Data-Independent Mass Spectrometry Approach for Screening and Identification of DNA Adducts
2017
Guo, Jingshu | Villalta, Peter W. | Turesky, Robert J.
Long-term exposures to environmental toxicants and endogenous electrophiles are causative factors for human diseases including cancer. DNA adducts reflect the internal exposure to genotoxicants and can serve as biomarkers for risk assessment. Liquid chromatography-multistage mass spectrometry (LC-MSⁿ) is the most common method for biomonitoring DNA adducts, generally targeting single exposures and measuring up to several adducts. However, the data often provide limited evidence for a role of a chemical in the etiology of cancer. An “untargeted” method is required that captures global exposures to chemicals, by simultaneously detecting their DNA adducts in the genome; some of which may induce cancer-causing mutations. We established a wide selected ion monitoring tandem mass spectrometry (wide-SIM/MS²) screening method utilizing ultraperformance-LC nanoelectrospray ionization Orbitrap MSⁿ with online trapping to enrich bulky, nonpolar adducts. Wide-SIM scan events are followed by MS² scans to screen for modified nucleosides by coeluting peaks containing precursor and fragment ions differing by −116.0473 Da, attributed to the neutral loss of deoxyribose. Wide-SIM/MS² was shown to be superior in sensitivity, specificity, and breadth of adduct coverage to other tested adductomic methods with detection possible at adduct levels as low as 4 per 10⁹ nucleotides. Wide-SIM/MS² data can be analyzed in a “targeted” fashion by generation of extracted ion chromatograms or in an “untargeted” fashion where a chromatographic peak-picking algorithm can be used to detect putative DNA adducts. Wide-SIM/MS² successfully detected DNA adducts, derived from chemicals in the diet and traditional medicines and from lipid peroxidation products, in human prostate and renal specimens.
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