{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T22:31:49Z","timestamp":1792794709729,"version":"4.5.0"},"reference-count":33,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T00:00:00Z","timestamp":1740528000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100004343","name":"3M Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004343","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000199","name":"USDA","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000199","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Institute of Food and Agriculture and Hatch Appropriations","id":[{"id":"https:\/\/ror.org\/05qx3fv49","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Exposure of perfluorohexane sulfonate (PFHxS) is associated with hepatomegaly and accumulation of lipids that may be mediated by nuclear receptors like peroxisome proliferator-activated receptor-\u03b1 (PPAR\u03b1), constitutive androstane receptor (CAR), or pregnane X receptor (PXR). This study tested the hypotheses that: (i) PFHxS causes changes in liver by activating PPAR\u03b1, CAR, or PXR, and (ii) there is a species difference in PPAR\u03b1 activity by PFHxS. Wild-type, Ppara-null, and PPARA-humanized mice were fed either a control diet, or one containing 2.2\u2009mg PFHxS\/kg diet or 25.8\u2009mg PFHxS\/kg diet for either 7 or 28\u00a0days, and target gene expression was examined. Relative liver weights were similar after 7\u00a0days with either 2.2 or 25.8\u2009mg PFHxS\/kg dietary exposure compared with controls. Relative liver weights were higher after treatment for 28\u00a0days in all 3 genotypes fed 25.8\u2009mg PFHxS\/kg diet compared with controls. The concentration of PFHxS was dose-dependently increased in serum and liver compared with controls. PFHxS exposure of 2.2 and 25.8\u2009mg PFHxS\/kg diet caused an increase in expression of PPAR\u03b1 target genes in wild-type mice and this effect was not observed in similarly treated Ppara-null mice or PPARA-humanized mice. Administration of PFHxS caused increased expression of the CAR target gene Cyp2b10 in all 3 genotypes at both timepoints, and the PXR target gene Cyp3a11 in all 3 genotypes after 28\u00a0days. Exposure to PFHxS can increase liver weight due in part to the activation of mouse, but not human, PPAR\u03b1. Activation of CAR and PXR by PFHxS also likely contributes to the observed hepatomegaly in all 3 genotypes.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf026","type":"journal-article","created":{"date-parts":[[2025,2,25]],"date-time":"2025-02-25T07:50:39Z","timestamp":1740469839000},"page":"47-52","source":"Crossref","is-referenced-by-count":3,"title":["Differential hepatic activation of mouse and human peroxisome proliferator-activated receptor-\u03b1 by perfluorohexane sulfonate"],"prefix":"10.1093","volume":"205","author":[{"given":"Yahya","family":"Khan","sequence":"first","affiliation":[{"name":"Department of Veterinary and Biomedical Science, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]},{"name":"Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalee M","family":"Schmidt","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Science, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]},{"name":"Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle J","family":"Oldro","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Science, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]},{"name":"Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Science, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]},{"name":"Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelina R","family":"Kramer","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Science, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]},{"name":"Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah R","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Science, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]},{"name":"Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine O","family":"Bleil","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Science, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]},{"name":"Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan M","family":"Krisko","sequence":"additional","affiliation":[{"name":"3M Company , St Paul, MN 55144,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremiah D","family":"Zitzow","sequence":"additional","affiliation":[{"name":"3M Company , St Paul, MN 