.2023.168573","journal-title":"Sci Total Environ"},{"key":"4294_CR64","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1093\/toxsci\/kfz037","volume":"169","author":"A Sobh","year":"2019","unstructured":"Sobh A, Loguinov A, Stornetta A et al (2019) Genome-Wide CRISPR screening identifies the tumor suppressor candidate OVCA2 as a determinant of tolerance to acetaldehyde. Toxicol Sci 169:235\u2013245. https:\/\/doi.org\/10.1093\/toxsci\/kfz037","journal-title":"Toxicol Sci"},{"key":"4294_CR65","doi-asserted-by":"publisher","first-page":"D1210","DOI":"10.1093\/nar\/gkad986","volume":"52","author":"Z Sondka","year":"2024","unstructured":"Sondka Z, Dhir NB, Carvalho-Silva D et al (2024) COSMIC: a curated database of somatic variants and clinical data for cancer. Nucleic Acids Res 52:D1210\u2013D1217. https:\/\/doi.org\/10.1093\/nar\/gkad986","journal-title":"Nucleic Acids Res"},{"key":"4294_CR66","doi-asserted-by":"publisher","first-page":"15854","DOI":"10.1038\/s41598-017-16193-9","volume":"7","author":"PN Spahn","year":"2017","unstructured":"Spahn PN, Bath T, Weiss RJ et al (2017) PinAPL-Py: a comprehensive web-application for the analysis of CRISPR\/Cas9 screens. Sci Rep 7:15854. https:\/\/doi.org\/10.1038\/s41598-017-16193-9","journal-title":"Sci Rep"},{"key":"4294_CR67","doi-asserted-by":"publisher","first-page":"110690","DOI":"10.1016\/j.envres.2020.110690","volume":"194","author":"K Steenland","year":"2021","unstructured":"Steenland K, Winquist A (2021) PFAS and cancer, a scoping review of the epidemiologic evidence. Environ Res 194:110690. https:\/\/doi.org\/10.1016\/j.envres.2020.110690","journal-title":"Environ Res"},{"key":"4294_CR68","doi-asserted-by":"publisher","first-page":"D638","DOI":"10.1093\/nar\/gkac1000","volume":"51","author":"D Szklarczyk","year":"2023","unstructured":"Szklarczyk D, Kirsch R, Koutrouli M et al (2023) The STRING database in 2023: protein-protein association networks and functional enrichment analyses for any sequenced genome of interest. Nucleic Acids Res 51:D638\u2013D646. https:\/\/doi.org\/10.1093\/nar\/gkac1000","journal-title":"Nucleic Acids Res"},{"key":"4294_CR69","doi-asserted-by":"publisher","first-page":"e0294236","DOI":"10.1371\/journal.pone.0294236","volume":"18","author":"D Tang","year":"2023","unstructured":"Tang D, Chen M, Huang X et al (2023) SRplot: A free online platform for data visualization and graphing. PLoS ONE 18:e0294236. https:\/\/doi.org\/10.1371\/journal.pone.0294236","journal-title":"PLoS ONE"},{"key":"4294_CR2","unstructured":"US EPA (2024) pfos-report-2024.pdf. Available at: https:\/\/www.epa.gov\/system\/files\/documents\/2024-09\/pfos-report-2024.pdf?utm_source=chatgpt.com. Accessed 27 June 2025"},{"key":"4294_CR27","doi-asserted-by":"publisher","unstructured":"van Gerwen M, Colicino E, Guan H et al (2023) Per- and polyfluoroalkyl substances (PFAS) exposure and thyroid cancer risk. eBioMedicine. https:\/\/doi.org\/10.1016\/j.ebiom.2023.104831","DOI":"10.1016\/j.ebiom.2023.104831"},{"key":"4294_CR70","doi-asserted-by":"publisher","first-page":"D368","DOI":"10.1093\/nar\/gkad1011","volume":"52","author":"M Varadi","year":"2024","unstructured":"Varadi M, Bertoni D, Magana P et al (2024) AlphaFold protein structure database in 2024: providing structure coverage for over 214 million protein sequences. Nucleic Acids Res 52:D368\u2013D375. https:\/\/doi.org\/10.1093\/nar\/gkad1011","journal-title":"Nucleic Acids Res"},{"key":"4294_CR71","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1093\/toxsci\/kfae061","volume":"200","author":"E Vujic","year":"2024","unstructured":"Vujic E, Ferguson SS, Brouwer KLR (2024) Effects of PFAS on human liver transporters: implications for health outcomes. Toxicol Sci 200:213. https:\/\/doi.org\/10.1093\/toxsci\/kfae061","journal-title":"Toxicol Sci"},{"key":"4294_CR72","doi-asserted-by":"publisher","DOI":"10.3389\/fvets.2022.1014286","author":"X Wang","year":"2022","unstructured":"Wang X, Wang J, Raza SHA et al (2022) Identification of the hub genes related to adipose tissue metabolism of bovine. Front Vet Sci. https:\/\/doi.org\/10.3389\/fvets.2022.1014286","journal-title":"Front Vet Sci"},{"key":"4294_CR73","doi-asserted-by":"publisher","first-page":"115663","DOI":"10.1016\/j.ecoenv.2023.115663","volume":"267","author":"SY Wee","year":"2023","unstructured":"Wee SY, Aris AZ (2023) Environmental impacts, exposure pathways, and health effects of PFOA and PFOS. Ecotoxicol Environ Saf 267:115663. https:\/\/doi.org\/10.1016\/j.ecoenv.2023.115663","journal-title":"Ecotoxicol Environ Saf"},{"key":"4294_CR74","doi-asserted-by":"publisher","unstructured":"Wei Y, Li R, Meng Y et al (2024) Transport mechanism and pharmacology of the human GlyT1. Cell 187:1719\u20131732. https:\/\/doi.org\/10.1016\/j.cell.2024.02.026","DOI":"10.1016\/j.cell.2024.02.026"},{"key":"4294_CR75","doi-asserted-by":"publisher","first-page":"127007","DOI":"10.1289\/EHP13174","volume":"131","author":"A Winquist","year":"2023","unstructured":"Winquist A, Hodge JM, Diver WR et al (2023) Case\u2013Cohort study of the association between PFAS and selected cancers among participants in the American Cancer Society\u2019s cancer prevention study II lifelink cohort. Environ Health Perspect 131:127007. https:\/\/doi.org\/10.1289\/EHP13174","journal-title":"Environ Health Perspect"},{"key":"4294_CR76","doi-asserted-by":"publisher","first-page":"117524","DOI":"10.1016\/j.ecoenv.2024.117524","volume":"290","author":"L Xue","year":"2025","unstructured":"Xue L, Xu J, Xiao P et al (2025) Perfluorooctane sulfonate (PFOS) induced bone loss by inhibiting FoxO1-mediated defense against oxidative stress in osteoblast. Ecotoxicol Environ Saf 290:117524. https:\/\/doi.org\/10.1016\/j.ecoenv.2024.117524","journal-title":"Ecotoxicol Environ Saf"},{"issue":"23","key":"4294_CR77","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1016\/S1470-2045","volume":"25","author":"S Zahm","year":"2024","unstructured":"Zahm S, Bonde JP, Chiu WA et al (2024) Carcinogenicity of perfluorooctanoic acid and perfluorooctanesulfonic acid. Lancet Oncol 25(23):16\u201317. https:\/\/doi.org\/10.1016\/S1470-2045","journal-title":"Lancet Oncol"},{"key":"4294_CR78","doi-asserted-by":"publisher","first-page":"598","DOI":"10.1016\/j.envint.2019.03.002","volume":"126","author":"Z Zeng","year":"2019","unstructured":"Zeng Z, Song B, Xiao R et al (2019) Assessing the human health risks of perfluorooctane sulfonate by in vivo and in vitro studies. Environ Int 126:598\u2013610. https:\/\/doi.org\/10.1016\/j.envint.2019.03.002","journal-title":"Environ Int"},{"key":"4294_CR80","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1126\/science.1200508","volume":"332","author":"Z Zhang","year":"2011","unstructured":"Zhang Z, Wippo CJ, Wal M et al (2011) A packing mechanism for nucleosome organization reconstituted across a eukaryotic genome. Science 332:977\u2013980. https:\/\/doi.org\/10.1126\/science.1200508","journal-title":"Science"},{"key":"4294_CR79","doi-asserted-by":"publisher","first-page":"100694","DOI":"10.1016\/j.jhepr.2023.100694","volume":"5","author":"X Zhang","year":"2023","unstructured":"Zhang X, Zhao L, Ducatman A et al (2023) Association of per- and polyfluoroalkyl substance exposure with fatty liver disease risk in US adults. JHEP Rep 5:100694. https:\/\/doi.org\/10.1016\/j.jhepr.2023.100694","journal-title":"JHEP Rep"},{"key":"4294_CR81","doi-asserted-by":"publisher","unstructured":"Zhao Y, Wei L, Tagmount A et al (2021) Applying genome-wide CRISPR to identify known and novel genes and pathways that modulate formaldehyde toxicity. Chemosphere 269:128701. https:\/\/doi.org\/10.1016\/j.chemosphere.2020.128701","DOI":"10.1016\/j.chemosphere.2020.128701"}],"container-title":["Archives of Toxicology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-025-04294-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00204-025-04294-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00204-025-04294-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T09:38:36Z","timestamp":1775036316000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00204-025-04294-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,27]]},"references-count":81,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["4294"],"URL":"https:\/\/doi.org\/10.1007\/s00204-025-04294-8","relation":{},"ISSN":["0340-5761","1432-0738"],"issn-type":[{"value":"0340-5761","type":"print"},{"value":"1432-0738","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,27]]},"assertion":[{"value":"13 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 December 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 January 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}