Oncogenic and tumor suppressor pathways in subchronic aflatoxicosis in rats: Association with serum and urinary aflatoxin exposure biomarkers

• Published in: Food and chemical toxicology 2021-07, Vol.153, p.112263, Article 112263
• Main Authors: Apolinário, Letícia A., Ramalho, Leandra N.Z., Moosavi, Motahareh Hashemi, Jager, Alessandra V., Augusto, Marlei J., Trotta, Maurício R., Petta, Tânia, Khaneghah, Amin Mousavi, Oliveira, Carlos A.F., Ramalho, Fernando S.
• Format: Article
• Language: English
• Subjects: AFB1; AFB1-Lysine; AFB1-N7-guanine; Aflatoxin B1 - analogs & derivatives; Aflatoxin B1 - blood; Aflatoxin B1 - metabolism; Aflatoxin B1 - toxicity; Aflatoxin B1 - urine; Aflatoxin M1 - urine; AFM1; Alanine Transaminase - metabolism; Animals; Aspartate Aminotransferases - metabolism; beta Catenin - metabolism; Biomarkers; Biomarkers - blood; Biomarkers - urine; Cyclin D1; Cyclin D1 - metabolism; Cyclin-Dependent Kinase Inhibitor p27 - metabolism; Gene Expression - drug effects; Guanine - analogs & derivatives; Guanine - urine; Hepatocytes - drug effects; Hepatotoxicity; Liver - drug effects; Liver - pathology; Lysine - blood; Male; Precancerous Conditions - chemically induced; Precancerous Conditions - pathology; Rats; Rats, Wistar; Retinoblastoma; Retinoblastoma Protein - metabolism; β-catenin
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2021.112263

In this study, the changes in oncogenic and tumor suppressor signaling pathways in liver and their association with serum and urinary biomarkers of aflatoxin exposure were evaluated in Wistar rats fed diets containing aflatoxin B1 (AFB1) for 90 days. Rats were divided into four groups (n = 15 per group) and assigned to dietary treatments containing 0 (control), 50 (AFB50), 100 (AFB100) and 200 μg AFB1 kg−1 diet (AFB200). Multiple preneoplastic foci of hepatocytes marked with glutathione-S-transferase-placental form (GST-P) were identified in AFB100 and AFB200 groups. Hepatocellular damage induced by AFB1 resulted in overexpression of cyclin D1 and β-catenin. The liver expression of retinoblastoma (Rb) and p27Kip1 decreased in AFB100 and AFB200 groups, confirming the favorable conditions for neoplastic progression to hepatocellular carcinoma. All samples from rats fed AFB1-contaminated diets had quantifiable AFB1-lysine in serum or urinary AFM1 and AFB1-N7-guanine, with mean levels of 20.42–50.34 ng mL−1, 5.31–37.68 and 39.15–126.37 ng mg−1 creatinine, respectively. Positive correlations were found between AFB1-lysine, AFM1 or AFB1-N7-guanine and GST-P+, β-catenin+ and cyclin D1+ hepatocytes, while Rb + cells negatively correlated with those AFB1 exposure biomarkers. The pathways evaluated are critical molecular mechanisms of AFB1-induced hepatocarcinogenesis in rats. [Display omitted] •Oncogenic and tumor suppressor pathways in liver of rats fed AFB1 were investigated.•AFB1-induced hepatocyte damage resulted in overexpression of cyclin D1 and β-catenin.•Rats fed 200 μg kg−1 AFB1 had reduced liver expression of retinoblastoma and p27Kip1.•Oncogenic markers correlated with serum AFB1-lysine and urinary AFM1 and AFB1-N7-guanine.•The pathways evaluated are mechanisms of AFB1-induced hepatocarcinogenesis in rats.