Long-term exposures to environmental toxicants and endogenous electrophiles are causative factors for human diseases including cancer. The formation of DNA adducts reflects the internal exposure to these chemicals and they can serve as biomarkers for risk assessment. Liquid chromatography-multistage mass spectrometry (LC-MSn) is the most common method for biomonitoring DNA adducts of carcinogens. This “targeted” approach is often used to biomonitor a single exposure and a single adduct, and generally offers limited evidence for a role of a chemical in cancer risk. In the era of the “exposome”, an “untargeted” method that simultaneously detects many DNA adducts present in the genome provides an “adductomics” signature reflecting global chemical exposures that can lead to mutations and cancer. We have developed a Wide-SIM-MS2 screening method utilizing ultra-performance LC nanoelectrospray ionization high resolution Orbitrap MSn with on-line enrichment of hydrophobic DNA adducts, where ten consecutive SIM scan windows of 30 m/z were performed to detect the precursors of modified nucleosides. After each SIM scan event, the same mass range is subjected to MS/MS fragmentation. The SIM and MS/MS data are analyzed for the presence of co-eluting chromatographic peaks with masses differing by -116.0473 Da, the mass of the neutral loss of deoxyribose. We have compared our method with published adductomics methods using multiple reaction monitoring via triple quadrupole MS, and by constant neutral loss triggering MS3 by ion trap MS. Wide-SIM-MS2 is superior in sensitivity, specificity, and breadth of adduct coverage to the other methods. It can be used in a “targeted” manner by extracting adducts of interest, or in an “untargeted” fashion where a chromatographic peak-picking algorithm is applied to retrieve putative DNA adducts. Wide-SIM-MS2 was successfully used to detect DNA adducts derived from the diet, environment and endogenous electrophiles in human prostate and bladder specimens.

Wide selected ion monitoring (SIM)/MS2 data independent acquisition method for DNA adduct omics analysis

254th National Meeting (2017)

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