{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:11:39Z","timestamp":1787029899404,"version":"build-2736575974"},"reference-count":116,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2025,8,17]],"date-time":"2025-08-17T00:00:00Z","timestamp":1755388800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000066","name":"NIH, National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["ZIAES103385"],"award-info":[{"award-number":["ZIAES103385"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"NIH, National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["AES22010-001-00001"],"award-info":[{"award-number":["AES22010-001-00001"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"NIH, National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["W81XWH20C0031"],"award-info":[{"award-number":["W81XWH20C0031"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000066","name":"NIH, National Institute of Environmental Health Sciences","doi-asserted-by":"publisher","award":["HT942524F0189"],"award-info":[{"award-number":["HT942524F0189"]}],"id":[{"id":"10.13039\/100000066","id-type":"DOI","asserted-by":"publisher"}]},{"name":"U.S. Army Medical Research and Development Command","award":["ZIAES103385"],"award-info":[{"award-number":["ZIAES103385"]}]},{"name":"U.S. Army Medical Research and Development Command","award":["AES22010-001-00001"],"award-info":[{"award-number":["AES22010-001-00001"]}]},{"name":"U.S. Army Medical Research and Development Command","award":["W81XWH20C0031"],"award-info":[{"award-number":["W81XWH20C0031"]}]},{"name":"U.S. Army Medical Research and Development Command","award":["HT942524F0189"],"award-info":[{"award-number":["HT942524F0189"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxics"],"abstract":"<jats:p>Per- and polyfluoroalkyl substances (PFASs) are widespread in the environment, bioaccumulate in humans, and lead to disease and organ injury, such as liver steatosis. However, we lack a clear understanding of how these chemicals cause organ-level toxicity. Here, we aimed to analyze PFAS-induced metabolic perturbations in male and female rat livers by combining a genome-scale metabolic model (GEM) and toxicogenomics. The combined approach overcomes the limitations of the individual methods by taking into account the interaction between multiple genes for metabolic reactions and using gene expression to constrain the predicted mechanistic possibilities. We obtained transcriptomic data from an acute exposure study, where male and female rats received a daily PFAS dose for five consecutive days, followed by liver transcriptome measurement. We integrated the transcriptome expression data with a rat GEM to computationally predict the metabolic activity in each rat\u2019s liver, compare it between the control and PFAS-exposed rats, and predict the benchmark dose (BMD) at which each chemical induced metabolic changes. Overall, our results suggest that PFAS-induced metabolic changes occurred primarily within the lipid and amino acid pathways and were similar between the sexes but varied in the extent of change per dose based on sex and PFAS type. Specifically, we identified that PFASs affect fatty acid-related pathways (biosynthesis, oxidation, and sphingolipid metabolism), energy metabolism, protein metabolism, and inflammatory and inositol metabolite pools, which have been associated with fatty liver and\/or insulin resistance. Based on these results, we hypothesize that PFAS exposure induces changes in liver metabolism and makes the organ sensitive to metabolic diseases in both sexes. Furthermore, we conclude that male rats are more sensitive to PFAS-induced metabolic aberrations in the liver than female rats. This combined approach using GEM-based predictions and BMD analysis can help develop mechanistic hypotheses regarding how toxicant exposure leads to metabolic disruptions and how these effects may differ between the sexes, thereby assisting in the metabolic risk assessment of toxicants.<\/jats:p>","DOI":"10.3390\/toxics13080684","type":"journal-article","created":{"date-parts":[[2025,8,18]],"date-time":"2025-08-18T15:34:53Z","timestamp":1755531293000},"page":"684","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Genome-Scale Metabolic Modeling Predicts Per- and Polyfluoroalkyl Substance-Mediated Early Perturbations in Liver Metabolism"],"prefix":"10.3390","volume":"13","author":[{"given":"Archana","family":"Hari","sequence":"first","affiliation":[{"name":"Department of Defense Biotechnology High Performance Computing Software Applications Institute, Defense Health Agency Research & Development, Medical Research and Development Command, Fort Detrick, MD 21702, USA"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1568-0614","authenticated-orcid":false,"given":"Michele R.","family":"Balik-Meisner","sequence":"additional","affiliation":[{"name":"Sciome