1,3-butadiene (BD) is a known carcinogen. However, the DNA adducts responsible for mutations remain unknown. The overall goals of the proposed research are to examine the molecular dose of previously unexplored DNA adducts in rodents exposed to BD and 3-butene-1, 2-diol (BD-diol), comparing the data with mutation frequencies and mutational spectra to determine if a particular adduct could be used as a quantitative indicator of mutagenesis, and to evaluate effects of exposure on gene expression. The first hypothesis to be tested is that hydroxymethylvinyl ketone (HMVK) is formed in vivo during exposure to BD and BD-diol in a sex, species, and exposure concentration dependent manner resulting in important differences in mutagenicity. The second hypothesis is that promutagenic N1 adenine adducts convert to the more stable inosine adducts which are poorly repaired and accumulate during chronic exposure to BD. Several specific aims will be accomplished while addressing these hypotheses.
Specific Aim 1 is to examine the formation of potentially mutagenic DNA adducts (specifically 1, N2-propanodeoxyguanosine) by HMVK in vivo.
The second aim i s to determine the utility of the N-terminal valine adduct of HMVK (HMVK-Val) as a biomarker of HMVK formation by BD and BD-diol.
Specific Aim 3 is to develop methods for detecting N1- inosine, N1 - and N6 adenine adducts derived from BD metabolites in vivo.
Specific Aim 4 is to determine the mutagenic responses induced by BD exposures and characterize the impact of BD-diol derived metabolites on the spectra of mutations induced by BD exposure in the B6C3F1 mouse and F344 rat to identify which adducts studied in Aims 1 and 3 are quantitative indicators of mutagenesis.
Specific Aim 5 will examine the effects of exposure to BD and BD-diol on gene expression and DNA repair pathways. Collectively, these experiments have been designed to look at adduct formation, DNA repair, mutagenicity, and genomic alterations in rodents exposed BD and BD-diol, as well as the impact of glutathione depletion and DNA repair deficiency. Finally, HMVK-Val adducts will be measured in samples from BD exposed humans. Our research will identify critical metabolites and adducts that are responsible for BD mutagenicity, as well as develop biomarkers suitable for future molecular epidemiology studies. Ultimately these data will improve our understanding of critical mechanisms of toxicity and ability to accurately assess the risk of BD to humans.
|Kotapati, Srikanth; Sangaraju, Dewakar; Esades, Amanda et al. (2014) Bis-butanediol-mercapturic acid (bis-BDMA) as a urinary biomarker of metabolic activation of butadiene to its ultimate carcinogenic species. Carcinogenesis 35:1371-8|
|Boysen, Gunnar; Georgieva, Nadia I; Bordeerat, Narisa K et al. (2012) Formation of 1,2:3,4-diepoxybutane-specific hemoglobin adducts in 1,3-butadiene exposed workers. Toxicol Sci 125:30-40|
|Sangaraju, Dewakar; Goggin, Melissa; Walker, Vernon et al. (2012) 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. Anal Chem 84:1732-9|
|Koturbash, Igor; Scherhag, Anne; Sorrentino, Jessica et al. (2011) Epigenetic alterations in liver of C57BL/6J mice after short-term inhalational exposure to 1,3-butadiene. Environ Health Perspect 119:635-40|
|Jeannot, Emmanuelle; Pogribny, Igor P; Beland, Frederick A et al. (2011) Chronic administration of ethanol leads to an increased incidence of hepatocellular adenoma by promoting H-ras-mutated cells. Cancer Lett 301:161-7|
|Koturbash, Igor; Scherhag, Anne; Sorrentino, Jessica et al. (2011) Epigenetic mechanisms of mouse interstrain variability in genotoxicity of the environmental toxicant 1,3-butadiene. Toxicol Sci 122:448-56|
|Swenberg, James A; Bordeerat, Narisa K; Boysen, Gunnar et al. (2011) 1,3-Butadiene: Biomarkers and application to risk assessment. Chem Biol Interact 192:150-4|
|Goggin, Melissa; Sangaraju, Dewakar; Walker, Vernon E et al. (2011) Persistence and repair of bifunctional DNA adducts in tissues of laboratory animals exposed to 1,3-butadiene by inhalation. Chem Res Toxicol 24:809-17|
|Boysen, Gunnar; Collins, Leonard B; Liao, Shengkai et al. (2010) Analysis of 8-oxo-7,8-dihydro-2'-deoxyguanosine by ultra high pressure liquid chromatography-heat assisted electrospray ionization-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci 878:375-80|
|Goggin, Melissa; Seneviratne, Uthpala; Swenberg, James A et al. (2010) Column switching HPLC-ESI(+)-MS/MS methods for quantitative analysis of exocyclic dA adducts in the DNA of laboratory animals exposed to 1,3-butadiene. Chem Res Toxicol 23:808-12|
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