{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:59:15Z","timestamp":1791608355419,"version":"4.3.4"},"reference-count":86,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T00:00:00Z","timestamp":1706227200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Environmental Health Sciences (NIEHS)","doi-asserted-by":"publisher","award":["R15ES017321"],"award-info":[{"award-number":["R15ES017321"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Environmental Health Sciences (NIEHS)","doi-asserted-by":"publisher","award":["Z01 ES025034"],"award-info":[{"award-number":["Z01 ES025034"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Intramural Research Program of the NIH","award":["R15ES017321"],"award-info":[{"award-number":["R15ES017321"]}]},{"name":"Intramural Research Program of the NIH","award":["Z01 ES025034"],"award-info":[{"award-number":["Z01 ES025034"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Perfluorooctanesulfonate (PFOS) is a widespread environmental pollutant with a long half-life and clearly negative outcomes on metabolic diseases such as fatty liver disease and diabetes. Male and female Cyp2b-null and humanized CYP2B6-transgenic (hCYP2B6-Tg) mice were treated with 0, 1, or 10 mg\/kg\/day PFOS for 21 days, and surprisingly it was found that PFOS was retained at greater concentrations in the serum and liver of hCYP2B6-Tg mice than those of Cyp2b-null mice, with greater differences in the females. Thus, Cyp2b-null and hCYP2B6-Tg mice provide new models for investigating individual mechanisms for PFOS bioaccumulation and toxicity. Overt toxicity was greater in hCYP2B6-Tg mice (especially females) as measured by mortality; however, steatosis occurred more readily in Cyp2b-null mice despite the lower PFOS liver concentrations. Targeted lipidomics and transcriptomics from PFOS-treated Cyp2b-null and hCYP2B6-Tg mouse livers were performed and compared to PFOS retention and serum markers of toxicity using PCA. Several oxylipins, including prostaglandins, thromboxanes, and docosahexaenoic acid metabolites, are associated or inversely associated with PFOS toxicity. Both lipidomics and transcriptomics indicate PFOS toxicity is associated with PPAR activity in all models. GO terms associated with reduced steatosis were sexually dimorphic with lipid metabolism and transport increased in females and circadian rhythm associated genes increased in males. However, we cannot rule out that steatosis was initially protective from PFOS toxicity. Moreover, several transporters are associated with increased retention, probably due to increased uptake. The strongest associations are the organic anion transport proteins (Oatp1a4-6) genes and a long-chain fatty acid transport protein (fatp1), enriched in female hCYP2B6-Tg mice. PFOS uptake was also reduced in cultured murine hepatocytes by OATP inhibitors. The role of OATP1A6 and FATP1 in PFOS transport has not been tested. In summary, Cyp2b-null and hCYP2B6-Tg mice provided unique models for estimating the importance of novel mechanisms in PFOS retention and toxicity.<\/jats:p>","DOI":"10.3390\/toxics12020106","type":"journal-article","created":{"date-parts":[[2024,1,26]],"date-time":"2024-01-26T08:56:01Z","timestamp":1706259361000},"page":"106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Increased Perfluorooctanesulfonate (PFOS) Toxicity and Accumulation Is Associated with Perturbed Prostaglandin Metabolism and Increased Organic Anion Transport Protein (OATP) Expression"],"prefix":"10.3390","volume":"12","author":[{"given":"Lanie","family":"Williams","sequence":"first","affiliation":[{"name":"Biological Sciences, Clemson University, Clemson, SC 29634, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Biological Sciences, Clemson University, Clemson, SC 29634, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Edin","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, Washington, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2260-816X","authenticated-orcid":false,"given":"Fred","family":"Lih","sequence":"additional","affiliation":[{"name":"Division of Intramural Research, National Institute of Environmental Health Sciences, National Institute of Health, Research Triangle Park, Washington, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jazmine","family":"Eccles-Miller","sequence":"additional","affiliation":[{"name":"Biological Sciences, Clemson University, Clemson, SC 29634, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nishanth","family":"Tharayil","sequence":"additional","affiliation":[{"name":"Plant and Environmental Sciences, Clemson University, Clemson, SC 29634, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Leonard","sequence":"additional","affiliation":[{"name":"Plant and Environmental Sciences, Clemson University, Clemson, SC 29634, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9491-3403","authenticated-orcid":false,"given":"William","family":"Baldwin","sequence":"additional","affiliation":[{"name":"Biological Sciences, Clemson University, Clemson, SC 29634, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Patel, V.B., Preedy, V.R., and Rajendram, R. (2023). Biomarkers in Toxicology. Biomarkers in Disease: Methods, Discoveries and Applications, Springer.","DOI":"10.1007\/978-3-031-07392-2"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1873","DOI":"10.1289\/ehp.0800379","article-title":"The C8 health project: Design, methods, and participants","volume":"117","author":"Frisbee","year":"2009","journal-title":"Environ. Health Perspect."