Physiologically based toxicokinetic modeling of secondary acute myelolytic leukemia.
Benzene, designated as environmental and occupational carcinogen and hematotoxin, has been associated with secondary leukemia. To develop a toxicokinetic model of AML, benzene can be used as leukemogenic agent. The aim of the present study was to optimize the dose, period and time of cumulative benzene exposure of Swiss Albino mice and to analyze survival rate; alteration in cell cycle regulation and other clinical manifestations in mice exposed to benzene vapour at a dose 300 ppm × 6 h/day × 5 days/week for 2 weeks, i.e., 9000(a)ppm cumulative dose. Analyzing physiological parameters like plasma enzyme profile, complete hematology (Hb %, RBC indices and WBC differentials), hematopoietic cells morphology, expression of cell cycle regulatory proteins, tissue histology and analysis of DNA fragmentation, optimum conditions were established. Down regulation of p53 and p21 and up regulation of CDK2, CDK4, CDK6, cyclin D1 and E in this exposed group were marked as the optimum conditions of cellular deregulation for the development of secondary AML. Elevated level of Plasma AST/ALT with corresponding changes in liver histology showing extended sinusoids within the hepatocytic cell cords in optimally exposed animals also confirmed the toxicokinetic relation of benzene with leukemia. It can be concluded from the above observations that the 9000(a)ppm exposed animals can serve as the induced laboratory model of secondary acute myeloid leukemia.
Cytogenetics & Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani 741235, Nadia, West Bengal, India.
Manas Kumar
MK
Mukhopadhyay
Cytogenetics & Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani 741235, Nadia, West Bengal, India. Electronic address: nath_debjani@yahoo.co.in.
Debjani
D
Nath
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001554:Benzene / Q000633:toxicity*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002273:Carcinogens / Q000633:toxicity*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002869:Chromosome Aberrations / Q000139:chemically induced; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D004909:Erythrocyte Indices / Q000187:drug effects; D006400:Hematocrit; D015470:Leukemia, Myeloid, Acute / Q000097:blood / Q000378:metabolism / Q000473:pathology; D007958:Leukocyte Count; D008099:Liver / Q000473:pathology; D008297:Male; D051379:Mice
D002273:Carcinogens; D018797:Cell Cycle Proteins; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001554:Benzene
Benzene exposure; Hematotoxicity; Secondary AML; Survival analysis