LLC, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepak","family":"Mav","sequence":"additional","affiliation":[{"name":"Sciome LLC, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dhiral P.","family":"Phadke","sequence":"additional","affiliation":[{"name":"Sciome LLC, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2727-1954","authenticated-orcid":false,"given":"Elizabeth H.","family":"Scholl","sequence":"additional","affiliation":[{"name":"Sciome LLC, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruchir R.","family":"Shah","sequence":"additional","affiliation":[{"name":"Sciome LLC, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Warren","family":"Casey","sequence":"additional","affiliation":[{"name":"Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott S.","family":"Auerbach","sequence":"additional","affiliation":[{"name":"Division of Translational Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9775-7469","authenticated-orcid":false,"given":"Anders","family":"Wallqvist","sequence":"additional","affiliation":[{"name":"Department of Defense Biotechnology High Performance Computing Software Applications Institute, Defense Health Agency Research & Development, Medical Research and Development Command, Fort Detrick, MD 21702, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3368-2496","authenticated-orcid":false,"given":"Venkat R.","family":"Pannala","sequence":"additional","affiliation":[{"name":"Department of Defense Biotechnology High Performance Computing Software Applications Institute, Defense Health Agency Research & Development, Medical Research and Development Command, Fort Detrick, MD 21702, USA"},{"name":"The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD 20817, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1038\/s41370-018-0094-1","article-title":"A review of the pathways of human exposure to poly- and perfluoroalkyl substances (PFASs) and present understanding of health effects","volume":"29","author":"Sunderland","year":"2019","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2508","DOI":"10.1021\/acs.est.6b04806","article-title":"A never-ending story of per- and polyfluoroalkyl substances (PFASs)?","volume":"51","author":"Wang","year":"2017","journal-title":"Environ. Sci. Technol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1002\/etc.4890","article-title":"Per- and polyfluoroalkyl substance toxicity and human health review: Current state of knowledge and strategies for informing future research","volume":"40","author":"Fenton","year":"2021","journal-title":"Environ. Toxicol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/02772248.2020.1763997","article-title":"Per- and polyfluoroalkyl substances and obesity, type 2 diabetes and non-alcoholic fatty liver disease: A review of epidemiologic findings","volume":"102","author":"Qi","year":"2020","journal-title":"Toxicol. Environ. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2345","DOI":"10.1039\/D0EM00291G","article-title":"An overview of the uses of per- and polyfluoroalkyl substances (PFAS)","volume":"22","author":"Gluge","year":"2020","journal-title":"Environ. Sci. Process Impacts"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1002\/ieam.258","article-title":"Perfluoroalkyl and polyfluoroalkyl substances in the environment: Terminology, classification, and origins","volume":"7","author":"Buck","year":"2011","journal-title":"Integr. Environ. Assess. Manag."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1038\/s41370-024-00742-2","article-title":"Associations between per-and polyfluoroalkyl substances (PFAS) and county-level cancer incidence between 2016 and 2021 and incident cancer burden attributable to PFAS in drinking water in the United States","volume":"35","author":"Li","year":"2025","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1484","DOI":"10.1111\/hepr.12876","article-title":"Liver tissue metabolic profiling and pathways of non-alcoholic steatohepatitis in rats","volume":"47","author":"Qi","year":"2017","journal-title":"Hepatol. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1021\/acs.est.4c08701","article-title":"Per- and polyfluoroalkyl substances and female health concern: Gender-based accumulation differences, adverse outcomes, and mechanisms","volume":"59","author":"Li","year":"2025","journal-title":"Environ. Sci. Technol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.tibs.2024.11.001","article-title":"Confronting PFAS persistence: Enzymes catalyzing C-F bond cleavage","volume":"50","author":"Wackett","year":"2024","journal-title":"Trends Biochem. