DNA adducts contribute to an increased risk of cancer and are associated with normal aging. N7-(1-hydroxyl-3-buten-1-yl) guanine (EB-GII) and N7-(2,3,4-trihydroxybut-1-yl) guanine (THBG) form in genomic DNA as a result of exposure to 1,3-butadiene, a known human carcinogen. Workers occupationally exposed to BD in rubber and plastic industry and smokers have increased levels of EB-GII and THBG in their genomes. Unexpectedly, small but measurable amounts of THBG and EB-GII were detected in individuals with no known exposure to 1,3-butadiene, unexposed laboratory animals, and untreated human cells in culture. This suggests the existence of endogenous and/or dietary sources of both adducts. To quantify the contributions of endogenous THBG and EB-GII adducts to the overall adduct load, Fisher F344 rats were exposed to low ppm levels of isotopically labeled butadiene-d6 (0, 0.3, 0.5, and 3 ppm) for 6 h/day for 7 days. At the completion of the experiment, target tissues for BD induced cancer (liver, lung, heart, pancreas, and mammary glands) were collected. THBG and EB-GII were quantified in genomic DNA using isotope dilution mass spectrometry methods. Adducts resulting from butadiene-d6 exposure carry a d6 isotope label, while endogenous adducts are unlabeled. A dose-dependent increase in THBG-d6 and EB-GII-d6 adducts was observed in genomic DNA isolated from the liver with increasing butadiene-d6 exposure. In the liver, we also observed endogenous THBG and EB-GII amounts comparable to the exogenous adducts at low ppm treatment with butadiene-d6, suggesting that endogenous adducts represent a significant contribution to the overall adduct load. To identify the sources of endogenous adducts, HT1080 cells were treated with stable isotope labeled cellular metabolites and potential dietary precursors of THBG adducts (D-erythrose, erythritol, and U-13C-glucose). Our results provide important information regarding the relative contributions of endogenous and exogenous DNA damage, which is critical for identification of risk factors for human disease.

Endogenous versus exogenous sources of N7-(2,3,4-trihydroxybut-1-yl) guanine and N7-(1-hydroxyl-3-buten-1-yl) guanine DNA adducts

ACS Fall 2020 Virtual Meeting

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