Integrative toxicopathological evaluation of aflatoxin B exposure in F344 rats.
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abstract
In this study, male F344 rats were orally exposed to a single dose of aflatoxin B (AFB) at 0, 50, 250, or 1,000 g/kg body weight (BW) or repeated dose of 0, 5, 10, 25, or 75 g/kg BW for up to 5 weeks. Biochemical and histological changes were assessed together with the formation of AFB1-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 g/kg AFB 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 g/kg AFB, 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 g/kg), and reached the maximum after 2-week exposure at 75 g/kg. This integrative study demonstrated that liver GST-P cells and foci are sensitive biomarkers for AFB toxic effect and correlated with bile duct proliferation and biochemical alterations in F344 rats.