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Mi\u0161\u013eanov\u00e1, C., and Valachovi\u010dov\u00e1, M. (2025). Health impacts of per- and polyfluoroalkyl substances (PFASs): A comprehensive review. Life, 15.","DOI":"10.3390\/life15040573"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/s41545-023-00274-6","article-title":"Revisiting the \u201cforever chemicals\u201d, PFOA and PFOS exposure in drinking water","volume":"6","author":"Wee","year":"2023","journal-title":"npj Clean. Water"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1038\/s41370-023-00545-x","article-title":"Associations of perfluoroalkyl substances (PFAS) with lipid and lipoprotein profiles","volume":"33","author":"Haug","year":"2023","journal-title":"J. Expo. Sci. Environ. Epidemiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/j.toxlet.2025.02.003","article-title":"Toxicological mode-of-action and developmental toxicity of different carbon chain length PFAS","volume":"405","author":"Sodani","year":"2025","journal-title":"Toxicol. Lett."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.envint.2014.11.013","article-title":"Hazard assessment of fluorinated alternatives to long-chain perfluoroalkyl acids (PFAAs) and their precursors: Status quo, ongoing challenges and possible solutions","volume":"75","author":"Wang","year":"2015","journal-title":"Environ. Int."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1021\/acs.est.2c06600","article-title":"Impacts of environmental and engineered processes on the PFAS fingerprint of fluorotelomer-based AFFF","volume":"57","author":"Balgooyen","year":"2023","journal-title":"Environ. Sci. Technol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Kolanczyk, R.C., Saley, M.R., Serrano, J.A., Daley, S.M., and Tapper, M.A. (2023). PFAS biotransformation pathways: A species comparison study. Toxics, 11.","DOI":"10.3390\/toxics11010074"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1007\/s40572-024-00441-y","article-title":"Public health risks of PFAS-related immunotoxicity are real","volume":"11","author":"Bline","year":"2024","journal-title":"Curr. Environ. Health Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"117436","DOI":"10.1016\/j.ecoenv.2024.117436","article-title":"Triglycerides mediate the relationships of per- and poly-fluoroalkyl substance (PFAS) exposure with nonalcoholic fatty liver disease (NAFLD) risk in US participants","volume":"289","author":"Qiao","year":"2024","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"100694","DOI":"10.1016\/j.jhepr.2023.100694","article-title":"Association of per- and polyfluoroalkyl substance exposure with fatty liver disease risk in US adults","volume":"5","author":"Zhang","year":"2023","journal-title":"JHEP Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1016\/j.jhep.2021.09.039","article-title":"Exposure to environmental contaminants is associated with altered hepatic lipid metabolism in non-alcoholic fatty liver disease","volume":"76","author":"Sen","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100550","DOI":"10.1016\/j.jhepr.2022.100550","article-title":"Exposure to perfluoroalkyl substances and risk of hepatocellular carcinoma in a multiethnic cohort","volume":"4","author":"Goodrich","year":"2022","journal-title":"JHEP Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1016\/j.envpol.2019.01.064","article-title":"Environmental perfluoroalkyl acid exposures are associated with liver disease characterized by apoptosis and altered serum adipocytokines","volume":"247","author":"Bassler","year":"2019","journal-title":"Environ. Pollut."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"176717","DOI":"10.1016\/j.scitotenv.2024.176717","article-title":"Effects of per- and polyfluoroalkyl substances on the liver: Human-relevant mechanisms of toxicity","volume":"954","author":"Maerten","year":"2024","journal-title":"Sci. Total Environ."},{"key":"ref_25","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 beta-oxidation and lipid transport","volume":"1820","author":"Wan","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1093\/toxsci\/kfx185","article-title":"Perfluorooctane sulfonate-induced hepatic steatosis in male Sprague Dawley rats is not attenuated by dietary choline supplementation","volume":"160","author":"Bagley","year":"2017","journal-title":"Toxicol. Sci."},{"key":"ref_27","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_28","doi-asserted-by":"crossref","first-page":"41303","DOI":"10.1289\/EHP11149","article-title":"Invited perspective: PFAS and liver disease: Bringing all the evidence together","volume":"130","author":"Ducatman","year":"2022","journal-title":"Environ. Health Perspect."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"106843","DOI":"10.1016\/j.envint.2021.106843","article-title":"Exposure to a mixture of legacy, alternative, and replacement per- and polyfluoroalkyl substances (PFAS) results in sex-dependent modulation of cholesterol metabolism and liver injury","volume":"157","author":"Roth","year":"2021","journal-title":"Environ. Int."