Integrative Toxicopathological Evaluation of Aflatoxin B1 Exposure in F344 Rats

In this study, male F344 rats were orally exposed to a single dose of aflatoxin B-1 (AFB(1)) at 0, 50, 250, or 1,000 mu g/kg body weight (BW) or repeated dose of 0, 5, 10, 25, or 75 mu g/kg BW for up to 5 weeks. Biochemical and histological changes were assessed together with the formation of AFB(1)-lysine adduct (AFB-Lys) and liver foci positive for placental form glutathione S transferase (GST-P+). In single-dose protocol, serum aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) showed dose-related elevation, with maximal changes observed (>100-fold) at day 3 after treatment. Animals that received 250 mu g/kg AFB(1) showed concurrent bile duct proliferation, necrosis, and GST-P+ hepatocytes at 3 day, followed by liver GST-P+ foci appearance at 1 week. In repeated-dose protocol, bile duct proliferation and liver GST-P+ foci co-occurred after 3-week exposure to 75 mu g/kg AFB(1), followed by proliferation foci formation after 4 week and dramatic ALT, AST, and CK elevations after 5 weeks. Liver GST-P+ foci were induced temporally and in a dose-related manner. Serum AFB-Lys increased temporally at low doses (5-25 mu g/kg), and reached the maximum after 2-week exposure at 75 mu g/kg. This integrative study demonstrated that liver GST-P+ cells and foci are sensitive biomarkers for AFB(1) toxic effect and correlated with bile duct proliferation and biochemical alterations in F344 rats.