Hepatic damage caused by chronic arsenic toxicity in experimental animals

Objective: Noncirrhotic fibrosis of the liver is common in subjects chronic ally 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 f ibrosis, including iron and copper overload, we have explored the roles of oxidative stress and lipid peroxidation in the causation of hepatic fibrosi s 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-f ree (< 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 r educed 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 s ignificantly as did serum aspartate aminotransferase and alanine aminotrans ferase. After 6 months of arsenic feeding, hepatic glutathione and the enzy mes glucose-6-phosphate dehydrogenase and glutathione peroxidase were signi ficantly lower than those of the control group. Hepatic catalase activity w as significantly reduced at 9 months in the arsenic-fed group, while glutat hione-S-transferase and glutathione reductase activities were also signific antly reduced at 12 and 15 months. Plasma membrane Na+/K+ ATPase activity w as 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 fe eding. Histologic evidence of fibrosis was observed after 15 months. Conclu sion: We have demonstrated hepatic fibrosis due to long-term arsenic toxici ty in an animal model. Initial biochemical evidence of hepatic membrane dam age, 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.