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"201","DOI":"10.2131\/jts.36.201","article-title":"Induction of apoptosis and CYP4A1 expression in Sprague-Dawley rats exposed to low doses of perfluorooctane sulfonate","volume":"36","author":"Kim","year":"2011","journal-title":"J. Toxicol. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"120556","DOI":"10.1016\/j.envres.2024.120556","article-title":"Associations between per- and polyfluoroalkyl substances (PFAS) and female sexual function in a preconception cohort","volume":"266","author":"Schildroth","year":"2024","journal-title":"Environ. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Hari, A., AbdulHameed, M.D.M., Balik-Meisner, M.R., Mav, D., Phadke, D.P., Scholl, E.H., Shah, R.R., Casey, W., Auerbach, S.S., and Wallqvist, A. (2024). Exposure to PFAS chemicals induces sex-dependent alterations in key rate-limiting steps of lipid metabolism in liver steatosis. Front. Toxicol., 6.","DOI":"10.3389\/ftox.2024.1390196"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"120038","DOI":"10.1016\/j.cca.2024.120038","article-title":"Navigating liver health with metabolomics: A comprehensive review","volume":"566","author":"Singh","year":"2025","journal-title":"Clin. Chim. Acta"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Chen, M. (2024). Environmental chemical exposomics and metabolomics in toxicology: The latest updates. Toxics, 12.","DOI":"10.3390\/toxics12090647"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"338298","DOI":"10.1016\/j.aca.2021.338298","article-title":"Metabolomics in chemical risk analysis\u2014A review","volume":"1154","author":"Dervilly","year":"2021","journal-title":"Anal. Chim. Acta"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"112","DOI":"10.14573\/altex.1502091","article-title":"The human toxome project","volume":"32","author":"Bouhifd","year":"2015","journal-title":"ALTEX"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Tsouka, S., and Masoodi, M. (2023). Metabolic pathway analysis: Advantages and pitfalls for the functional interpretation of metabolomics and lipidomics data. Biomolecules, 13.","DOI":"10.3390\/biom13020244"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1002\/bit.29020","article-title":"RSEA: A web server for pathway enrichment analysis of metabolic reaction sets","volume":"122","author":"Yarici","year":"2025","journal-title":"Biotechnol. Bioeng."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Pandey, V. (2025). MiNEApy: Enhancing enrichment network analysis in metabolic networks. Bioinformatics, 41.","DOI":"10.1093\/bioinformatics\/btaf077"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/nbt.1614","article-title":"What is flux balance analysis?","volume":"28","author":"Orth","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Gu, C., Kim, G.B., Kim, W.J., Kim, H.U., and Lee, S.Y. (2019). Current status and applications of genome-scale metabolic models. Genome Biol., 20.","DOI":"10.1186\/s13059-019-1730-3"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/bib\/bbad439","article-title":"Applications of genome-scale metabolic models to investigate microbial metabolic adaptations in response to genetic or environmental perturbations","volume":"25","author":"Carter","year":"2023","journal-title":"Brief. Bioinform."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7356","DOI":"10.1038\/s41467-022-35017-7","article-title":"Genetically personalised organ-specific metabolic models in health and disease","volume":"13","author":"Foguet","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"3083","DOI":"10.1038\/ncomms4083","article-title":"Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease","volume":"5","author":"Mardinoglu","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Moskon, M., and Rezen, T. (2023). Context-specific genome-scale metabolic modelling and its application to the analysis of COVID-19 metabolic signatures. Metabolites, 13.","DOI":"10.3390\/metabo13010126"},{"key":"ref_46","first-page":"154","article-title":"Quantifying liver-toxic responses from dose-dependent chemical exposures using a rat genome-scale metabolic model","volume":"204","author":"Pannala","year":"2025","journal-title":"Toxicol. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1093\/toxsci\/kfz228","article-title":"Genome-scale model-based identification of metabolite indicators for early detection of kidney toxicity","volume":"173","author":"Pannala","year":"2020","journal-title":"Toxicol. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.taap.2019.04.001","article-title":"Mechanistic identification of biofluid metabolite changes as markers of acetaminophen-induced liver toxicity in rats","volume":"372","author":"Pannala","year":"2019","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1093\/toxsci\/kfz197","article-title":"Genome-scale characterization of toxicity induced metabolic alterations in primary hepatocytes","volume":"172","author":"Rawls","year":"2019","journal-title":"Toxicol. