Chemical suppression of a subpopulation of primitive hematopoietic progenitor cells: 1,3-butadiene produces a hematopoietic defect similar to steel or white spotted mutations in mice.
Chronic exposure of mice to 1,3-butadiene produces a macrocytic-megaloblastic anemia, thymic hypoplasia, and an increased incidence of T-cell lymphoma/leukemia. This is reminiscent of pathologies observed in mice bearing mutations at the W and Sl loci, which are deficient in c-kit and c-kit ligand (CKL), respectively. The influence of 3,4-epoxybutene (EB), the primary metabolite of 1,3-butadiene, on the colony-forming response of hematopoietic progenitor cells (HPCs) from C57BL/6, Sl, and W mice was investigated in order to elucidate the role of altered HPC regulation in the pathogenesis of 1,3-butadiene toxicity. EB pretreatment suppressed interleukin 3 colony formation and abrogated CKL synergism of the granulocyte-macrophage/colony-stimulating factor (GM-CSF) response in C57BL/6 cells, had no effect on colony formation induced by GM-CSF or granulocyte/colony-stimulating factor (G-CSF) alone, and failed to suppress CKL-induced synergism of the G-CSF response. Experiments conducted with cells from Sl and W mice revealed that they lack the same primitive HPC targeted by EB. EB pretreatment in vitro and butadiene exposure in vivo mimic hematopoietic defects seen in W and Sl mice, suggesting that the pleotypic pathologies encountered in these murine models may be largely due to a common defect in primitive HPCs. Susceptibility to EB appears to define a functional subpopulation of primitive HPCs and illustrates that differences observed in the susceptibility of specific cytokine responses to chemical/drug exposure may provide a valuable tool for characterizing functional subpopulations of HPCs.
Colagiovanni
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Molecular Toxicology and Environmental Health Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver 80262.
Stillman
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Irons
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D000818:Animals; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology*; D002070:Butadienes / Q000633:toxicity*; D003114:Colony-Forming Units Assay; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D016298:Hematopoietic Cell Growth Factors / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D007377:Interleukin-3 / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D009153:Mutagens / Q000633:toxicity*; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit; D011519:Proto-Oncogenes; D011994:Recombinant Proteins / Q000494:pharmacology; D019089:Stem Cell Factor
D002070:Butadienes; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D009153:Mutagens; D011518:Proto-Oncogene Proteins; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; C031763:1,3-butadiene