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Its interaction with environmental pollutants might exacerbate NAFLD\u2019s severity. Haloacetamides (HAcAms), a group of emerging nitrogenous disinfection byproducts (DBPs) and potent oxidative stressors, are found in chlorinated drinking water. Since oxidative stress is associated with HAcAms-DBP cytotoxicity and a key factor in NAFLD pathogenesis, we hypothesize that HAcAms-DBPs could exacerbate liver injury and NAFLD, particularly with high-fat diets. This study examined HAcAms-DBPs\u2019 impact on liver lipid metabolism in mice treated with 1 to 100 times the background drinking water level (13.05\u2009\u00b5g\/L) for up to 16\u2009weeks of oral administration. Compared to a high-fat-only group, mice co-exposed to a high-fat diet and HAcAms-DBPs for 16\u2009weeks had elevated serum alanine transaminase, aspartate transaminase, triglyceride, hepatic lipid aggregation, and inflammation response. Under high-fat conditions, background drinking water levels of HAcAms significantly upregulated liver Acetyl-CoA carboxylase 1, fatty acid synthase, peroxisome proliferator-activated receptor gamma (PPAR\u03b3), PPAR\u03b3 coactivator-1\u03b1, glucose transporter 1 and 4 protein expression in C57BL\/6J mice; 10 times background significantly increased expression of inflammatory marker tumor necrosis factor and liver fibrosis marker protein alpha-smooth muscle actin; 100 times further increased both liver damage and markers of early non-alcoholic steatohepatitis phenotypes like steatosis and lobular inflammation. HAcAms-DBPs plus high-fat conditions worsened liver damage. The possible health risks of NAFLD induced by HAcAms in obese individuals deserve further study.<\/jats:p>","DOI":"10.1093\/toxsci\/kfae160","type":"journal-article","created":{"date-parts":[[2024,12,17]],"date-time":"2024-12-17T18:07:25Z","timestamp":1734458845000},"page":"57-69","source":"Crossref","is-referenced-by-count":1,"title":["Haloacetamides exacerbate non-alcoholic fatty liver disease induced by a high-fat diet in C57BL\/6J mice"],"prefix":"10.1093","volume":"204","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6198-2445","authenticated-orcid":false,"given":"Zhiqiang","family":"Jiang","sequence":"first","affiliation":[{"name":"Center for Water and Health, Key Laboratory of the Public Health Safety, Ministry of Education, Department of Environmental Health, School of Public Health, Fudan University , Shanghai 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