title: Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice.
abstract: Arsenic is a ubiquitous contaminant in drinking water. Whereas arsenic can be directly hepatotoxic, the concentrations/doses required are generally higher than present in the US water supply. However, physiological/biochemical changes that are alone pathologically inert can enhance the hepatotoxic response to a subsequent stimulus. Such a '2-hit' paradigm is best exemplified in chronic fatty liver diseases. Here, the hypothesis that low arsenic exposure sensitizes liver to hepatotoxicity in a mouse model of non-alcoholic fatty liver disease was tested. Accordingly, male C57Bl/6J mice were exposed to low fat diet (LFD; 13% calories as fat) or high fat diet (HFD; 42% calories as fat) and tap water or arsenic (4.9 ppm as sodium arsenite) for ten weeks. Biochemical and histologic indices of liver damage were determined. High fat diet (± arsenic) significantly increased body weight gain in mice compared with low-fat controls. HFD significantly increased liver to body weight ratios; this variable was unaffected by arsenic exposure. HFD caused steatohepatitis, as indicated by histological assessment and by increases in plasma ALT and AST. Although arsenic exposure had no effect on indices of liver damage in LFD-fed animals, it significantly increased the liver damage caused by HFD. This effect of arsenic correlated with enhanced inflammation and fibrin extracellular matrix (ECM) deposition. These data indicate that subhepatotoxic arsenic exposure enhances the toxicity of HFD. These results also suggest that arsenic exposure might be a risk factor for the development of fatty liver disease in human populations.
authors: Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.
authors: Min
authors: M
authors: Tan
authors: Robin H
authors: RH
authors: Schmidt
authors: Juliane I
authors: JI
authors: Beier
authors: Walter H
authors: WH
authors: Watson
authors: Hai
authors: H
authors: Zhong
authors: J Christopher
authors: JC
authors: States
authors: Gavin E
authors: GE
authors: Arteel
mesh_terms: D000818:Animals; D018053:Arsenites / Q000008:administration & dosage / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D004041:Dietary Fats / Q000009:adverse effects*; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology*; D005337:Fibrin / Q000378:metabolism; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D012307:Risk Factors; D017670:Sodium Compounds / Q000008:administration & dosage / Q000633:toxicity*; D015430:Weight Gain
chemical_list: D018053:Arsenites; D004041:Dietary Fats; D017670:Sodium Compounds; C017947:sodium arsenite; D005337:Fibrin