55144,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6174-3359","authenticated-orcid":false,"given":"Yuan","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Science, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]},{"name":"Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Ching","family":"Chang","sequence":"additional","affiliation":[{"name":"3M Company , St Paul, MN 55144,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6114-6714","authenticated-orcid":false,"given":"Vonn","family":"Walter","sequence":"additional","affiliation":[{"name":"Department of Public Health Sciences, The Pennsylvania State University, College of Medicine , Hershey, PA 17033,","place":["United States"]},{"name":"Department of Molecular and Precision Medicine, The Pennsylvania State University, College of Medicine , Hershey, PA 17033,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5047-0962","authenticated-orcid":false,"given":"Samuel M","family":"Cohen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Microbiology and Immunology, University of Nebraska Medical Center , Omaha, NE 68182,","place":["United States"]},{"name":"Buffett Cancer Center, University of Nebraska Medical Center , Omaha, NE 68182,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank J","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Cancer Innovation Laboratory, Center for Cancer Research, National Cancer Institute , Bethesda, MD 20892,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2073-0070","authenticated-orcid":false,"given":"Andrew D","family":"Patterson","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Science, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]},{"name":"Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M","family":"Peters","sequence":"additional","affiliation":[{"name":"Department of Veterinary and Biomedical Science, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]},{"name":"Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University , University Park, PA 16802,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,2,26]]},"reference":[{"key":"2026022520014226200_kfaf026-B1","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1093\/toxsci\/kfr142","article-title":"Perfluoroalkyl sulfonates cause alkyl chain length-dependent hepatic steatosis and hypolipidemia mainly by impairing lipoprotein production in APOE3-Leiden CETP mice","volume":"123","author":"Bijland","year":"2011","journal-title":"Toxicol Sci."},{"key":"2026022520014226200_kfaf026-B2","author":"Blystone","year":"2022"},{"key":"2026022520014226200_kfaf026-B3","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1016\/j.reprotox.2009.01.004","article-title":"Evaluation of potential reproductive and developmental toxicity of potassium perfluorohexanesulfonate in Sprague Dawley rats","volume":"27","author":"Butenhoff","year":"2009","journal-title":"Reprod Toxicol."},{"key":"2026022520014226200_kfaf026-B4","doi-asserted-by":"crossref","first-page":"166101","DOI":"10.1016\/j.bbadis.2021.166101","article-title":"The xenobiotic receptors PXR and CAR in liver physiology, an update","volume":"1867","author":"Cai","year":"2021","journal-title":"Biochim Biophys Acta Mol Basis Dis."},{"key":"2026022520014226200_kfaf026-B5","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1016\/j.reprotox.2018.04.007","article-title":"Reproductive and developmental toxicity of potassium perfluorohexanesulfonate in CD-1 mice","volume":"78","author":"Chang","year":"2018","journal-title":"Reprod Toxicol."},{"key":"2026022520014226200_kfaf026-B6","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1007\/s00204-017-2094-7","article-title":"The PPAR\u03b1-dependent rodent liver tumor response is not relevant to humans: addressing misconceptions","volume":"92","author":"Corton","year":"2018","journal-title":"Arch Toxicol."},{"key":"2026022520014226200_kfaf026-B7","doi-asserted-by":"crossref","first-page":"46001","DOI":"10.1289\/EHP10092","article-title":"Exposure to per- and polyfluoroalkyl substances and markers of liver injury: a systematic review and meta-analysis","volume":"130","author":"Costello","year":"2022","journal-title":"Environ Health Perspect."