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Vinnakota, K.C., Pannala, V.R., Wall, M.L., Rahim, M., Estes, S.K., Trenary, I., O\u2019Brien, T.P., Printz, R.L., Reifman, J., and Shiota, M. (2019). Network modeling of liver metabolism to predict plasma metabolite changes during short-term fasting in the laboratory rat. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00161"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Guil, F., Garcia, R., and Garcia, J.M. (2024). Adding metabolic tasks to Human GEM models to improve the study of gene targets and their associated toxicities. Sci. Rep., 14.","DOI":"10.1038\/s41598-024-68073-8"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Moore, C.J., Holstege, C.P., and Papin, J.A. (2023). Metabolic modeling of sex-specific liver tissue suggests mechanism of differences in toxicological responses. PLoS Comput. Biol., 19.","DOI":"10.1101\/2023.02.07.527430"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1289\/ehp.1307539","article-title":"Standardizing benchmark dose calculations to improve science-based decisions in human health assessments","volume":"122","author":"Wignall","year":"2014","journal-title":"Environ. Health Perspect."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.taap.2010.10.016","article-title":"Introduction to benchmark dose methods and U.S. EPA\u2019s benchmark dose software (BMDS) version 2.1.1","volume":"254","author":"Davis","year":"2011","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1780","DOI":"10.1093\/bioinformatics\/bty878","article-title":"BMDExpress 2: Enhanced transcriptomic dose-response analysis workflow","volume":"35","author":"Phillips","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Yang, L., Allen, B.C., and Thomas, R.S. (2007). BMDExpress: A software tool for the benchmark dose analyses of genomic data. BMC Genom., 8.","DOI":"10.1186\/1471-2164-8-387"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Sen, P., and Ore\u0161i\u010d, M. (2023). Integrating omics data in genome-scale metabolic modeling: A methodological perspective for precision medicine. Metabolites, 13.","DOI":"10.3390\/metabo13070855"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"106201","DOI":"10.1016\/j.isci.2023.106201","article-title":"Phenotype-specific estimation of metabolic fluxes using gene expression data","volume":"26","author":"Inostroza","year":"2023","journal-title":"iScience"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Auerbach, S.S., Aillon, K.L., Ballin, J.D., Collins, B.J., Cora, M.C., Duncan, N.S., Fostel, J.M., Liu, Y.F., Luh, J., and Machesky, N.J. (2023). NIEHS Report on the In Vivo Repeat Dose Biological Potency Study of 6:1 Fluorotelomer Alcohol (CASRN 375-82-6) in Sprague Dawley (Hsd:Sprague Dawley\u00ae SD\u00ae) Rats (Gavage Studies), NIEHS. NIEHS Report 07.","DOI":"10.22427\/NIEHS-07"},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Auerbach, S.S., Ballin, J.D., Blake, J.C., Browning, D.B., Collins, B.J., Cora, M.C., Fernando, R.A., Fostel, J.M., Liu, Y.F., and Luh, J. (2023). NIEHS Report on the In Vivo Repeat Dose Biological Potency Study of Perfluorohexanesulfonamide (CASRN 41997-13-1) in Sprague Dawley (Hsd:Sprague Dawley\u00ae SD\u00ae) Rats (Gavage Studies), NIEHS. NIEHS Report 10.","DOI":"10.22427\/NIEHS-10"},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Auerbach, S.S., Ballin, J.D., Blake, J.C., Browning, D.B., Collins, B.J., Cora, M.C., Fernando, R.A., Fostel, J.M., Liu, Y.F., and Luh, J. (2023). NIEHS Report on the In Vivo Repeat Dose Biological Potency Study of 1,1,2,2-Tetrahydroperfluoro-1-dodecanol (CASRN 865-86-1) in Sprague Dawley (Hsd:Sprague Dawley\u00ae SD\u00ae) Rats (Gavage Studies), NIEHS. NIEHS Report 08.","DOI":"10.22427\/NIEHS-08"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Mav, D., Shah, R.R., Howard, B.E., Auerbach, S.S., Bushel, P.R., Collins, J.B., Gerhold, D.L., Judson, R.S., Karmaus, A.L., and Maull, E.A. (2018). A hybrid gene selection approach to create the S1500+ targeted gene sets for use in high-throughput transcriptomics. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0191105"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1186\/s13321-018-0263-1","article-title":"OPERA models for predicting physicochemical properties and environmental fate endpoints","volume":"10","author":"Mansouri","year":"2018","journal-title":"J. Cheminform"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Yeakley, J.M., Shepard, P.J., Goyena, D.E., VanSteenhouse, H.C., McComb, J.D., and Seligmann, B.E. (2017). A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0178302"},{"key":"ref_65","unstructured":"Sciome (2025, July 31). GeniE. Available online: https:\/\/apps.sciome.com\/genie\/home."