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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 withmore » 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. -- Highlights: Black-Right-Pointing-Pointer Characterizes a mouse model of arsenic enhanced NAFLD. Black-Right-Pointing-Pointer Arsenic synergistically enhances experimental fatty liver disease at concentrations that cause no overt hepatotoxicity alone. Black-Right-Pointing-Pointer This effect is associated with increased inflammation.« less

Authors:
; ;  [1];  [2];  [1];  [1]
  1. Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States)
  2. Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 (United States)
Publication Date:
OSTI Identifier:
22212581
Resource Type:
Journal Article
Journal Name:
Toxicology and Applied Pharmacology
Additional Journal Information:
Journal Volume: 257; Journal Issue: 3; Other Information: Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); Journal ID: ISSN 0041-008X
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; ARSENIC; CONCENTRATION RATIO; DIET; DRINKING WATER; FATS; FIBRIN; INFLAMMATION; INJURIES; LIVER; METABOLIC DISEASES; MICE; SODIUM; WATER SUPPLY

Citation Formats

Tan, Min, Schmidt, Robin H., Beier, Juliane I., Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292, Watson, Walter H., University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292, Zhong, Hai, University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292, States, J. Christopher, Arteel, Gavin E., E-mail: gavin.arteel@louisville.edu, and University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292. Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice. United States: N. p., 2011. Web. doi:10.1016/J.TAAP.2011.09.019.
Tan, Min, Schmidt, Robin H., Beier, Juliane I., Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292, Watson, Walter H., University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292, Zhong, Hai, University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292, States, J. Christopher, Arteel, Gavin E., E-mail: gavin.arteel@louisville.edu, & University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292. Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice. United States. https://doi.org/10.1016/J.TAAP.2011.09.019
Tan, Min, Schmidt, Robin H., Beier, Juliane I., Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292, Watson, Walter H., University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292, Zhong, Hai, University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292, States, J. Christopher, Arteel, Gavin E., E-mail: gavin.arteel@louisville.edu, and University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292. 2011. "Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice". United States. https://doi.org/10.1016/J.TAAP.2011.09.019.
@article{osti_22212581,
title = {Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice},
author = {Tan, Min and Schmidt, Robin H. and Beier, Juliane I. and Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY 40292 and Watson, Walter H. and University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292 and Zhong, Hai and University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292 and States, J. Christopher and Arteel, Gavin E., E-mail: gavin.arteel@louisville.edu and University of Louisville Alcohol Research Center, University of Louisville Health Sciences Center, Louisville, KY 40292},
abstractNote = {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. -- Highlights: Black-Right-Pointing-Pointer Characterizes a mouse model of arsenic enhanced NAFLD. Black-Right-Pointing-Pointer Arsenic synergistically enhances experimental fatty liver disease at concentrations that cause no overt hepatotoxicity alone. Black-Right-Pointing-Pointer This effect is associated with increased inflammation.},
doi = {10.1016/J.TAAP.2011.09.019},
url = {https://www.osti.gov/biblio/22212581}, journal = {Toxicology and Applied Pharmacology},
issn = {0041-008X},
number = 3,
volume = 257,
place = {United States},
year = {Thu Dec 15 00:00:00 EST 2011},
month = {Thu Dec 15 00:00:00 EST 2011}
}