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1093\/toxsci\/kfl135","article-title":"Activation of mouse and human peroxisome proliferator-activated receptor (a,b\/d,g) perfluorooctanoic acid and perfluorooctane sulfonate","volume":"95","author":"Takacs","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.envres.2014.10.004","article-title":"Associations of perfluorinated chemical serum concentrations and biomarkers of liver function and uric acid in the US population (NHANES), 2007\u20132010","volume":"136","author":"Gleason","year":"2015","journal-title":"Environ. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.envres.2015.03.012","article-title":"Longitudinal measures of perfluoroalkyl substances (PFAS) in serum of Gullah African Americans in South Carolina: 2003\u20132013","volume":"143","author":"Gribble","year":"2015","journal-title":"Environ. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"105620","DOI":"10.1016\/j.aquatox.2020.105620","article-title":"20th pollutant responses in marine organisms (PRIMO): Global issues and fundamental mechanisms caused by pollutant stress in marine and freshwater organisms","volume":"227","author":"Baldwin","year":"2020","journal-title":"Aquat. Toxicol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.1016\/j.bbagen.2012.03.010","article-title":"PFOS-induced hepatic steatosis, the mechanistic actions on \u03b2-oxidation and lipid transport","volume":"1820","author":"Wan","year":"2012","journal-title":"Biochim. Et Biophys. Acta"},{"key":"ref_8","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":"ref_9","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":"ref_10","doi-asserted-by":"crossref","first-page":"112175","DOI":"10.1016\/j.fct.2021.112175","article-title":"Increased toxicity and retention of perflouroctane sulfonate (PFOS) in humanized CYP2B6-transgenic mice compared to Cyp2b-null mice is relieved by a high-fat diet (HFD)","volume":"152","author":"Hamilton","year":"2021","journal-title":"Food Chem. Toxicol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Heintz, M.M., Eccles, J.A., Olack, E.M., Maner-Smith, K.M., Ortlund, E.A., and Baldwin, W.S. (2022). Human CYP2B6 produces oxylipins from polyunsaturated fatty acids and reduces diet-induced obesity. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0277053"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Eccles, J.A., and Baldwin, W.S. (2023). Detoxification Cytochrome P450s (CYPs) in Families 1-3 Produce Functional Oxylipins from Polyunsaturated Fatty Acids. Cells, 12.","DOI":"10.3390\/cells12010082"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.pharmthera.2006.10.002","article-title":"The importance of cytochrome P450 2B6 in the human metabolism of environmental chemicals","volume":"113","author":"Hodgson","year":"2007","journal-title":"Pharmacol. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 enzymes in drug metabolism: Regulation of gene expression, enzyme activities, and impact of genetic variation","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"598","DOI":"10.2174\/138920008785821710","article-title":"CYP2B6: New insights into a historically overlooked cytochrome P450 isozyme","volume":"9","author":"Wang","year":"2008","journal-title":"Curr. Drug Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"721507","DOI":"10.3389\/fgene.2021.721507","article-title":"Lipidomic Analyses Reveal Modulation of Lipid Metabolism by the PFAS Perfluoroundecanoic Acid (PFUnDA) in Non-Obese Diabetic Mice","volume":"12","author":"Bodin","year":"2021","journal-title":"Front. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"13181","DOI":"10.1038\/s41598-018-31342-4","article-title":"Identification of a dioxin-responsive oxylipin signature in roots of date palm: Involvement of a 9-hydroperoxide fatty acid reductase, caleosin\/peroxygenase PdPXG2","volume":"8","author":"Hanano","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"27629","DOI":"10.1007\/s11356-021-12503-x","article-title":"Oxylipins at intermediate larval stages of damselfly Coenagrion hastulatum as biochemical biomarkers for anthropogenic pollution","volume":"28","author":"Brodin","year":"2021","journal-title":"Environ. Sci. Poll. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7122738","DOI":"10.1155\/2022\/7122738","article-title":"Age- and Diet-Dependent Changes in Hepatic Lipidomic Profiles of Phospholipids in Male Mice: Age Acceleration in Cyp2b-Null Mice","volume":"2022","author":"Heintz","year":"2022","journal-title":"J. Lipids"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.jnutbio.2019.05.004","article-title":"Cyp2b-null male mice are susceptible to diet-induced obesity and perturbations in lipid homeostasis","volume":"70","author":"Heintz","year":"2019","journal-title":"J. Nutr. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kumar, R., Mota, L.C., Litoff, E.J., Rooney, J.P., Boswell, W.T., Courter, E., Henderson, C.M., Hernandez, J.P., Corton, J.C., and Moore, D.D. (2017). Compensatory changes in CYP expression in three different toxicology mouse models: CAR-null, Cyp3a-null, and Cyp2b9\/10\/13-null mice. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174355"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1144","DOI":"10.1124\/dmd.112.044826","article-title":"Generation and Characterization of a CYP2A13\/2B6\/2F1-Transgenic Mouse Model","volume":"40","author":"Wei","year":"2012","journal-title":"Drug Metab. Dispos."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Heintz, M.M., McRee, R., Kumar, R., and Baldwin, W.S. (2020). Gender differences in diet-induced steatotic disease in Cyp2b-null mice. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0229896"},{"key":"ref_24","unstructured":"Andrews, S. (2023, November 01). FastQC: A Quality Control Tool for High Throughput Sequence Data. Babraham Bioinformatics, Babraham Institute. Available online: http:\/\/www.bioinformatics.babraham.ac.uk\/projects\/fastqc\/."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1038\/nprot.2013.084","article-title":"De novo transcript sequence reconstruction from RNA-Seq: Reference generation and analysis with Trinity","volume":"8","author":"Haas","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"featureCounts: An efficient general purpose program for assigning sequence reads to genomic features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1093\/bioinformatics\/btp616","article-title":"edgeR: A Bioconductor package for differential expression analysis of digital gene expression data","volume":"26","author":"Robinson","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1002\/pro.4218","article-title":"PANTHER: Making genome-scale phylogenetics accessible to all","volume":"31","author":"Thomas","year":"2022","journal-title":"Protein Sci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Supek, F., Bo Snjak, M., Skunca, N., and Smuc, T. (2011). Revigo summarizes and visualizes long lists of gene ontology terms. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021800"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Huang, D.W., Sherman, B.T., Tan, Q., Collins, J.R., Alvord, W.G., Roayaei, J., Stephens, R., Baseler, M.W., Lane, H.C., and Lempicki, R.A. (2007). The david Gene Functional Classification Tool: A novel biological module-centric algorithm to functionally analyze large gene lists. Genome Biol., 8.","DOI":"10.1186\/gb-2007-8-9-r183"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"W90","DOI":"10.1093\/nar\/gkw377","article-title":"Enrichr: A comprehensive gene set enrichment analysis web server 2016 update","volume":"44","author":"Kuleshov","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_32","first-page":"84","article-title":"Organic Anion Transporting Polypeptides Contribute to the Disposition of Perfluoroalkyl Acids in Humans and Rats","volume":"156","author":"Zhao","year":"2017","journal-title":"Toxicol. Sci."},{"key":"ref_33","unstructured":"Shoemaker, J., and Tettehorst, D. (2020). Method 537.1 Determination of Selected Per- and Polyfluorinated Alkyl Substances in Drinking Water by Solid Phase Extraction and Liquid Chromatography\/Tandem Mass Spectrometry (LC\/MS\/MS), United States Enviornmental Protecdtion Agency, National Center for Environmental Assessment."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"115250","DOI":"10.1016\/j.taap.2020.115250","article-title":"Perfluorooctanesulfonic acid (PFOS) administration shifts the hepatic proteome and augments dietary outcomes related to hepatic steatosis in mice","volume":"408","author":"Marques","year":"2020","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1124\/dmd.110.035287","article-title":"Activation of the acute inflammatory response alters cytochrome P450 expression and eicosanoid metabolism","volume":"39","author":"Theken","year":"2011","journal-title":"Drug Metab. Dispos."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Schuck, R.N., Zha, W., Edin, M.L., Gruzdev, A., Vendrov, K.C., Miller, T.M., Xu, Z., Lih, F.B., DeGraft, L.M., and Tomer, K.B. (2014). The Cytochrome P450 Epoxygenase Pathway Regulates the Hepatic Inflammatory Response in Fatty Liver Disease. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0110162"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3281","DOI":"10.1074\/jbc.RA117.000298","article-title":"Epoxide hydrolase 1 (EPHX1) hydrolyzes epoxyeicosanoids and impairs cardiac recovery after ischemia","volume":"293","author":"Edin","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1016\/j.reprotox.2008.05.061","article-title":"Developmental toxicity of perfluorooctane sulfonate (PFOS) is not dependent on expression of peroxisome proliferator activated receptor-alpha (PPAR alpha) in the mouse","volume":"27","author":"Abbott","year":"2008","journal-title":"Reprod. Toxicol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"104700","DOI":"10.1016\/j.tiv.2019.104700","article-title":"Activation of human nuclear receptors by perfluoroalkylated substances (PFAS)","volume":"62","author":"Behr","year":"2020","journal-title":"Toxicol. Vitr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1093\/toxsci\/kfaa172","article-title":"An \u2018Omics Approach to Unraveling the Paradoxical Effect of Diet on Perfluorooctanesulfonic Acid (PFOS) and Perfluorononanoic Acid (PFNA)-Induced Hepatic Steatosis","volume":"180","author":"Pfohl","year":"2021","journal-title":"Toxicol. Sci."},{"key":"ref_41","unstructured":"LeBlanc, G.A., Norris, D.O., Kloas, W., Kullman, S.W., Baldwin, W.S., and Greally, J.M. (2012). Series on Testing & Assessment: No. 178, Organisation for Economic Co-operation and Development."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101447","DOI":"10.32527\/2019\/101447","article-title":"Phase 0 of the Xenobiotic Response: Nuclear Receptors and Other Transcription Factors as a First Step in Protection from Xenobiotics","volume":"6","author":"Baldwin","year":"2019","journal-title":"Nucl. Recept. Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1983","DOI":"10.1210\/me.2011-1228","article-title":"Commentary: The year in orphan nuclear receptors and their coregulators","volume":"25","author":"Moore","year":"2011","journal-title":"Mol. Endocrinol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.mce.2010.06.016","article-title":"Evolution of promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR, and CAR","volume":"334","author":"Krasowski","year":"2011","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1016\/j.taap.2016.05.006","article-title":"Activation of the Constitutive Androstane Receptor induces hepatic lipogenesis and regulates Pnpla3 gene expression in a LXR-independent way","volume":"303","author":"Marmugi","year":"2016","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1210\/me.2005-0046","article-title":"The nuclear receptor superfamily: A rosetta stone for physiology","volume":"19","author":"Evans","year":"2005","journal-title":"Mol. Endocrinol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1124\/mol.114.097402","article-title":"Activating and Inhibitory Functions of WNT\/\u03b2-Catenin in the Induction of Cytochromes P450 by Nuclear Receptors in HepaRG Cells","volume":"87","author":"Thomas","year":"2015","journal-title":"Mol. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1139\/h2012-059","article-title":"Perilipin family (PLIN) proteins in human skeletal muscle: The effect of sex, obesity, and endurance training","volume":"37","author":"Peters","year":"2012","journal-title":"Appl. Physiol. Nutr. Metab."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6042162","DOI":"10.1155\/2016\/6042162","article-title":"PPARgene: A Database of Experimentally Verified and Computationally Predicted PPAR Target Genes","volume":"2016","author":"Fang","year":"2016","journal-title":"PPAR Res."},{"key":"ref_50","first-page":"1","article-title":"Intestinal cytochrome P450 3A plays an important role in the regulation of detoxifying systems in the liver","volume":"23","author":"Rooswinkel","year":"2009","journal-title":"FASEB J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1124\/mol.112.082305","article-title":"Induced CYP3A4 Expression in Confluent Huh7 Hepatoma Cells as a Result of Decreased Cell Proliferation and Subsequent Pregnane X Receptor Activations","volume":"83","author":"Sivertsson","year":"2013","journal-title":"Mol. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1038\/379540a0","article-title":"Dose-response relationships for resetting of human circadian clock by light","volume":"379","author":"Boivin","year":"1996","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"26242","DOI":"10.1038\/srep26242","article-title":"Preventing High Fat Diet-induced Obesity and Improving Insulin Sensitivity through Neuregulin 4 Gene Transfer","volume":"6","author":"Ma","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Rakhshandehroo, M., Hooiveld, G., M\u00fcller, M., and Kersten, S. (2009). Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0006796"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1093\/nar\/gkq012","article-title":"Profiling of promoter occupancy by PPAR\u03b1 in human hepatoma cells via ChIP-chip analysis","volume":"38","author":"Degenhardt","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2036","DOI":"10.1007\/s00125-007-0776-z","article-title":"Fatty acid-induced mitochondrial uncoupling in adipocytes as a key protective factor against insulin resistance and beta cell dysfunction: A new concept in the pathogenesis of obesity-associated type 2 diabetes mellitus","volume":"k50","author":"Maassen","year":"2007","journal-title":"Diabetologia"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"2699","DOI":"10.1073\/pnas.0711278105","article-title":"GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current","volume":"105","author":"Lauckner","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1093\/toxsci\/kfm065","article-title":"Toxicogenomic study of triazole fungicides and perfluoroalkyl acids in rat livers predicts toxicity and categorizes chemicals based on mechanisms of toxicity","volume":"97","author":"Martin","year":"2007","journal-title":"Toxicol. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Wen, L.-L., Lin, C.-Y., Chou, H.-C., Chang, C.-C., Lo, H.-Y., and Juan, S.-H. (2016). Perfluorooctanesulfonate Mediates Renal Tubular Cell Apoptosis through PPARgamma Inactivation. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155190"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.1124\/dmd.118.080770","article-title":"Transport Kinetics, Selective Inhibition, and Successful Prediction of In Vivo Inhibition of Rat Hepatic Organic Anion Transporting Polypeptides","volume":"46","author":"Ishida","year":"2018","journal-title":"Drug Metab. Dispos."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1002\/bdd.1809","article-title":"Active intestinal absorption of fluoroquinolone antibacterial agent ciprofloxacin by organic anion transporting polypeptide, Oatp1a5","volume":"33","author":"Arakawa","year":"2012","journal-title":"Biopharm. Drug Dispos."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Kimura, O., Fujii, Y., Haraguchi, K., Kato, Y., Ohta, C., Koga, N., and Endo, T. (2020). Effects of perfluoroalkyl carboxylic acids on the uptake of sulfobromophthalein via organic anion transporting polypeptides in human intestinal Caco-2 cells. Biochem. Biophys. Rep., 24.","DOI":"10.1016\/j.bbrep.2020.100807"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1093\/toxsci\/kfv102","article-title":"Na+\/Taurocholate Cotransporting Polypeptide and Apical Sodium-Dependent Bile Acid Transporter Are Involved in the Disposition of Perfluoroalkyl Sulfonates in Humans and Rats","volume":"146","author":"Zhao","year":"2015","journal-title":"Toxicol. Sci."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1260","DOI":"10.1111\/j.1476-5381.2011.01724.x","article-title":"OATPs, OATs and OCTs: The organic anion and cation transporters of the SLCO and SLC22A gene superfamilies","volume":"165","author":"Roth","year":"2012","journal-title":"Br. J. Pharmacol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1124\/dmd.105.003640","article-title":"Tissue distribution and ontogeny of mouse organic anion transporting polypeptides (Oatps)","volume":"33","author":"Cheng","year":"2005","journal-title":"Drug Metab. Dispos."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2340","DOI":"10.1194\/jlr.R900012-JLR200","article-title":"Bile acid transporters","volume":"50","author":"Dawson","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1093\/toxsci\/kfq219","article-title":"Characterization of cellular uptake of perfluorooctanoate via organic anion-transporting polypeptide 1A2, organic anion transporter 4, and urate transporter 1 for their potential roles in mediating human renal reabsorption of perfluorocarboxylates","volume":"117","author":"Yang","year":"2010","journal-title":"Toxicol. Sci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"076002","DOI":"10.1289\/EHP11885","article-title":"A State-of-the-Science Review of Interactions of Per- and Polyfluoroalkyl Substances (PFAS) with Renal Transporters in Health and Disease: Implications for Population Variability in PFAS Toxicokinetics","volume":"131","author":"Niu","year":"2023","journal-title":"Environ. Health Perspect."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.bcp.2013.05.020","article-title":"Organic anion-transporting polypeptide 1a4 (Oatp1a4) is important for secondary bile acid metabolism","volume":"86","author":"Zhang","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1007\/s11095-007-9472-4","article-title":"Involvement of Organic Anion Transporting Polypeptide 1a5 (Oatp1a5) in the Intestinal Absorption of Endothelin Receptor Antagonist in Rats","volume":"25","author":"Tani","year":"2008","journal-title":"Pharm. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"107951","DOI":"10.1016\/j.envint.2023.107951","article-title":"Insight into the binding model of per- and polyfluoroalkyl substances to proteins and membranes","volume":"175","author":"Zhao","year":"2023","journal-title":"Environ. Int."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1055\/s-0036-1597248","article-title":"Regulation of Hepatocellular Fatty Acid Uptake in Mouse Models of Fatty Liver Disease with and without Functional Leptin Signaling: Roles of NfKB and SREBP-1C and the Effects of Spexin","volume":"36","author":"Ge","year":"2016","journal-title":"Semin. Liver Dis."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1146\/annurev-pharmtox-010617-052713","article-title":"The SLC22 transporter family: A paradigm for the impact of drug transporter on metabolic pathways, signaling, and disase","volume":"58","author":"Nigam","year":"2018","journal-title":"Ann. Rev. Pharmacol. Toxicol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"2885","DOI":"10.1038\/s41598-017-03119-8","article-title":"Ketogenic diet induces expression of the muscle circadian gene Slc25a25 via neural pathway that miht be involved in muscle thermogenesis","volume":"7","author":"Nakao","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"111386","DOI":"10.1016\/j.envres.2021.111386","article-title":"Exploring associations between prenatal exposure to multiple endocrine disruptors and birth weight with exposure continuum mapping","volume":"200","author":"Pearce","year":"2021","journal-title":"Environ. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1042\/BJ20080740","article-title":"Unsaturated fatty acid regulation of cytochrome P450 expression via a CAR-dependent pathway","volume":"417","author":"Finn","year":"2009","journal-title":"Biochem. J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1073\/pnas.1422590112","article-title":"Inhibition of souble epoxide hydrolase modulates inflammation and autophagy in obese adipose tissue and liver: Role for omega-3 epoxides","volume":"112","author":"Rius","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/j.alcohol.2022.08.012","article-title":"Profiling the oxylipidome in aged mice after chronic ethanol feeding: Identifying ipid metabolites as drivers of hepatocyte stress","volume":"107","author":"Anton","year":"2023","journal-title":"Alcohol"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1597","DOI":"10.1038\/labinvest.2012.128","article-title":"Stimulation of fat accumulation in hepatocytes by PGE(2)-dependent repression of hepatic lipolysis, beta-oxidation, and VLDL synthesis","volume":"92","author":"Henkel","year":"2012","journal-title":"Lab. Investig."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"106429","DOI":"10.1016\/j.prostaglandins.2020.106429","article-title":"Lipocalin-type prostaglanding D(2) synthase deletion induces dyslipidemia and non-alcoholic fatty liver disease","volume":"149","author":"Kumar","year":"2020","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Lau-Corona, D., Bae, W.K., Hennighausen, L., and Waxman, D.J. (2020). Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2. PLoS Genet., 16.","DOI":"10.1371\/journal.pgen.1008796"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/s11695-011-0539-2","article-title":"Sexual dimorphism in clock genes expression in human adipose tissue","volume":"22","author":"Madrid","year":"2012","journal-title":"Obes. Surg."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1016\/j.taap.2006.05.014","article-title":"Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB\/NJ mice","volume":"216","author":"Hernandez","year":"2006","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1006\/taap.1997.8319","article-title":"Endosulfan elevates testosterone biotransformation and clearance in CD-1 mice","volume":"148","author":"Wilson","year":"1998","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1097\/MOL.0b013e3282ff5e55","article-title":"Hepatic triglyceride synthesis and nonalcoholic fatty liver disease","volume":"19","author":"Choi","year":"2008","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"375","DOI":"10.3389\/fneur.2019.00375","article-title":"The Paradoxical Protective Effect of Liver Steatosis on Severity and Functional Outcome of Ischemic Stroke","volume":"10","author":"Baik","year":"2019","journal-title":"Front. Neurol."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/12\/2\/106\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:49:49Z","timestamp":1760104189000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/12\/2\/106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,26]]},"references-count":86,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["toxics12020106"],"URL":"https:\/\/doi.org\/10.3390\/toxics12020106","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,26]]}}}