Butadiene diolepoxide- and diepoxybutane-derived DNA adducts at N7-guanine: a high occurrence of diolepoxide-derived adducts in mouse lung after 1,3-butadiene exposure.
Pertti Koivisto,Ilkka Kilpeläinen,Ilpo Rasanen,Ilse-Dore Adler,Francesca Pacchierotti,Kimmo Peltonen +5 more
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TL;DR: In vivo, 98% of N7-dGMP alkylation after BD exposure is derived from BDE, and approximately 2% of the adducts were derived from DEB and BMO, and the data presented in this paper indicate that in vivo, the N7-(2,3, 4-trihydroxybutan-1-yl)-dG MPs can be used as a marker of BDE exposure.
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Abstract: Butadiene (BD) is a high production volume chemical and is known to be tumorigenic in rodents BD is metabolized to butadiene monoepoxide (BMO), diepoxybutane (DEB) and butadiene diolepoxide (BDE) These epoxides are genotoxic and alkylate DNA both in vitro and in vivo, mainly at the N7 position of guanine In this study, a 32P-post-labeling/thin-layer chromatography (TLC)/high-pressure liquid chromatography (HPLC) assay for BDE and DEB adducts at the N7 of guanine was developed and was used in determining the enantiomeric composition of the adducts and the organ dose of BD exposure in lung Exposure of 2'-deoxyguanosine (dGuo), 2'-deoxyguanosine-5'-phosphate (5'-dGMP) and 2'-deoxyguanosine-3'-phosphate (3'-dGMP) to racemic BDE followed by neutral thermal hydrolysis gave two products (products 1 and 2) that were identified by MS and UV and NMR spectroscopy as a diastereomeric pair of N7-(2,3,4-trihydroxybutan-1-yl)-guanines Exposure of dGuo nucleotides to RR/SS DEB (also referred to as dl DEB) followed by thermal depurination resulted in a single product coeluting with the BDE product 1 If the reaction mixture of BDE and 5'-dGMP was analyzed by HPLC before hydrolysis of the glycosidic bond, four major nucleotide alkylation products (A, B, C and D) with identical UV sepectra were detected The products were isolated and hydrolyzed, after which A and C coeluted with product 1 and B and D coeluted with the product 2 The major adduct of DEB-exposed 5'-dGMP was N7-(2-hydroxy-3,4-epoxy-1-yl)-dGMP (product E) A 32P-post-labeling assay was used to detect BDE- and DEB-derived N7-dGMP adducts in DNA Levels of adducts increased with a dose of BDE and DEB and exhibited a half life of 30 +/- 3 (r = 098) and 31 +/- 4 h (r = 095), respectively Incubation of DEB-modified DNA at 37 degrees C at neutral pH for up to 142 h did not lead to an increase of N7-(2,3,4-trihydroxybutan-1-yl)-dGMP in the DNA These observations led to the conclusion that the N7-(2,3, 4-trihydroxybutan-1-yl)-dGMP adducts in DNA can be used as a marker of BDE exposure and that N7-(2-hydroxy-3,4-epoxy-1-yl)-dGMP adducts are related to DEB exposure Dose-related levels of BDE- and DEB-derived adducts were detected in lungs of mice inhaling butadiene Most of the N7-dGMP adducts (73%; product D) were derived from the 2R-diol-3S-epoxide of 1,3-butadiene The data presented in this paper indicate that in vivo, 98% of N7-dGMP alkylation after BD exposure is derived from BDE, and approximately 2% of the adducts were derived from DEB and BMO
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Dose-dependent transitions in mechanisms of toxicity: case studies.
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Biomarkers for assessing occupational exposures to 1,3-butadiene.
Richard J. Albertini,Radim J. Sram,Pamela M. Vacek,Jeremiah Lynch,Michael Wright,Janice A. Nicklas,Peter J. Boogaard,Rogene F. Henderson,James A. Swenberg,Ad D. Tates,Jonathan B. Ward +10 more
TL;DR: Urinary M1 and M2 metabolites and HBVal and THBVal hemoglobinAdducts were all significantly correlated with BD exposure levels, with adducts being the most highly associated.
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TL;DR: It is concluded that the amount of di-(guanin-7-yl) derivative formed by alkylation of DNA is the best measure of the extent of interstrand cross-linking, since the result with E. coli DNA shows that the majority of the product of this type results from such cross- linking, although the possibility that a smaller proportion could be produced by intrastrand reaction cannot be ruled out.
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Mutagenicity of butadiene and its epoxide metabolites: I. Mutagenic potential of 1,2-epoxybutene, 1,2,3,4-diepoxybutane and 3,4-epoxy-1,2-butanediol in cultured human lymphoblasts.
J.E. Cochrane,Thomas R. Skopek +1 more
TL;DR: The mutagenic potential of the epoxide metabolites of butadiene (BD) was measured at the tk and hprt loci in TK6 human lymphoblastoid cells, and the ability of DEB to induce deletions may be related to its ability to form DNA-DNA and DNA-protein cross-links.
214
A follow-up study of synthetic rubber workers
Elizabeth Delzell,Nalini Sathiakumar,Mary Hovinga,Maurizio Macaluso,Jim A. Julian,Rodney R. Larson,Philip A. Cole,David C.F. Muir +7 more
TL;DR: Exposures in the SBR industry cause leukemia, with more than expected leukemia deaths occurred in the overall cohort and among ever hourly subjects and among subjects in polymerization, maintenance labor, and laboratories.
188
Mutagenicity of butadiene and its epoxide metabolites. II: Mutational spectra of butadiene, 1,2-epoxybutene and diepoxybutane at the hprt locus in splenic T cells from exposed B6C3F1 mice
J.E. Cochrane,Thomas R. Skopek +1 more
TL;DR: The mutagenic potential and mutational spectra of butadiene (BD), 1,2-epoxybutene (EB), and diepoxybutane (DEB) were determined in splenic T cells from exposed B6C3F1 mice, suggesting that these epoxide agents may be working through a similarmutagenic mechanism.
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