Integrative toxicopathological evaluation of aflatoxin B₁ exposure in F344 rats

Toxicol Pathol. 2013;41(8):1093-105. doi: 10.1177/0192623313477256. Epub 2013 Feb 19.

Abstract

In this study, male F344 rats were orally exposed to a single dose of aflatoxin B₁ (AFB₁) at 0, 50, 250, or 1,000 µg/kg body weight (BW) or repeated dose of 0, 5, 10, 25, or 75 µg/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 µg/kg AFB₁ 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 µg/kg AFB₁, 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 µg/kg), and reached the maximum after 2-week exposure at 75 µg/kg. This integrative study demonstrated that liver GST-P⁺ cells and foci are sensitive biomarkers for AFB₁ toxic effect and correlated with bile duct proliferation and biochemical alterations in F344 rats.

Keywords: aflatoxin B1; aflatoxin B1-lysine; biochemistry.; histology; placental form glutathione S transferase.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aflatoxin B1 / blood
  • Aflatoxin B1 / metabolism
  • Aflatoxin B1 / toxicity*
  • Analysis of Variance
  • Animals
  • Bile Ducts / chemistry
  • Bile Ducts / drug effects
  • Bile Ducts / pathology
  • Blood Chemical Analysis
  • Body Weight / drug effects
  • Glutathione Transferase / metabolism
  • Histocytochemistry
  • Liver / chemistry
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Lysine / blood
  • Lysine / metabolism
  • Male
  • Random Allocation
  • Rats
  • Rats, Inbred F344
  • Toxicity Tests / methods*

Substances

  • aflatoxin B1-lysine adduct
  • Aflatoxin B1
  • Glutathione Transferase
  • Lysine