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"W427","DOI":"10.1093\/nar\/gkaa409","article-title":"Fluxer: A web application to compute, analyze and visualize genome-scale metabolic flux networks","volume":"48","author":"Hari","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Pannala, V.R., Wall, M.L., Estes, S.K., Trenary, I., O\u2019Brien, T.P., Printz, R.L., Vinnakota, K.C., Reifman, J., Shiota, M., and Young, J.D. (2018). Metabolic network-based predictions of toxicant-induced metabolite changes in the laboratory rat. Sci. Rep., 8.","DOI":"10.1038\/s41598-018-30149-7"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"14250","DOI":"10.1038\/ncomms14250","article-title":"Reconciled rat and human metabolic networks for comparative toxicogenomics and biomarker predictions","volume":"8","author":"Blais","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"e2102344118","DOI":"10.1073\/pnas.2102344118","article-title":"Genome-scale metabolic network reconstruction of model animals as a platform for translational research","volume":"118","author":"Wang","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"D587","DOI":"10.1093\/nar\/gkac963","article-title":"KEGG for taxonomy-based analysis of pathways and genomes","volume":"51","author":"Kanehisa","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Ebrahim, A., Lerman, J.A., Palsson, B.O., and Hyduke, D.R. (2013). COBRApy: COnstraints-Based Reconstruction and Analysis for Python. BMC Syst. Biol., 7.","DOI":"10.1186\/1752-0509-7-74"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/j.reprotox.2019.07.013","article-title":"Python BMDS: A Python interface library and web application for the canonical EPA dose-response modeling software","volume":"90","author":"Pham","year":"2019","journal-title":"Reprod. Toxicol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"108620","DOI":"10.1016\/j.envint.2024.108620","article-title":"Understanding PFAS toxicity through cell culture metabolomics: Current applications and future perspectives","volume":"186","author":"Nguyen","year":"2024","journal-title":"Environ. Int."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Hasegawa, T., Iino, C., Endo, T., Mikami, K., Kimura, M., Sawada, N., Nakaji, S., and Fukuda, S. (2020). Changed amino acids in NAFLD and liver fibrosis: A large cross-sectional study without influence of insulin resistance. Nutrients, 12.","DOI":"10.20944\/preprints202005.0127.v1"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"van den Berg, E.H., Flores-Guerrero, J.L., Gruppen, E.G., de Borst, M.H., Wolak-Dinsmore, J., Connelly, M.A., Bakker, S.J.L., and Dullaart, R.P.F. (2019). Non-alcoholic fatty liver disease and risk of incident type 2 diabetes: Role of circulating branched-chain amino acids. Nutrients, 11.","DOI":"10.3390\/nu11030705"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/hep.29465","article-title":"Altered amino acid concentrations in NAFLD: Impact of obesity and insulin resistance","volume":"67","author":"Gaggini","year":"2018","journal-title":"Hepatology"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Mardinoglu, A., Bjornson, E., Zhang, C., Klevstig, M., Soderlund, S., Stahlman, M., Adiels, M., Hakkarainen, A., Lundbom, N., and Kilicarslan, M. (2017). Personal model-assisted identification of NAD(+) and glutathione metabolism as intervention target in NAFLD. Mol. Syst. Biol., 13.","DOI":"10.15252\/msb.20167422"},{"key":"ref_79","doi-asserted-by":"crossref","unstructured":"Fritsche, K., Zikova-Kloas, A., Marx-Stoelting, P., and Braeuning, A. (2023). Metabolism-disrupting chemicals affecting the liver: Screening, testing, and molecular pathway identification. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24032686"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"3381","DOI":"10.1007\/s00204-024-03814-2","article-title":"In vitro screening of understudied PFAS with a focus on lipid metabolism disruption","volume":"98","author":"Kashobwe","year":"2024","journal-title":"Arch. Toxicol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Ma, X., Cai, D., Chen, Q., Zhu, Z., Zhang, S., Wang, Z., Hu, Z., Shen, H., and Meng, Z. (2024). Hunting metabolic biomarkers for exposure to per- and polyfluoroalkyl substances: A review. Metabolites, 14.","DOI":"10.3390\/metabo14070392"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"6133","DOI":"10.1021\/acs.est.1c02471","article-title":"Exposure to GenX and its novel analogs disrupts hepatic bile acid metabolism in male mice","volume":"56","author":"Guo","year":"2022","journal-title":"Environ. Sci. Technol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1093\/toxsci\/kfx237","article-title":"Alteration of bile acid and cholesterol biosynthesis and transport by perfluorononanoic acid (PFNA) in mice","volume":"162","author":"Zhang","year":"2018","journal-title":"Toxicol. Sci."