Persistence and Repair of Bifunctional DNA Adducts in Tissues of Laboratory Animals Exposed to 1,3-Butadiene by Inhalation

Abstract

1,3-butadiene (BD) is an important industrial and environmental chemical classified as a human carcinogen. The mechanism of BD-mediated cancer is of significant interest because of the widespread exposure of humans to BD from cigarette smoke and urban air. BD is metabolically activated to 1,2,3,4-diepoxybutane (DEB), which is a highly genotoxic and mutagenic bis-alkylating agent believed to be the ultimate carcinogenic species of BD. We have previously identified several types of DEB-specific DNA adducts, including bis-N7-guanine cross-links (bis-N7-BD), N6-adenine-N7-guanine cross-links (N6A-N7G-BD), and 1,N6-dA exocyclic adducts. These lesions were detected in tissues of laboratory rodents exposed to BD by inhalation (Goggin et al. Cancer Res. 2009;69:2479–2486). In the present work, persistence and repair of bifunctional DEB-DNA adducts in tissues of mice and rats exposed to BD by inhalation were investigated. The half-lives of the most abundant cross-links, bis-N7G-BD, in mouse liver, kidney, and lungs were 2.3–2.4 days, 4.6–5.7 days, and 4.9 days, respectively. The in vitro half-lives of bis-N7G-BD were 3.5 days (S,S isomer) and 4.0 days (meso isomer) due to their spontaneous depurination. In contrast, tissue concentrations of the minor DEB adducts, N7G-N1A-BD and 1,N6-HMHP-dA, remained essentially unchanged during the course of the experiment, with an estimated t 1/2 of 36–42 days. No differences were observed between DEB-DNA adduct levels in BD-treated wild type mice and the corresponding animals deficient in methyl purine glycosylase or the Xpa gene. Our results indicate that DEB-induced N7G-N1A-BD and 1,N6-HMHP-dA adducts persist in vivo, potentially contributing to mutations and cancer observed as a result of BD exposure.

NanoLC/ESI+ HRMS3 Quantitation of DNA Adducts Induced by 1,3-Butadiene

“…EB-GII adduct concentrations in rat tissues gradually decreased 1, 3 and 6 days post exposure to BD (Figure 5A). Data processing via first order kinetics analysis yielded the EB-GII half-life in rat liver DNA as 2.20 ± 0.12 days (Figure 5B), which is significantly shorter than the half-life of structurally analogous N7-THBG adducts in vivo (t 1/2 = 3.6–4.0 days) [16]. …”

“…The animals were sacrificed either immediately at the end of the exposure period or 1, 3, or 6 days post exposure as reported previously [16]. Liver tissue was collected, flash frozen, and shipped to the University of MN on dry ice, where they were stored at − 80 °C until DNA extraction.…”

Replication past the Butadiene Diepoxide-Derived DNA Adduct S-[4-(N6-Deoxyadenosinyl)-2,3-dihydroxybutyl]glutathione by DNA Polymerases

“…14,15 Many DNA adducts derived from DEB have been reported, including mono-adducts and DNA-DNA intra- and inter-crosslinks adducts (≥ 25 adducts, with the number being even higher when stereochemistry is considered), 6–21 and some of these adducts have been found in vivo . 16,17 …”

Introduction and Conclusion: The Rationale for Thresholds for Genotoxic Carcinogens

“…Recently Goggin et al 46 determined the persistence and repair of several types of butadiene-specific DNA adducts, which results from the metabolic activation of butadiene to 1,2,3,4-di-epoxybutane (DEB). These lesions were detected in tissues of laboratory rodents exposed to butadiene (BD) by inhalation.…”