{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T16:21:37Z","timestamp":1783441297300,"version":"3.54.6"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2018,2,9]],"date-time":"2018-02-09T00:00:00Z","timestamp":1518134400000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Communications"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:p>Vinyl chloride (VC), a common industrial organochlorine and environmental pollutant, has been shown to directly cause hepatic angiosarcoma and toxicant\u2010associated steatohepatitis at high exposure levels. However, the impact of lower concentrations of VC on the progression of underlying liver diseases (e.g., nonalcoholic fatty liver disease [NAFLD]) is unclear. Given the high prevalence of NAFLD in the United States (and worldwide) population, this is an important concern. Recent studies by our group with VC metabolites suggest a potential interaction between VC exposure and underlying liver disease to cause enhanced damage. Here, a novel mouse model determined the effects of VC inhalation at levels below the current Occupational Safety and Health Administration limit (&lt;1 ppm) in the context of NAFLD to better mimic human exposure and identify potential mechanisms of VC\u2010induced liver injury. VC exposure caused no overt liver injury in mice fed a low\u2010fat diet. However, in mice fed a high\u2010fat diet (HFD), VC significantly increased liver damage, steatosis, and increased neutrophil infiltration. Moreover, VC further enhanced HFD\u2010induced oxidative and endoplasmic reticulum stress. Importantly, VC exposure dysregulated energy homeostasis and impaired mitochondrial function, even in mice fed a low\u2010fat diet. In toto, the results indicate that VC exposure causes metabolic stress that sensitizes the liver to steatohepatitis caused by HFD. <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: The hypothesis that low\u2010level (below the Occupational Safety and Health Administration limit) chronic exposure to VC by inhalation enhances liver injury caused by an HFD is supported. Importantly, our data raise concerns about the potential for overlap between fatty diets (i.e., Western diet) and exposure to VC and the health implications of this co\u2010exposure for humans. It also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity. (<jats:italic toggle=\"yes\">Hepatology Communications<\/jats:italic> 2018;2:270\u2010284)<\/jats:p>","DOI":"10.1002\/hep4.1151","type":"journal-article","created":{"date-parts":[[2018,2,9]],"date-time":"2018-02-09T16:52:48Z","timestamp":1518195168000},"page":"270-284","source":"Crossref","is-referenced-by-count":46,"title":["Vinyl chloride dysregulates metabolic homeostasis and enhances diet\u2010induced liver injury in mice"],"prefix":"10.1097","volume":"2","author":[{"given":"Anna L.","family":"Lang","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Toxicology,University of Louisville Health Sciences Center,Louisville,KY"},{"name":"Hepatobiology and Toxicology Program,University of Louisville Health Sciences Center,Louisville,KY"},{"name":"University of Louisville Alcohol Research Center,University of Louisville Health Sciences Center,Louisville,KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liya","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology,University of Louisville Health Sciences Center,Louisville,KY"},{"name":"Hepatobiology and Toxicology Program,University of Louisville Health Sciences Center,Louisville,KY"},{"name":"University of Louisville Alcohol Research Center,University of Louisville Health Sciences Center,Louisville,KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin D.","family":"Poff","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology,University of Louisville Health Sciences Center,Louisville,KY"},{"name":"Hepatobiology and Toxicology Program,University of Louisville Health Sciences Center,Louisville,KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen\u2010Xing","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Toxicology and Therapeutics,University of Kansas Medical Center,Kansas City,KS"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russel A.","family":"Barnett","sequence":"additional","affiliation":[{"name":"Kentucky Institute for the Environment and Sustainable Development,University of Louisville,Louisville,KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin E.","family":"Arteel","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology,University of Louisville Health Sciences Center,Louisville,KY"},{"name":"Hepatobiology and Toxicology Program,University of Louisville Health Sciences Center,Louisville,KY"},{"name":"University of Louisville Alcohol Research Center,University of Louisville Health Sciences Center,Louisville,KY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane I.","family":"Beier","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Toxicology,University of Louisville Health Sciences Center,Louisville,KY"},{"name":"Hepatobiology and Toxicology Program,University of Louisville Health Sciences Center,Louisville,KY"},{"name":"University of Louisville Alcohol Research Center,University of Louisville Health Sciences Center,Louisville,KY"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2018,2,9]]},"reference":[{"key":"hep41151-bib-0002-20240114","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1289\/ehp.7716","article-title":"Vinyl chloride: a case study of data suppression and misrepresentation","volume":"113","year":"2005","journal-title":"Environ Health Perspect"},{"key":"hep41151-bib-0003-20240114","first-page":"311","article-title":"IARC Monographs on the Evaluation of Carcinogenic Risks to Humans","volume":"97","year":"2008","journal-title":"1,3\u2010Butadiene, ethylene oxide and vinyl halides (vinyl fluoride, vinyl chloride and vinyl bromide)"},{"key":"hep41151-bib-0004-20240114","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1289\/ehp.00108579","article-title":"Vinyl chloride: still a cause for concern","volume":"108","year":"2000","journal-title":"Environ Health Perspect"},{"key":"hep41151-bib-0005-20240114","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1080\/10473289.1991.10466844","article-title":"The transfer of trichloroethylene (TCE) from a shower to indoor air: experimental measurements and their implications","volume":"41","year":"1991","journal-title":"J Air Waste Manage Assoc"},{"key":"hep41151-bib-0007-20240114","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/hep.1840040310","article-title":"Early hepatic histologic alterations among chemical (vinyl monomer) workers","volume":"4","year":"1984","journal-title":"Hepatology"},{"key":"hep41151-bib-0008-20240114","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1001\/jama.1974.03230390029019","article-title":"Angiosarcoma of the liver following vinyl chloride exposure","volume":"229","year":"1974","journal-title":"JAMA"},{"key":"hep41151-bib-0009-20240114","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.taap.2016.10.001","article-title":"Occupational exposures at a polyvinyl chloride production facility are associated with significant changes to the plasma metabolome","volume":"313","year":"2016","journal-title":"Toxicol Appl Pharmacol"},{"key":"hep41151-bib-0010-20240114","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1002\/hep.23321","article-title":"Toxicant\u2010associated steatohepatitis in vinyl chloride workers","volume":"51","year":"2010","journal-title":"Hepatology"},{"key":"hep41151-bib-0011-20240114","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1001\/jama.2009.2014","article-title":"Prevalence and trends in obesity among US adults, 1999\u20102008","volume":"303","year":"2010","journal-title":"JAMA"},{"key":"hep41151-bib-0012-20240114","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1016\/S0016-5085(98)70599-2","article-title":"Steatohepatitis: a tale of two \u201chits\u201d?","volume":"114","year":"1998","journal-title":"Gastroenterology"},{"key":"hep41151-bib-0013-20240114","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/nrendo.2017.42","article-title":"Endocrine\u2010disrupting chemicals and fatty liver disease","volume":"13","year":"2017","journal-title":"Nat Rev Endocrinol"},{"key":"hep41151-bib-0014-20240114","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/nrgastro.2013.171","article-title":"The global NAFLD epidemic","volume":"10","year":"2013","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep41151-bib-0015-20240114","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.taap.2016.09.026","article-title":"Role of dietary fatty acids in liver injury caused by vinyl chloride metabolites in mice","volume":"311","year":"2016","journal-title":"Toxicol Appl Pharmacol"},{"key":"hep41151-bib-0016-20240114","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/0041-008X(83)90361-7","article-title":"The effect of age and exposure duration on cancer induction by a known carcinogen in rats, mice, and hamsters","volume":"68","year":"1983","journal-title":"Toxicol Appl Pharmacol"},{"key":"hep41151-bib-0017-20240114","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1038\/nprot.2009.151","article-title":"Isolation of mitochondria\u2010associated membranes and mitochondria from animal tissues and cells","volume":"4","year":"2009","journal-title":"Nat Protoc"},{"key":"hep41151-bib-0018-20240114","doi-asserted-by":"crossref","first-page":"1545","DOI":"10.1002\/hep.22847","article-title":"Fibrin accumulation plays a critical role in the sensitization to lipopolysaccharide\u2010induced liver injury caused by ethanol in