},{"key":"ref_84","doi-asserted-by":"crossref","unstructured":"Vairetti, M., Di Pasqua, L.G., Cagna, M., Richelmi, P., Ferrigno, A., and Berardo, C. (2021). Changes in glutathione content in liver diseases: An update. Antioxidants, 10.","DOI":"10.3390\/antiox10030364"},{"key":"ref_85","first-page":"100579","article-title":"Per- and polyfluoroalkyl substances (PFAS) exposure in biota and remediation strategies: Toxicological and biochemical perspectives","volume":"17","author":"Hossain","year":"2025","journal-title":"J. Hazard. Mater. Adv."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1186\/s12940-024-01145-4","article-title":"Integrated analysis of per- and polyfluoroalkyl substances and plasma lipidomics profiles in multi-ethnic Asian subjects for exposome research","volume":"23","author":"Narasimhan","year":"2024","journal-title":"Environ. Health"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1007\/s40726-023-00269-4","article-title":"PFAS exposures and the human metabolome: A systematic review of epidemiological studies","volume":"9","author":"Yao","year":"2023","journal-title":"Curr. Pollut. Rep."},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Wang, P., Liu, D., Yan, S., Cui, J., Liang, Y., and Ren, S. (2022). Adverse effects of perfluorooctane sulfonate on the liver and relevant mechanisms. Toxics, 10.","DOI":"10.3390\/toxics10050265"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"108820","DOI":"10.1016\/j.envint.2024.108820","article-title":"Metabolic and phenotypic changes induced by PFAS exposure in two human hepatocyte cell models","volume":"190","author":"Alijagic","year":"2024","journal-title":"Environ. Int."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"111099","DOI":"10.1016\/j.cellsig.2024.111099","article-title":"Ceramides and mitochondrial homeostasis","volume":"117","author":"Ding","year":"2024","journal-title":"Cell. Signal."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Simon, J., Ouro, A., Ala-Ibanibo, L., Presa, N., Delgado, T.C., and Martinez-Chantar, M.L. (2019). Sphingolipids in non-alcoholic fatty liver disease and hepatocellular carcinoma: Ceramide turnover. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010040"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"105935","DOI":"10.1016\/j.envint.2020.105935","article-title":"Prenatal exposure to perfluoroalkyl substances modulates neonatal serum phospholipids, increasing risk of type 1 diabetes","volume":"143","author":"McGlinchey","year":"2020","journal-title":"Environ. Int."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1968450","DOI":"10.1155\/2018\/1968450","article-title":"Inositols in insulin signaling and glucose metabolism","volume":"2018","author":"Bevilacqua","year":"2018","journal-title":"Int. J. Endocrinol."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Auger, C., Alhasawi, A., Contavadoo, M., and Appanna, V.D. (2015). Dysfunctional mitochondrial bioenergetics and the pathogenesis of hepatic disorders. Front. Cell Dev. Biol., 3.","DOI":"10.3389\/fcell.2015.00040"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1836","DOI":"10.1002\/hep.24001","article-title":"Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis","volume":"52","author":"Tilg","year":"2010","journal-title":"Hepatology"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/j.freeradbiomed.2007.12.029","article-title":"Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases","volume":"44","author":"Mantena","year":"2008","journal-title":"Free Radic. Biol. Med."},{"key":"ref_97","doi-asserted-by":"crossref","unstructured":"Allameh, A., Niayesh-Mehr, R., Aliarab, A., Sebastiani, G., and Pantopoulos, K. (2023). Oxidative stress in liver pathophysiology and disease. Antioxidants, 12.","DOI":"10.3390\/antiox12091653"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"474","DOI":"10.37349\/edd.2024.00062","article-title":"Mitochondrial ROS, a trigger for mitochondrial dysfunction and inflammasome activation and a therapeutic target in liver diseases","volume":"3","author":"Jaara","year":"2024","journal-title":"Explor. Dig. Dis."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1016\/j.plipres.2010.05.003","article-title":"Biosynthesis and bioavailability of long-chain polyunsaturated fatty acids in non-alcoholic fatty liver disease","volume":"49","author":"Gormaz","year":"2010","journal-title":"Prog. Lipid Res."