1,3-butadiene (butadiene) is a known human carcinogen produced industrially and also found in automobile exhaust, cigarette smoke, and forest fires. Epoxide metabolites of butadiene, i.e. 1,2,3,4-diepoxybutane (DEB), 3,4-epoxy-1-butene (EB), and 3,4-epoxy-1,2-butanediol (EB-diol), are thought to be the ultimate genotoxic species of BD. These epoxides preferentially modify the N7-guanine position in DNA to give rise to N7- (2-hydroxy-3,4-epoxybutene-1-yl)-guanine (EB- Gua I), N7-(1-hydroxy-3-buten-2-yl)-guanine (EB-Gua II), N7-(trihydroxybutyl) guanine (THB- Gua), and bis-N7G-butanediol cross-links (bis-N7G-BD). These N7-guanine adducts are hydrolytically labile and are slowly released from DNA to give apurinic sites. Our studies within the previous funding period have detected measurable amounts of EB-Gua and THB-Gua adducts in untreated cells, laboratory animals, and humans with no known exposure to BD. We have also shown that EB-Gua adducts can be spontaneously converted to stable 2-hydroxy-3,4- epoxybut-1-yl-FAPy-dG (EB-FAPy) adducts. The long-range goal of our research is to establish the molecular mechanisms by which BD elicits its genotoxic and carcinogenic effects. The objective of this research is to elucidate the metabolic/dietary origins of endogenous THB-Gua and EB-Gua adducts and to elucidate the genotoxic effects of EB-FAPy and THB-FAPy adducts. The central hypothesis of this research is that DNA lesions identical to those generated by butadiene exposure can be formed by endogenous sources such as carbohydrate metabolism. We further propose that butadiene-derived FAPy adducts contribute to carcinogenic and mutagenic properties of butadiene. Our proposed studies will improve the current understanding of the mechanisms of mutagenesis and cytotoxicity resulting from butadiene exposure and afford new insights into the origins of endogenously formed DNA lesions, reducing the uncertainty in cancer risk assessment in exposed populations.
The main goal of this investigation is to elucidate the mechanisms of carcinogenic effects of butadiene, a known human carcinogen present in cigarette smoke, automobile exhaust, and in forest fires. Butadiene is metabolically activated to several reactive species that bind to genomic DNA and form promutagenic DNA adducts. In this application, we will employ ultra-sensitive mass spectrometry based methodologies to accurately quantify butadiene-DNA adducts in human cell culture and in tissues of laboratory animals exposed to low levels of butadiene. We will also elucidate the role of ring open butadiene-DNA adducts in its genotoxic effects. These studies will improve our understanding of the contributions of environmental, dietary, and endogenous exposures to DNA damage to human cancer risk and elucidate the mechanisms of butadiene-mediated cancer.
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