Acute exposure of human lung cells to 1,3-butadiene diepoxide results in G1 and G2 cell cycle arrest

Abstract

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.

Mechanism of diepoxybutane‐induced p53 regulation in human cells

“…The determination of the mechanism of DEB-induced p53 accumulation contributes toward the understanding of the molecular toxicity of DEB and butadiene. Since DEB-induced p53-mediated apoptosis in human TK6 lymphoblasts has previously been described [19,39,73], these studies are a necessary prerequisite to the understanding of the role p53 plays in DEB-induced apoptosis in this experimental system as well as other DEB systems.…”

“…Our laboratory previously reported the induction of elevated p53 levels in TK6 cells undergoing DEB-induced apoptosis [19]. Schmiederer et al [39] reported an increase in the percentage of p53-positive nuclei in human lung cells after treatment with DEB. Sjoblom et al [40], however, found no evidence of p53 elevation in rat testis exposed to DEB.…”

Desmosomes as Signaling Hubs in the Regulation of Cell Behavior

“…The overall rate of protein synthesis has to keep pace with the proliferation rate to maintain cell size and functionality (Miettinen et al, 2019). Therefore, cell proliferation strongly depends on the synthesis of new proteins (Pardee, 1989;Polymenis and Aramayo, 2015). This is supported by reports showing that modifications of the translation machinery can affect cell proliferation rates and that deregulation of protein synthesis can be a driver of cell transformation (Silvera et al, 2010;Truitt and Ruggero, 2016).…”

Pulmonary Toxicity and Environmental Contamination: Radicals, Electron Transfer, and Protection by Antioxidants

“…In one investigation this chemical was found to cause genetic damage, mutations, and cell cycle perturbation (Schmiederer et al 2005) . The diepoxide of 1,3-butadiene appears to be the most active metabolite and can produce harmful adducts by undergoing nucleophilic reactions with amines in nucleic acids and proteins.…”