title: Chronic radiation-induced alteration in hematopoietic repair during preclinical phases of aplastic anemia and myeloproliferative disease: assessing unscheduled DNA synthesis responses.
abstract: Protracted, low-daily-dose gamma-ray exposure (3.8-7.5 cGy/day) segregates canines into separate survival- and pathology-based subgroups by the early elicitation of distinct, repair-mediated hemopathological response pathways. In this study, we verified the blood and marrow responses of two major subgroups prone to either aplastic anemia or myeloproliferative disease, along with two variants, and extended our analyses of hematopoietic repair to include studies of DNA repair in bone marrow blasts using an autoradiographically based unscheduled DNA synthesis (UDS) assay. The myeloproliferative disease-prone subgroup exhibited extended survival (> 200 days), related to partial, gradual restoration of blood leukocyte, platelet, and marrow progenitor levels following an initial phase of acute suppression. Marrow blasts taken during the restoration phase showed expanded and qualitatively modified UDS relative to marrow blasts of age-matched control animals. The amount of UDS per blast (signal strength) increased significantly, as did the number of UDS-positive cells and their sensitivities to high-dose UV induction and 1-beta-D-arabinofuranosylcytosine chemical inhibition. A nonevolving myeloproliferative disease-prone variant having prolonged survival (> 200 days) and restored blood cells and marrow progenitor levels also had marrow blasts with expanded UDS responses, but these were uniquely evoked by low (but not high) doses of UV inducer. The aplastic anemia-prone subgroup was characterized by short survival (< 200 days), progressive decline (without restoration) in all measured blood and marrow compartments, and largely nonsignificant changes in UDS responses of marrow blasts. A variant of this aplastic anemia-prone subgroup (with comparable short survival due to markedly ineffective hematopoiesis, but expressing select preleukemic features) exhibited reduced numbers (relative to age-matched controls) of highly responsive, UDS-positive marrow blasts (in terms of UDS signal strength and increased to sensitivity 1-beta-D-arabinofuranosylcytosine-induced UDS inhibition). From these observations we conclude that: (a) the UDS response of marrow blasts, a correlate of hematopoietic progenitorial repair, is altered differentially within selected subgroups of animals under chronic radiation exposure; and (b) the nature of altered UDS repair response patterns appears to be largely related to the preclinical status/predisposition of the individual animal and thus may provide prognostically useful information in the clinical monitoring of chronically irradiated individuals with minimal but evolving hematological disease.
authors.affiliation: Biological and Medical Research Division, Argonne National Laboratory, Illinois 60439.
authors.forename: T M
authors.initials: TM
authors.lastname: Seed
authors.forename: S M
authors.initials: SM
authors.lastname: Meyers
mesh_terms: D000741:Anemia, Aplastic / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D001345:Autoradiography; D001853:Bone Marrow / Q000473:pathology; D002453:Cell Cycle / Q000528:radiation effects; D003037:Cobalt Radioisotopes; D004247:DNA / Q000096:biosynthesis*; D004260:DNA Repair / Q000528:radiation effects*; D004285:Dogs; D004906:Erythrocyte Count / Q000528:radiation effects; D005260:Female; D005720:Gamma Rays; D006410:Hematopoiesis / Q000528:radiation effects*; D006412:Hematopoietic Stem Cells / Q000473:pathology* / Q000528:radiation effects*; D007958:Leukocyte Count / Q000528:radiation effects; D008297:Male; D009196:Myeloproliferative Disorders / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D010976:Platelet Count / Q000528:radiation effects; D013936:Thymidine / Q000378:metabolism; D014316:Tritium; D014466:Ultraviolet Rays
chemical_list: D003037:Cobalt Radioisotopes; D014316:Tritium; D004247:DNA; D013936:Thymidine