Molecular Dosimetry of 1,2,3,4-Diepoxybutane–Induced DNA-DNA Cross-Links in B6C3F1 Mice and F344 Rats Exposed to 1,3-Butadiene by Inhalation

Abstract

Abstract1,3-Butadiene (BD) is an important industrial and environmental chemical classified as a human carcinogen based on epidemiologic studies in occupationally exposed workers and animal studies in laboratory rats and mice. BD is metabolically activated to three epoxides that can react with nucleophilic sites in biomolecules. Among these, 1,2,3,4-diepoxybutane (DEB) is considered the ultimate carcinogen due to its high genotoxicity and mutagenicity attributed to its ability to form DNA-DNA cross-links. Our laboratory has developed quantitative high-performance liquid chromatography-MESI + -tandem mass spectrometry methods for two DEB-specific DNA-DNA cross-links, 1,4-bis-(guan-7-yl)-2,3-butanediol (bis-N7G-BD) and 1-(guan-7-yl)-4-(aden-1-yl)-2,3-butanediol (N7G-N1A-BD). This report describes molecular dosimetry analysis of these adducts in tissues of B6C3F1 mice and F344 rats exposed to a range of BD concentrations (0-625 ppm). Much higher (4-to 10-fold) levels of DEB-DNA crosslinks were observed in mice compared with rats exposed to the same BD concentrations. In both species, bis-N7G-BD levels were 1.5-to 4-fold higher in the liver than in other tissues examined. Interestingly, tissues of female animals exposed to BD contained higher concentrations of bis-N7G-BD adducts than tissues of male animals, which is in accord with previously reported differences in tumor incidence. The molecular dosimetry data presented herein suggest that species and gender differences observed in BD-induced cancer are directly related to differences in the extent of BD metabolism to DEB. Furthermore, a rat model of sensitivity to BD may be more appropriate than a mouse model for assessing human risk associated with BD exposure, because rats and humans seem to be similar with respect to DEB formation.

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

“…These electrophilic epoxides are held responsible for the carcinogenicity and mutagenicity of BD because of their propensity to react with DNA to form covalent nucleobase adducts [15–19], which can cause DNA polymerase errors [20–23]. Sensitive and specific quantitative methods for BD-DNA adducts in vivo are needed because they can be used in human cancer risk assessment [24, 25].…”

NanoHPLC-nanoESI+-MS/MS Quantitation of Bis-N7-Guanine DNA–DNA Cross-Links in Tissues of B6C3F1 Mice Exposed to subppm Levels of 1,3-Butadiene

“…20–25 DEB-specific bifunctional DNA adducts have been quantified in tissues of laboratory rats and mice that were exposed to 6.25–625 ppm of BD by inhalation. 26 Among DEB-DNA adducts, bis -N7G-BD were present at the highest concentration (3.95 ± 0.89 adducts/10 7 nucleotides (nts) in livers of mice exposed to 625 ppm BD), followed by N7G-N1A-BD(0.27 ± 0.07 adducts/10 7 nts) and 1,N 6 -HMHP-dA (0.044 ± 0.008 adducts/10 7 nts). 23;26 …”

Microdoses Levels of Butadiene Diepoxide (BDO<sub>2</sub>) Induced Toxicity in Prostate Cancer Cells

“…The reactive intermediates 1,2-epoxy-3-butene, 1,3,4-diepoxybutane, and 3,4-epoxy-1, 2-butanediol all play significant roles in the toxicity of 1,3-butadiene. These metabolites are capable of reacting with macromolecules such as DNA to induce a variety of genotoxic effects in mice and rats as well as in human cells in vitro [1][2][3][4][5][6]. The metabolism and genetic toxicity of 1,3-butadiene and its oxidative metabolites in humans and rodents is well established.…”