An unexpected butadiene diolepoxide-mediated genotoxicity implies alternative mechanism for 1, 3-butadiene carcinogenicity. (March 2021)

• Record Type: Journal Article
• Authors: Nakamura, Jun; Carro, Sujey; Gold, Avram; Zhang, Zhenfa
• Is Part Of: Chemosphere. Volume 266(2021)
• Publication Date: 2021-03
• Subjects: Butadiene -- EBD -- DEB -- FANCD2 -- DSB -- Alcohol dehydrogenase; Pollution -- Periodicals; Pollution -- Physiological effect -- Periodicals; Environmental sciences -- Periodicals; Atmospheric chemistry -- Periodicals; 551.511
• DOI: 10.1016/j.chemosphere.2020.129149
• Languages: English
• ISSNs: 0045-6535

Abstract

Abstract: 1, 3-Butadiene (BD) is abundant in combustion products such as cigarette smoke. While BD has been classified as a known human carcinogen, a long-standing question is the identity of the ultimate carcinogenic metabolite in humans. We hypothesize that 3, 4-epoxybutane-1, 2-diol (EBD) may play a critical role in human carcinogenesis due to its high bioavailability. We utilized a differential toxicity assay for BD metabolites and newly synthesized EBD analogs in a series of isogenic chicken cells lacking specific DNA repair proteins to address the mode of action of BD genotoxicity and infer a mode of action. Surprisingly, as with the diepoxide 1, 2:3, 4-diepoxybutane (DEB), the monoepoxide EBD showed remarkable toxicity to cells deficient in Fanconi anemia ( FANC ) genes. This observation suggests that EBD may be transformed into a bifunctional metabolite and forms interstrand cross-links. EBD and its analog with a hydroxy substituent at C1 were found to be highly toxic to FANCD2 -deficient chicken and human cells. The Results suggest that EBD may be transformed to a bifunctional epoxy aldehyde, perhaps by alcohol dehydrogenase, to which the observed FANC sensitivity could be attributed. The implications of this study are very important in considering mechanisms by which EBD may cause leukemia and lymphoma in humans exposed to BD. Graphical abstract: Image 1 Highlights: Unlike EB, both DEB and EBD caused DNA damage required various DNA repair pathways. Surprisingly, as with DEB, EBD caused remarkable toxicity in FANC-deficient cells. Cells lacking FANC gene were sensitive to OEO1, an EBD analog with –OH moiety at C1. OEO1 induced more double strand breaks in the FANC ko cells over the wild-type cells. EBD likely induces inter-strand crosslink (ICL) after metabolic activation by ADH.