},{"key":"2026022520014226200_kfaf026-B8","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.tox.2016.12.007","article-title":"Perfluoroalkyl acids-induced liver steatosis: effects on genes controlling lipid homeostasis","volume":"378","author":"Das","year":"2017","journal-title":"Toxicology"},{"key":"2026022520014226200_kfaf026-B9","doi-asserted-by":"crossref","first-page":"100086","DOI":"10.1016\/j.hazl.2023.100086","article-title":"Per- and polyfluoroalkyl substances (PFAS) in consumer products: current knowledge and research gaps","volume":"4","author":"Dewapriya","year":"2023","journal-title":"J Hazard Mater Lett"},{"key":"2026022520014226200_kfaf026-B10","doi-asserted-by":"crossref","first-page":"64","DOI":"10.3109\/10408444.2013.835786","article-title":"Mode of action and human relevance analysis for nuclear receptor-mediated liver toxicity: a case study with phenobarbital as a model constitutive androstane receptor (CAR) activator","volume":"44","author":"Elcombe","year":"2014","journal-title":"Crit Rev Toxicol."},{"key":"2026022520014226200_kfaf026-B11","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1093\/toxsci\/kfab067","article-title":"Differential hepatocarcinogenesis by a potent, high affinity human PPAR\u03b1 agonist in PPARA-humanized mice","volume":"183","author":"Foreman","year":"2021","journal-title":"Toxicol Sci"},{"key":"2026022520014226200_kfaf026-B12","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1093\/toxsci\/kfab068","article-title":"Species differences between mouse and human PPAR\u03b1 in modulating the hepatocarcinogenic effects of perinatal exposure to a high affinity human PPAR\u03b1 agonist in mice","volume":"183","author":"Foreman","year":"2021","journal-title":"Toxicol Sci"},{"key":"2026022520014226200_kfaf026-B13","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1093\/carcin\/bgh285","article-title":"Role of peroxisome proliferator-activated receptor-\u03b1 (PPAR\u03b1) in bezafibrate-induced hepatocarcinogenesis and cholestasis","volume":"26","author":"Hays","year":"2005","journal-title":"Carcinogenesis"},{"key":"2026022520014226200_kfaf026-B14","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1016\/j.molmet.2014.02.002","article-title":"Integrated physiology and systems biology of PPAR\u03b1","volume":"3","author":"Kersten","year":"2014","journal-title":"Mol Metab."},{"key":"2026022520014226200_kfaf026-B15","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1080\/713608372","article-title":"PPAR\u03b1 agonist-induced rodent tumors: modes of action and human relevance","volume":"33","author":"Klaunig","year":"2003","journal-title":"Crit Rev Toxicol."},{"key":"2026022520014226200_kfaf026-B16","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1080\/00498250903098184","article-title":"Species differences in the hepatic effects of inducers of CYP2B and CYP4A subfamily forms: relationship to rodent liver tumour formation","volume":"39","author":"Lake","year":"2009","journal-title":"Xenobiotica."},{"key":"2026022520014226200_kfaf026-B17","doi-asserted-by":"crossref","first-page":"3012","DOI":"10.1128\/MCB.15.6.3012","article-title":"Targeted disruption of the \u03b1 isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators","volume":"15","author":"Lee","year":"1995","journal-title":"Mol Cell Biol."},{"key":"2026022520014226200_kfaf026-B18","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1136\/oemed-2017-104651","article-title":"Half-lives of PFOS, PFHxS and PFOA after end of exposure to contaminated drinking water","volume":"75","author":"Li","year":"2018","journal-title":"Occup Environ Med."},{"key":"2026022520014226200_kfaf026-B19","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1093\/carcin\/bgi329","article-title":"Differential susceptibility of mice humanized for peroxisome proliferator-activated receptor \u03b1 to Wy-14,643-induced liver tumorigenesis","volume":"27","author":"Morimura","year":"2006","journal-title":"Carcinogenesis"},{"key":"2026022520014226200_kfaf026-B20","author":"National Center for Environmental Health","year":"2022"},{"key":"2026022520014226200_kfaf026-B21","doi-asserted-by":"crossref","first-page":"1298","DOI":"10.1289\/ehp.10009","article-title":"Half-life of serum elimination of perfluorooctanesulfonate, perfluorohexanesulfonate, and perfluorooctanoate in retired fluorochemical production workers","volume":"115","author":"Olsen","year":"2007","journal-title":"Environ Health Perspect"},{"key":"2026022520014226200_kfaf026-B22","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1093\/carcin\/18.11.2029","article-title":"Role of PPAR\u03b1 in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643","volume":"18","author":"Peters","year":"1997","journal-title":"Carcinogenesis"},{"key":"2026022520014226200_kfaf026-B23","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1007\/s00109-005-0678-9","article-title":"Peroxisome proliferator-activated receptor-\u03b1 and liver cancer: where do we stand?","volume":"83","author":"Peters","year":"2005","journal-title":"J Mol Med (Berl)"},{"key":"2026022520014226200_kfaf026-B24","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.yrtph.2019.05.008","article-title":"Interspecies differences in perfluoroalkyl substances (PFAS) toxicokinetics and application to health-based criteria","volume":"106","author":"Pizzurro","year":"2019","journal-title":"Regul Toxicol Pharmacol."