Implications of hemopoietic progenitor cell kinetics and experimental leukemogenesis: Relevance to Gompertzean mortality as possible hematotoxicological endpoint.
OBJECTIVE
The aim of this study is to investigate a possible implication in cell kinetics of the hematopoietic progenitors to the experimental leukemogenesis to elucidate the relevance of various leukemic mode of action to Gompertzean survival curves, a new parameter based on the lifespan.


METHODS
Mice, C3H/He, and C57BL/6 strain, male and female, with or without genetic modifications, e.g., p53-deficiency or thioredoxin overexpression were used in the present hemopoietic stem/progenitor research, radiation- or benzene-induced leukemogenesis followed by histopathological examination. A lethal dose of radiation for bone marrow transplantation, and a graded increased dose up to 5 Gy of x-rays for induction of hematopoietic malignancies were given. For caloric restriction studies, 77 kcal/week was maintained in accordance to different restriction-timing. For assays of hematopoietic colonization, colony-forming unit spleen and colony-forming unit granulocyte macrophage were evaluated. Hematopoietic progenitor cell-specific kinetics were studied by continuous labeling of bromodeoxyuridine for cycling cells, followed by ultraviolet (UV) exposure and hemopoietic colonization (bromodeoxyuridine UV [BUUV] method). Various experimental survival curves were applied to a mathematical analysis by Gompertz-Makeham law of mortality.


RESULTS
Referring current authors' studies on leukemogenesis induced by ionizing radiation and benzene exposure, implications of hematopoietic progenitor cell kinetics to the experimental leukemogenesis were evaluated by means of a novel experimental tool, the BUUV method. Comparative studies to elucidate relevancies of these data, including two prevention studies, one on caloric restriction and the other on antioxidative thioredoxin overexpression, to those Gompertzean survival curves of experimental animals were analyzed.


CONCLUSIONS
The Gompertzean expression may elucidate an appropriate toxicological endpoint for evaluating the effect of radiation and/or benzene-exposure on the lifespan and its modification by various experimental preventive measures.
Hirabayashi
Yoko
Y
Cellular and Molecular Toxicology Division, Center for Biological Safety and Research, National Institute of Health Sciences, Tokyo, Japan. yokohira@nihs.go.jp
Inoue
Tohru
T
D000818:Animals; D001554:Benzene / Q000633:toxicity*; D016026:Bone Marrow Transplantation; D031204:Caloric Restriction; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D023381:Endpoint Determination; D005260:Female; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007700:Kinetics; D007953:Leukemia, Radiation-Induced / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D008954:Models, Biological; D014410:Tumor Stem Cell Assay
D001554:Benzene