},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Alba, M.M., Ebright, B., Hua, B., Slarve, I., Zhou, Y., Jia, Y., Louie, S.G., and Stiles, B.L. (2023). Eicosanoids and other oxylipins in liver injury, inflammation and liver cancer development. Front. Physiol., 14.","DOI":"10.3389\/fphys.2023.1098467"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/978-1-0716-2128-8_22","article-title":"Analysis of the sphingolipidome in NAFLD","volume":"2455","author":"Montefusco","year":"2022","journal-title":"Methods Mol. Biol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"608","DOI":"10.1016\/j.bbrc.2018.05.078","article-title":"Non-alcoholic fatty liver disease: Insights from sphingolipidomics","volume":"504","author":"Montefusco","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_103","first-page":"178910","article-title":"Sphingolipid metabolic pathway: An overview of major roles played in human diseases","volume":"2013","author":"Vaidyanathan","year":"2013","journal-title":"J. Lipids"},{"key":"ref_104","doi-asserted-by":"crossref","unstructured":"Pani, A., Giossi, R., Menichelli, D., Fittipaldo, V.A., Agnelli, F., Inglese, E., Romandini, A., Roncato, R., Pintaudi, B., and Del Sole, F. (2020). Inositol and non-alcoholic fatty liver disease: A systematic review on deficiencies and supplementation. Nutrients, 12.","DOI":"10.3390\/nu12113379"},{"key":"ref_105","doi-asserted-by":"crossref","unstructured":"Delli Bovi, A.P., Marciano, F., Mandato, C., Siano, M.A., Savoia, M., and Vajro, P. (2021). Oxidative stress in non-alcoholic fatty liver disease. Front. Med., 8.","DOI":"10.3389\/fmed.2021.595371"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"156891","DOI":"10.1016\/j.scitotenv.2022.156891","article-title":"Serum concentrations of selected perfluoroalkyl substances for US females compared to males as they age","volume":"842","author":"Jain","year":"2022","journal-title":"Sci. Total Environ."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"153031","DOI":"10.1016\/j.tox.2021.153031","article-title":"Per- and poly-fluoroalkyl substances (PFAS) and female reproductive outcomes: PFAS elimination, endocrine-mediated effects, and disease","volume":"465","author":"Rickard","year":"2022","journal-title":"Toxicology"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1016\/j.cmet.2018.05.021","article-title":"Short-term fasting reveals amino acid metabolism as a major sex-discriminating factor in the liver","volume":"28","author":"Mitro","year":"2018","journal-title":"Cell Metab."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"C372","DOI":"10.1152\/ajpcell.00035.2005","article-title":"Gender dimorphism in rat liver mitochondrial oxidative metabolism and biogenesis","volume":"289","author":"Justo","year":"2005","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Phelps, T., Snyder, E., Rodriguez, E., Child, H., and Harvey, P. (2019). The influence of biological sex and sex hormones on bile acid synthesis and cholesterol homeostasis. Biol. Sex. Differ., 10.","DOI":"10.1186\/s13293-019-0265-3"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"3214","DOI":"10.1021\/acs.est.1c07176","article-title":"Effect of enterohepatic circulation on the accumulation of per- and polyfluoroalkyl substances: Evidence from experimental and computational studies","volume":"56","author":"Cao","year":"2022","journal-title":"Environ. Sci. Technol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1093\/toxsci\/kfaa081","article-title":"Evaluation of 5-day in vivo rat liver and kidney with high-throughput transcriptomics for estimating benchmark doses of apical outcomes","volume":"176","author":"Gwinn","year":"2020","journal-title":"Toxicol. Sci."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1038\/nbt.4072","article-title":"Recon3D enables a three-dimensional view of gene variation in human metabolism","volume":"36","author":"Brunk","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"157255","DOI":"10.1016\/j.scitotenv.2022.157255","article-title":"A review of omics-based PFAS exposure studies reveals common biochemical response pathways","volume":"845","author":"Beale","year":"2022","journal-title":"Sci. Total Environ."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.jhep.2023.02.034","article-title":"The exposome and liver disease\u2014How environmental factors affect liver health","volume":"79","author":"Barouki","year":"2023","journal-title":"J. Hepatol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"e4","DOI":"10.1017\/S1462399411002110","article-title":"Molecular mechanisms underlying chemical liver injury","volume":"14","author":"Gu","year":"2012","journal-title":"Expert Rev. Mol. Med."}],"container-title":["Toxics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2305-6304\/13\/8\/684\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:29:34Z","timestamp":1760034574000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2305-6304\/13\/8\/684"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,8,17]]},"references-count":116,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["toxics13080684"],"URL":"https:\/\/doi.org\/10.3390\/toxics13080684","relation":{},"ISSN":["2305-6304"],"issn-type":[{"value":"2305-6304","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,8,17]]}}}