mice","volume":"49","year":"2009","journal-title":"Hepatology"},{"key":"hep41151-bib-0019-20240114","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1139\/y59-099","article-title":"A rapid method of total lipid extraction and purification","volume":"37","year":"1959","journal-title":"Can J Biochem Physiol"},{"key":"hep41151-bib-0020-20240114","doi-asserted-by":"crossref","first-page":"18663","DOI":"10.1074\/jbc.M116.739821","article-title":"Sequestosome 1\/p62 protein is associated with autophagic removal of excess hepatic endoplasmic reticulum in mice","volume":"291","year":"2016","journal-title":"J Biol Chem"},{"key":"hep41151-bib-0021-20240114","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.bbabio.2010.02.011","article-title":"Hypoxia and mitochondrial oxidative metabolism","volume":"1797","year":"2010","journal-title":"Biochim Biophys Acta"},{"key":"hep41151-bib-0022-20240114","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1124\/jpet.105.087981","article-title":"Coagulation\u2010mediated hypoxia and neutrophil\u2010dependent hepatic injury in rats given lipopolysaccharide and ranitidine","volume":"314","year":"2005","journal-title":"J Pharmacol Exp Ther"},{"key":"hep41151-bib-0023-20240114","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/hep.21223","article-title":"In vivo assessment of liver cell apoptosis as a novel biomarker of disease severity in nonalcoholic fatty liver disease","volume":"44","year":"2006","journal-title":"Hepatology"},{"key":"hep41151-bib-0024-20240114","doi-asserted-by":"crossref","first-page":"809","DOI":"10.1002\/hep.29238","article-title":"SIRT1\/HSF1\/HSP pathway is essential for exenatide\u2010alleviated, lipid\u2010induced hepatic endoplasmic reticulum stress","volume":"66","year":"2017","journal-title":"Hepatology"},{"key":"hep41151-bib-0025-20240114","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1093\/toxsci\/kfw045","article-title":"Vinyl chloride metabolites potentiate inflammatory liver injury caused by LPS in mice","volume":"151","year":"2016","journal-title":"Toxicol Sci"},{"key":"hep41151-bib-0026-20240114","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.2337\/db07-0093","article-title":"Excess lipid availability increases mitochondrial fatty acid oxidative capacity in muscle: evidence against a role for reduced fatty acid oxidation in lipid\u2010induced insulin resistance in rodents","volume":"56","year":"2007","journal-title":"Diabetes"},{"key":"hep41151-bib-0027-20240114","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/B978-0-12-416618-9.00005-4","article-title":"Techniques to monitor glycolysis","volume":"542","year":"2014","journal-title":"Methods Enzymol"},{"key":"hep41151-bib-0028-20240114","first-page":"A152","article-title":"Applying research to public health questions: biologically relevant exposures","volume":"118","year":"2010","journal-title":"Environ Health Perspect"},{"key":"hep41151-bib-0029-20240114","first-page":"5183","article-title":"Differential induction of N,3\u2010ethenoguanine in rat brain and liver after exposure to vinyl chloride","volume":"62","year":"2002","journal-title":"Cancer Res"},{"key":"hep41151-bib-0030-20240114","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1289\/ehp.81413","article-title":"Carcinogenicity bioassays of vinyl chloride monomer: a model of risk assessment on an experimental basis","volume":"41","year":"1981","journal-title":"Environ Health Perspect"},{"key":"hep41151-bib-0031-20240114","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1002\/tox.22006","article-title":"Effects of co\u2010exposure to 2,3,7,8\u2010tetrachlorodibenzo\u2010p\u2010dioxin and polychlorinated biphenyls on nonalcoholic fatty liver disease in mice","volume":"30","year":"2015","journal-title":"Environ Toxicol"},{"key":"hep41151-bib-0032-20240114","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1530\/JOE-14-0356","article-title":"Perinatal exposure to bisphenol A exacerbates nonalcoholic steatohepatitis\u2010like phenotype in male rat offspring fed on a high\u2010fat diet","volume":"222","year":"2014","journal-title":"J Endocrinol"},{"key":"hep41151-bib-0033-20240114","doi-asserted-by":"crossref","first-page":"e61409","DOI":"10.1371\/journal.pone.0061409","article-title":"High fat diet feeding exaggerates perfluorooctanoic acid\u2010induced liver injury in mice via modulating multiple metabolic pathways","volume":"8","year":"2013","journal-title":"PLoS One"},{"key":"hep41151-bib-0034-20240114","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1016\/j.jnutbio.2013.01.009","article-title":"Polychlorinated biphenyl 153 is a diet\u2010dependent obesogen that worsens nonalcoholic fatty liver disease in male C57BL6\/J mice","volume":"24","year":"2013","journal-title":"J Nutr Biochem"},{"key":"hep41151-bib-0035-20240114","doi-asserted-by":"crossref","first-page":"1188","DOI":"10.1289\/ehp.6972","article-title":"Increased