Integrative toxicological evaluation of aflatoxin B1 exposure in Fischer 344 rats and biomarker based exposure assessment of aflatoxin B1 in human populations
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Aflatoxin B1 (AFB1) is a potent toxic and carcinogenic mycotoxin, which can adversely affect the immune system in animals and humans. Traditional toxicological evaluation of AFB1 has focused on alternations in the histopathological, serum biochemical, and immunohistological aspects, an integration of molecular biomarkers (such as AFB1-lysine adduct, AFB-Lys) data into these changes might provide useful information for a risk assessment purpose. Biomarkers based AFB1 exposure or risk assessment is currently favored copmared to food survey based exposure assessment. A rapid non-antibody based method for measuring serum AFB-Lys adduct in animals and humans was developed. The solid-phase-extraction based high performance liquid chromatography (HPLC) method has a limit of detection of 0.4 pg/mg albumin and recovery rates of 72.0-94.4%. The elimination kinetics of serum AFB-Lys and the toxicities of AFB1 in F344 rats were further studied using single- (50-1000 µg/kg b.w.) and repeated-dose (5-75 µg/kg b.w./day) designs. Several kinetic parameters of serum AFB-Lys were determined: the peak time (4 h), the half-life (2.31 days) and a conversion ratio of 1.12-1.98% at 24 h, as estimated by a physiologically based pharmacokinetic model. A linear increase in the adduct level was found only after repeated low doses (5-25 µg/kg). Liver damage, bile duct proliferation and necrosis, were most prominent at 3 days after a single dose (≥ 25 μg/kg), correlating with clinical biochemistry changes (ALT and AST) and liver glutathione S transferase placental form positive (GST-P+) hepatocytes formation. Repeated treatment induced concurrent appearance of liver GST-P+ foci and bile duct proliferation after 3 weeks. One-week treatment decreased the percentages of splenic CD4+ and CD8+ T cells as well as their production of IL-4 and IFN-γ (≥ 25 μg/kg), and TNF-α production by CD3-CD8a+NK cells (75 μg/kg). Five-week treatment increased IFN-γ production by CD4+ cells (25 μg/kg), and TNF-α production by NK cells (75 μg/kg) and inhibited IL-4 production by CD4+ and CD8+ cells, suggesting an inflammatory response. These results provide an integrative toxicopathologial evaluation of AFB1 exposure in F344 rats. Human exposures were also assessed based on the measurement of serum AFB-Lys levels. The rank from high exposure to low is: West Africa countries (Ghana and Burkina Faso) > Southeast Countries (China and Malaysia) > Uganda > Haiti > United States. Currently, AFB1 exposure remains prevalent in West Africa and Southeast Asia (detection rates > 90%), which warrants urgent and effective interventions. These data may facilitate human aflatoxin exposure assessment and improve our understanding of how AFB1 can affect immune response.