Acute exposure of human lung cells to 1,3-butadiene diepoxide results in G1 and G2 cell cycle arrest.
1,3-Butadiene (BD) causes genetic damage, including adduct formation, sister chomatid exchange, and point mutations. Previous studies have focused on the types of genetic damage and tumors found after long-term exposure of rodents to butadiene. This study examined the effect of the most active BD metabolite, butadiene diepoxide (BDO2), on cell cycle entry and progression in human lung fibroblasts (LU cells) with a normal diploid karyotype. Serum-arrested (G0) LU cells were exposed to BDO2 for 1 hr and stimulated to divide with medium containing 10% fetal bovine serum. The BDO2-treated LU cells were evaluated for cell cycle progression, nuclear localization of arrest mediators, mitotic index, and cellular proliferation. The BDO2-treated cells demonstrated a substantial inhibition of cell proliferation when treated with 100 microM BDO2 for 1 hr. No appreciable levels of apoptosis or mitotic figures were observed in the BDO2-treated cells through 96 hr posttreatment. Flow cytometric analysis revealed that the lack of proliferation in BDO2-treated LU cells was related to G1 arrest in about half of the cells and a delayed progression through S and G2 arrest in nearly all of the remaining cells. Both G1 and G2 arrest were prolonged and only a very small percentage of BDO2-treated cells were eventually able to replicate. Increased nuclear localization of both p53 and p21(cip1) was observed in BDO2-treated cells, suggesting that the cell cycle arrest was p21(cip1)-mediated. These results demonstrate that BDO2 induces cell cycle perturbation and arrest even with short-term exposure that does not produce other pathologic cellular effects.
Schmiederer
Michael
M
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas 77555, USA.
Knutson
Eugene
E
Muganda
Perpetua
P
Albrecht
Thomas
T
D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000032:analysis / Q000096:biosynthesis; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004305:Dose-Response Relationship, Drug; D004852:Epoxy Compounds / Q000633:toxicity*; D005347:Fibroblasts; D016193:G1 Phase / Q000187:drug effects; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008940:Mitotic Index; D009153:Mutagens / Q000633:toxicity*; D023382:Toxicity Tests, Acute; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004852:Epoxy Compounds; D009153:Mutagens; D016159:Tumor Suppressor Protein p53; C007366:diepoxybutane