risk of hepatocellular carcinoma and liver cirrhosis in vinyl chloride workers: synergistic effect of occupational exposure with alcohol intake","volume":"112","year":"2004","journal-title":"Environ Health Perspect"},{"key":"hep41151-bib-0036-20240114","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1053\/j.gastro.2014.03.014","article-title":"Lactate reduces liver and pancreatic injury in Toll\u2010like receptor\u2010 and inflammasome\u2010mediated inflammation via GPR81\u2010mediated suppression of innate immunity","volume":"146","year":"2014","journal-title":"Gastroenterology"},{"key":"hep41151-bib-0037-20240114","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1084\/jem.181.5.1763","article-title":"Fibrin regulates neutrophil migration in response to interleukin 8, leukotriene B4, tumor necrosis factor, and formyl\u2010methionyl\u2010leucyl\u2010phenylalanine","volume":"181","year":"1995","journal-title":"J Exp Med"},{"key":"hep41151-bib-0038-20240114","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1097\/00001721-199512000-00001","article-title":"Role of neutrophil membrane proteases in fibrin degradation","volume":"6","year":"1995","journal-title":"Blood Coagul Fibrinolysis"},{"key":"hep41151-bib-0039-20240114","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1258\/ebm.2011.011255","article-title":"Alcoholic liver disease and the potential role of plasminogen activator inhibitor\u20101 and fibrin metabolism","volume":"237","year":"2012","journal-title":"Exp Biol Med (Maywood)"},{"key":"hep41151-bib-0040-20240114","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1097\/JOM.0b013e31822cfd68","article-title":"Serum cytokeratin 18 and cytokine elevations suggest a high prevalence of occupational liver disease in highly exposed elastomer\/polymer workers","volume":"53","year":"2011","journal-title":"J Occup Environ Med"},{"key":"hep41151-bib-0041-20240114","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1093\/toxsci\/65.2.166","article-title":"Mechanisms of hepatotoxicity","volume":"65","year":"2002","journal-title":"Toxicol Sci"},{"key":"hep41151-bib-0042-20240114","doi-asserted-by":"crossref","first-page":"884S","DOI":"10.3945\/ajcn.110.001917","article-title":"Regulation of PGC\u20101alpha, a nodal regulator of mitochondrial biogenesis","volume":"93","year":"2011","journal-title":"Am J Clin Nutr"},{"key":"hep41151-bib-0043-20240114","first-page":"22","article-title":"Lactate is always the end product of glycolysis","volume":"9","year":"2015","journal-title":"Front Neurosci"},{"key":"hep41151-bib-0044-20240114","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1016\/j.redox.2014.11.006","article-title":"Mitochondrial dynamics and mitochondrial quality control","volume":"4","year":"2015","journal-title":"Redox Biol"},{"key":"hep41151-bib-0045-20240114","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1042\/CS20030285","article-title":"Oxidative stress\u2010related parameters in the liver of non\u2010alcoholic fatty liver disease patients","volume":"106","year":"2004","journal-title":"Clin Sci (Lond)"},{"key":"hep41151-bib-0046-20240114","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1016\/j.molmet.2014.05.004","article-title":"ER calcium release promotes mitochondrial dysfunction and hepatic cell lipotoxicity in response to palmitate overload","volume":"3","year":"2014","journal-title":"Mol Metab"},{"key":"hep41151-bib-0047-20240114","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1053\/j.gastro.2007.10.039","article-title":"Activation and dysregulation of the unfolded protein response in nonalcoholic fatty liver disease","volume":"134","year":"2008","journal-title":"Gastroenterology"},{"key":"hep41151-bib-0048-20240114","doi-asserted-by":"crossref","first-page":"4447","DOI":"10.1172\/JCI82204","article-title":"Mitochondrial metabolism mediates oxidative stress and inflammation in fatty liver","volume":"125","year":"2015","journal-title":"J Clin Invest"}],"container-title":["Hepatology Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fhep4.1151","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep4.1151","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep4.1151","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/02009842-201803000-00007","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,14]],"date-time":"2024-01-14T16:03:24Z","timestamp":1705248204000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/02009842-201803000-00007"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,9]]},"references-count":46,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2018]]}},"URL":"https:\/\/doi.org\/10.1002\/hep4.1151","relation":{},"ISSN":["2471-254X","2471-254X"],"issn-type":[{"value":"2471-254X","type":"print"},{"value":"2471-254X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,9]]}}}