Hepatic damage caused by chronic arsenic toxicity in experimental animals

J Toxicol Clin Toxicol. 2000;38(4):395-405. doi: 10.1081/clt-100100949.


Objective: Noncirrhotic fibrosis of the liver is common in subjects chronically consuming ground water geologically contaminated with arsenic, but the mechanism of the hepatic fibrosis is not known. Because lipid peroxidation has been implicated in the development of several other forms of hepatic fibrosis, including iron and copper overload, we have explored the roles of oxidative stress and lipid peroxidation in the causation of hepatic fibrosis in a murine model of chronic arsenic toxicity.

Methods: Male BALB/c mice were given drinking water contaminated with arsenic (3.2 mg/L) or arsenic-free (<0.01 mg/L, control) ad libitum. Mice were sacrificed at 3, 6, 9, 12, and 15 months for examination of hepatic histology and assays of hepatic reduced glutathione content, lipid peroxidation, enzymes of the antioxidant defense system, and membrane-bound sodium/potassium ATPase (Na+/K+ ATPase).

Results: After 12 months of arsenic feeding, the liver weights increased significantly as did serum aspartate aminotransferase and alanine aminotransferase. After 6 months of arsenic feeding, hepatic glutathione and the enzymes glucose-6-phosphate dehydrogenase and glutathione peroxidase were significantly lower than those of the control group. Hepatic catalase activity was significantly reduced at 9 months in the arsenic-fed group, while glutathione-S-transferase and glutathione reductase activities were also significantly reduced at 12 and 15 months. Plasma membrane Na+/K+ ATPase activity was reduced after 6 months while lipid peroxidation increased significantly after 6 months of arsenic feeding. Liver histology remained normal for the first 9 months, but showed fatty infiltration after 12 months of arsenic feeding. Histologic evidence of fibrosis was observed after 15 months.

Conclusion: We have demonstrated hepatic fibrosis due to long-term arsenic toxicity in an animal model. Initial biochemical evidence of hepatic membrane damage, probably due to reduction of glutathione and antioxidant enzymes, may be seen by 6 months. Continued arsenic feeding resulted in fatty liver with serum aminotransferase and alanine aminotransferase elevated at 12 months and hepatic fibrosis at 15 months. The murine model is proposed as relevant to epidemic human toxicity in areas of arsenic contamination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Alkaline Phosphatase / blood
  • Animals
  • Arsenic / analysis
  • Arsenic / toxicity*
  • Aspartate Aminotransferases / blood
  • Body Weight / drug effects
  • Chronic Disease
  • Glutathione / metabolism
  • Lipid Peroxidation / drug effects
  • Liver / drug effects*
  • Liver / enzymology
  • Liver / pathology
  • Liver Cirrhosis, Experimental / chemically induced*
  • Liver Cirrhosis, Experimental / metabolism
  • Liver Cirrhosis, Experimental / pathology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Organ Size / drug effects
  • Oxidative Stress / drug effects
  • Serum Albumin / metabolism
  • Sodium-Potassium-Exchanging ATPase / metabolism


  • Serum Albumin
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Alkaline Phosphatase
  • Sodium-Potassium-Exchanging ATPase
  • Glutathione
  • Arsenic