},{"key":"2026022520014226200_kfaf026-B25","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.tox.2017.05.013","article-title":"PPAR\u03b1-independent transcriptional targets of perfluoroalkyl acids revealed by transcript profiling","volume":"387","author":"Rosen","year":"2017","journal-title":"Toxicology"},{"key":"2026022520014226200_kfaf026-B26","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1093\/toxsci\/kfq118","article-title":"Human constitutive androstane receptor (CAR) and pregnane X receptor (PXR) support the hypertrophic but not the hyperplastic response to the murine nongenotoxic hepatocarcinogens phenobarbital and chlordane in vivo","volume":"116","author":"Ross","year":"2010","journal-title":"Toxicol Sci."},{"key":"2026022520014226200_kfaf026-B27","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1093\/toxsci\/kfad129","article-title":"Interaction with YAP underlies the species differences between humans and rodents in CAR-dependent hepatocyte proliferation","volume":"198","author":"Shizu","year":"2024","journal-title":"Toxicol Sci."},{"key":"2026022520014226200_kfaf026-B28","doi-asserted-by":"crossref","first-page":"2731","DOI":"10.1021\/acs.est.8b07031","article-title":"Breakdown products from perfluorinated alkyl substances (PFAS) degradation in a plasma-based water treatment process","volume":"53","author":"Singh","year":"2019","journal-title":"Environ Sci Technol."},{"key":"2026022520014226200_kfaf026-B29","doi-asserted-by":"crossref","first-page":"153056","DOI":"10.1016\/j.tox.2021.153056","article-title":"The role of mouse and human peroxisome proliferator-activated receptor-\u03b1 in modulating the hepatic effects of perfluorooctane sulfonate in mice","volume":"465","author":"Su","year":"2022","journal-title":"Toxicology"},{"key":"2026022520014226200_kfaf026-B30","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/j.reprotox.2011.07.004","article-title":"Comparative pharmacokinetics of perfluorohexanesulfonate (PFHxS) in rats, mice, and monkeys","volume":"33","author":"Sundstrom","year":"2012","journal-title":"Reprod Toxicol"},{"key":"2026022520014226200_kfaf026-B31","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1093\/toxsci\/kfl014","article-title":"Differential activation of nuclear receptors by perfluorinated fatty acid analogs and natural fatty acids: a comparison of human, mouse, and rat peroxisome proliferator-activated receptor-\u03b1, -\u03b2, and -\u03b3, liver X receptor-\u03b2, and retinoid X receptor-\u03b1","volume":"92","author":"Vanden Heuvel","year":"2006","journal-title":"Toxicol Sci."},{"key":"2026022520014226200_kfaf026-B32","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1093\/toxsci\/kfae061","article-title":"Effects of PFAS on human liver transporters: implications for health outcomes","volume":"200","author":"Vujic","year":"2024","journal-title":"Toxicol Sci."},{"key":"2026022520014226200_kfaf026-B33","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1080\/10408444.2021.1939654","article-title":"Critical evaluation of the human relevance of the mode of action for rodent liver tumor formation by activators of the constitutive androstane receptor (CAR)","volume":"51","author":"Yamada","year":"2021","journal-title":"Crit Rev Toxicol."}],"container-title":["Toxicological Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/toxsci\/advance-article-pdf\/doi\/10.1093\/toxsci\/kfaf026\/62178458\/kfaf026.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/205\/1\/47\/62178458\/kfaf026.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/toxsci\/article-pdf\/205\/1\/47\/62178458\/kfaf026.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T01:02:14Z","timestamp":1772067734000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/toxsci\/article\/205\/1\/47\/8043229"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,26]]},"references-count":33,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2025,5,1]]}},"URL":"https:\/\/doi.org\/10.1093\/toxsci\/kfaf026","relation":{},"ISSN":["1096-6080","1096-0929"],"issn-type":[{"value":"1096-6080","type":"print"},{"value":"1096-0929","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,5]]},"published":{"date-parts":[[2025,2,26]]}}}