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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

¹ Masonic Cancer Center and Department of Medicinal Chemistry, University of Minnesota, Minneapolis, Minnesota; ² University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; ³ Lovelace Respiratory Research Institute, Albuquerque, New Mexico; and ⁴ BioMosaics, Inc., Burlington, Vermont

Requests for reprints: Natalia Tretyakova, University of Minnesota Cancer Center, 760E CCRB, 806 Mayo, 420 Delaware Street Southeast, Minneapolis, MN 55455. Phone: 612-626-3432; Fax: 612-626-5135; E-mail: trety001{at}umn.edu.

Key Words: 1,3-butadiene • DNA-DNA crosslinks • interspecies differences • metabolism • mass spectrometry

1,3-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–µESI⁺–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 cross-links 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. [Cancer Res 2009;69(6):2479–8]