Toxicity of 1,3-butadiene to bone marrow mimics haematopoietic defects observed in mice bearing white spotted or steel mutations.
In order to clarify the role of haematopoietic stem and progenitor cells in bone-marrow toxicity induced by 1,3-butadiene, we examined the effects of its primary metabolite, 3,4-epoxybutene, on the cytokine response of these cells from C57B1/6 mice. Pretreatment with epoxybutene in vitro suppressed recombinant interleukin-3-stimulated colony formation in haematopoietic stem and progenitor cells, had no effect on colony formation with recombinant granulocyte/macrophage-colony stimulating factor or recombinant granulocyte-colony stimulating factor alone, and completely blocked the synergism of recombinant c-kit ligand and granulocyte/macrophage colony stimulating factor. Butadiene-induced leukaemogenesis, macrocytic anaemia and thymic atrophy are reminiscent of the conditions observed in mice bearing mutations at the W or Sl loci, which are deficient in the c-kit receptor and c-kit ligand, respectively. Epoxybutene did not suppress colony formation in cells from W/Wv and Sl/Sld mice, consistent with the absence of the population of haematopoietic stem and progenitor cells that is susceptible to butadiene in those genetically deficient strains. These findings indicate that the pathological conditions observed after either exposure to butadiene or W or Sl mutations are due to a functional defect in a subpopulation of primitive haematopoietic stem and progenitor cells that plays a major role in the pathogenesis of both T-cell leukaemia/lymphoma and anaemia in the mouse.
Irons
R D
RD
Molecular Toxicology and Environmental Health Sciences Program, School of Pharmacy, University of Colorado Health Sciences Center, Denver.
Colagiovanni
D B
DB
Stillman
W S
WS
D000818:Animals; D001853:Bone Marrow / Q000187:drug effects*; D002070:Butadienes / Q000633:toxicity*; D002478:Cells, Cultured; D003114:Colony-Forming Units Assay; D004852:Epoxy Compounds / Q000633:toxicity; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009153:Mutagens / Q000633:toxicity*; D011994:Recombinant Proteins; D019089:Stem Cell Factor
D002070:Butadienes; D004852:Epoxy Compounds; D016298:Hematopoietic Cell Growth Factors; D007377:Interleukin-3; D009153:Mutagens; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016179:Granulocyte Colony-Stimulating Factor; C024370:3,4-epoxy-1-butene; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; C031763:1,3-butadiene