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Recent epidemiological evidence has identified associations between per- and polyfluoroalkyl substances (PFAS) exposure and increased liver injury in alcohol consumers, suggesting potential interactions between these exposures. However, the intersection of pollutant exposures and alcohol-associated liver disease (ALD) is not well studied. We hypothesize that pollutants may disrupt hepatic metabolism to modify ALD severity. Recently, we developed a two-hit (ethanol [EtOH] plus pollutant) mouse model, enabling testing of this hypothesis. Here, we elucidate the metabolic and disease-modifying effects of PFOS in this model. Male C57BL\/6J mice were fed isocaloric control or 5% EtOH Lieber-DeCarli diet for 15\u2009days. From day 6 of feeding, mice were concurrently gavaged with 1\u2009mg\/kg PFOS or 2% tween-80 vehicle for 10\u2009days, followed by a 5\u2009g\/kg EtOH binge dose and euthanized 5 to 6\u2009h later. Approximately 60% of the administered PFOS dose accumulated in the liver. PFOS exacerbated EtOH-induced hepatic steatosis and was associated by higher levels of plasma very low-density lipoprotein and alanine aminotransferase. PFOS upregulated hepatic EtOH-metabolizing enzymes and lowered blood alcohol levels. Ingenuity Pathway Analysis (IPA) Top Toxicity Functions\/Lists associated with hepatic gene expression following PFOS co-exposure in EtOH-fed mice included: Fatty acid metabolism and liver steatosis; nuclear receptor activation, cytochrome P450, and reactive oxygen species; apoptosis; liver fibrosis; and hepatocellular carcinoma (HCC). Gene Ontology\/Kyoto Encyclopedia of Genes and Genomes analyses similarly revealed enrichment in fatty acid, xenobiotic, alcohol, or glutathione metabolic processes; and peroxisome proliferator-activated receptor (PPAR) signaling. PFOS upregulated hepatic expression of several nuclear receptors (e.g. Ppar\u03b1, Car, and Pxr) and their P450 target genes (e.g. Cyp4a10, Cyp2b10, and Cyp3a11) by real-time-PCR or Western blot, confirming key IPA predictions. PFOS is a metabolism-disrupting chemical that worsens ALD severity. PFOS activated hepatic nuclear receptors and enriched hepatic transcriptional pathways associated with steatosis, xenobiotic metabolism, oxidative stress, cell death, fibrosis, and HCC. These data demonstrate a novel mechanism whereby PFOS exacerbates ALD through coordinated dysregulation of lipid homeostasis and liver injury, potentially mediated by nuclear receptor activation. The identification of PFOS as an ALD risk modifier highlights the critical need to evaluate environmental pollutants as potential contributors to liver disease progression. More data are required on environmental pollution as a disease-modifying factor in ALD.<\/jats:p>\n                  <jats:p>Impact Statement: The present study demonstrates that PFOS exacerbates alcohol-induced liver injury through nuclear receptor activation and metabolic disruption. These findings provide novel insights into how environmental pollutants can act as significant risk modifiers in ALD, how PFAS exposures may contribute to the growing public health burden of liver disease, and underscore the importance of considering combined risk factors in developing targeted interventions.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf066","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T08:15:45Z","timestamp":1746778545000},"page":"388-408","source":"Crossref","is-referenced-by-count":6,"title":["Perfluorooctane sulfonate exposure and alcohol-associated liver disease severity in a mouse chronic-binge ethanol feeding model"],"prefix":"10.1093","volume":"206","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7181-7091","authenticated-orcid":false,"given":"Frederick A","family":"Ekuban","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine , Louisville, KY 40202,","place":["United States"]},{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"University of Louisville Superfund Research Program, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"The Center for Integrative Environmental Health Sciences, University of Louisville , Louisville, KY 40202,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tyler C","family":"Gripshover","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine , Louisville, KY 40202,","place":["United States"]},{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"University of Louisville Superfund Research Program, University of Louisville , Louisville, KY 40202,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paxton","family":"Ames","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine , Louisville, KY 40202,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kushal","family":"Biswas","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell , Lowell, MA 01854,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oluwanifemi E","family":"Bolatimi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine , Louisville, KY 40202,","place":["United 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Won","family":"Park","sequence":"additional","affiliation":[{"name":"The Center for Integrative Environmental Health Sciences Biostatistics and Informatics Facility Core, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"Brown Cancer Center Bioinformatics Core, Department of Medicine, University of Louisville , KY 40202,","place":["United States"]},{"name":"KY INBRE Bioinformatics Core, University of Louisville , Louisville, KY 40202,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3028-1192","authenticated-orcid":false,"given":"Mayukh","family":"Banerjee","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine , Louisville, KY 40202,","place":["United States"]},{"name":"The Center for Integrative Environmental Health Sciences, University of Louisville , Louisville, KY 40202,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walter H","family":"Watson","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine , Louisville, KY 40202,","place":["United States"]},{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"The Center for Integrative Environmental Health Sciences, University of Louisville , Louisville, KY 40202,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Banrida","family":"Wahlang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine , Louisville, KY 40202,","place":["United States"]},{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"University of Louisville Superfund Research Program, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"The Center for Integrative Environmental Health Sciences, University of Louisville , Louisville, KY 40202,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2402-5651","authenticated-orcid":false,"given":"Dhimiter","family":"Bello","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Nutritional Sciences, University of Massachusetts Lowell , Lowell, MA 01854,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6834-4369","authenticated-orcid":false,"given":"Jennifer J","family":"Schlezinger","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, Boston University School of Public Health , Boston, MA 02118,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig J","family":"McClain","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology, University of Louisville School of Medicine , Louisville, KY 40202,","place":["United States"]},{"name":"Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"University of Louisville Superfund Research Program, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"The Center for Integrative Environmental Health Sciences, University of Louisville , Louisville, KY 40202,","place":["United States"]},{"name":"Department of Biochemistry and Molecular Genetics, University of Louisville School of Medicine , Louisville, KY 40202,","place":["United States"]},{"name":"The Robley Rex 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