Title
Formation, Persistence, and Repair of 1,2,3,4-Diepoxybutane-Induced bifunctional DNA adducts in tissues of rodents exposed to 1,3-Butadiene by Inhalation.
Abstract
1, 3-butadiene (BD) is an industrial chemical and environmental pollutant. It is
also classified as a probable human carcinogen based on animal tumorigenesis studies
and human epidemiologic evidence. BD is metabolized to three reactive epoxides, of
which 1,2,3,4-diepoxybutane (DEB) is the most mutagenic, likely due to its bifunctional
electrophilic structure that enables it to form 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 (N7GN1A-
BD), and 1,N6-(2-hydroxy-3-hydroxymethyl-1,3-propanodiyl)-dA (1,N6-HMHPdA)
exocyclic DNA adducts. The purpose of this research is to identify mechanismbased
biomarkers of exposure to BD. Our laboratory has identified DNA-DNA crosslinks
and exocyclic deoxyadenosine adducts formed from DEB that could potentially be
used as biomarkers of exposure. Highly specific and sensitive isotope dilution HPLCESI+-
MS/MS methods have been developed to analyze DEB-induced DNA-DNA crosslinks and exocyclic DEB-dA adducts in DNA extracted from laboratory animals
exposed to BD by inhalation. bis-N7G-BD was the most abundant adduct, N7G-N1ABD
was ~10 times less abundant than bis-N7G-BD, and 1,N6-HMHP-dA was the least
abundant (~4 fold lower than N7G-N1A-BD). The quantitative isotope dilution mass
spectrometry methods developed in this work were employed to investigate the dose
dependent formation, persistence, and repair of the BD-induced DNA adducts in
laboratory rodents. Species, gender, and tissue differences in adduct levels were
observed. Mouse DNA contained a greater number of DEB-specific adducts than rat
DNA at identical exposures. Adduct levels were also higher in female as compared to
male rodents, and in liver DNA (compared to lung, brain, kidney, and thymus).
Although bis-N7G-BD was most abundant DEB-DNA adduct immediately following
exposure, it did not persist in mouse or rat liver while the other adducts did. We did not
observe repair of the bifunctional lesions by BER or NER, however, in vitro studies
suggest that 1,N6-HMHP-dA is repaired by AlkB. The research presented in this thesis
is consistent with animal inhalation studies where mice were more susceptible to tumor
formation. The data also suggests that these differences are due to species differences in the extent of BD metabolism to DEB. Two of the adducts, N7G-N1A-BD and 1,N6-
HMHP-dA were persistent in DNA and may be responsible for the mutagenicity of BD.
Description
University of Minnesota Ph.D. dissertation. September 2009. Major: Medicinal Chemistry. Advisor: Dr. Natalia Tretyakova. 1 computer file (PDF); xiii-220 pages.
Suggested Citation
Goggin, Melissa Mary.
(2009).
Formation, Persistence, and Repair of 1,2,3,4-Diepoxybutane-Induced bifunctional DNA adducts in tissues of rodents exposed to 1,3-Butadiene by Inhalation..
Retrieved from the University of Minnesota Digital Conservancy,
https://hdl.handle.net/11299/56687.