Tolerance of C57BL/6J male mice to arsenic toxicity
Epidemiological evidence suggests that ingestion of arsenic through drinking water may have links with diabetes mellitus-2. The purpose of this investigation was to establish an in vivo rodent model to investigate whether the chronic ingestion of drinking water contaminated with arsenic may induce or exacerbate diabetes. An initial study consisted of 3 groups of C57BL/6J wild-type mice (n=13/group) fed with a diet of 6% fat content, and exposed to 0, 5, or 75 ppm of arsenate [As(V)] in the drinking water for 12 weeks. Blood was collected bi-weekly to measure the levels of glucose and blood urea nitrogen (BUN), an indicator of risks of kidney damage. At the end point, blood serum was collected to measure the levels of insulin. In addition, the blood levels of the enzymes aspartate amino transferase (AST) and alanine amino transferase (ALT), both indicators of liver damage or problems with biliary ducts, were measured. Kidney, liver and pancreas tissues were fixed for histological and ultrastructural analyses. The group exposed to 75 ppm of As(V) significantly consumed more food (p≤0.0108), gained less weight than the 5 ppm and control mice (p<0.03), and consumed less water than the control group (p≤0.021). The group exposed to 5 ppm of As(V) exhibited lower small intestine weight to body weight ratio than the control group. The level of AST was significantly greater in the 75 ppm compared to the 5 ppm and control (p<0.01). The level of BUN increased over time for all 3 groups, indicative of aging. No significant differences between the groups were observed for blood glucose, catalase, insulin, ALT, triglycerides, liver-to-body weight ratio, or kidney-to-body weight ratio. No hepatic, renal or pancreatic pathology was observed. It was concluded that 12 weeks of oral exposure to 5 ppm or 75 ppm of As(V) did not provide evidence of arsenic-induced hyperglycemia, hyperinsulinemia, or diabetes in C57BL/6J mice. In a subsequent study, the arsenic form, dose, diet and timeline were changed to 4 groups (n=15/group) fed with either 4% (low) or 11% (high) fat diet, and exposed to drinking water containing 0 ppm or 22.5 ppm of arsenite [As (III)] for 9 months. One mouse per group was harvested on every 6 weeks to investigate trends of arsenic toxicity. During the last 10 weeks, the fat content of the 11% fat groups was increased to 14% in order to achieve the 50g weight threshold of diet-induced obesity. A significant difference was observed in the average accumulated weights (p<0.01) and blood glucose of the control and arsenic-treated groups fed with the high fat diet (p<0.001) compared to the low fat diet groups. No significant differences were found for water consumption, food consumption, insulin, BUN, liver-to-body weight ratio or kidney-to-body weight ratio. No trends of arsenic toxicity were found in any of the mice harvested every six weeks. It was concluded that 9 months of oral exposure to 22.5 ppm of As(III) does not provide evidence of arsenic-induced hyperglycemia, hyperinsulinemia, or diabetes in C57BL/6J mice. However, an arsenic-induced hepatic steatosis and inflammation were observed in the As(III)-treated low fat group compared to the control low-fat group. A diet-induced hepatic steatosis and inflammation were observed in both of the high fat diet groups with no significantly different pathology observed between the 2 groups. In comparison to other mouse models exposed to the same doses of arsenic for similar lengths of time, it was concluded that the C57BL/6J strain appeared to have tolerance to the doses of arsenic in our experiments. ^
Health Sciences, Toxicology|Environmental Sciences
Vigo, Jaime Bernardo, "Tolerance of C57BL/6J male mice to arsenic toxicity" (2006). ETD Collection for University of Texas, El Paso. AAI3242134.