Mass Spectrometric Mapping of the DNA Adductome as a Means to Study Genotoxin Exposure, Metabolism, and Effect

Abstract

Covalent binding of endo-or exogenous chemicals to DNA results in the formation of DNA adducts which are reflective of exposure of the human body to DNA-damaging molecules and their metabolic pathways. The study of DNA adduct types and levels in human tissue therefore offers an interesting tool in several fields of research, including toxicology and cancer epidemiology. Over the years, a range of techniques and methods have been developed to study the formation of endo-and exogenous DNA adducts. However, for the simultaneous detection, identification and quantification of both known and unknown DNA adducts, mass spectrometry (MS) is deemed to be the most promising technique. In this perspective, we focus on the analysis of multiple DNA adducts within a sample with the emphasis on untargeted analysis. The advantageous use of MS methodologies for DNA adductome mapping is discussed comprehensively with relevant field examples. In addition, several aspects of study design, sample pretreatment and analysis are addressed as these factors significantly affect the reliability of DNA adductomics studies.

The Future of DNA Adductomic Analysis

“…The field of DNA adductomics has been recently reviewed and [ 29 , 51 , 52 ] Table 2 summarizes the LC-MS based DNA adductomics analyses performed to date. Three recent studies [ 53 , 54 , 55 ] have used the conventional low resolution, nominal mass MS 2 approach for DNA adductomics, but the trend since our previous review is to use HRAM data acquisition for DNA adductomic experiments.…”

Quantitative analysis of malondialdehyde‐guanine adducts in genomic DNA samples by liquid chromatography/tandem mass spectrometry

“…Precursor-product ion scans are more suited to adductomics studies than MRM scans as the latter require the precursors and products to be known. [33] The methods were applied to CT-DNA samples and treatment with MDA resulted in a dose-response relationship as expected. However, only DNA was involved and no cellular responses could have repaired these adducts.…”

“…Most notably, we have identified a fragmentation pattern that appears to be unique to M 1 G. This could therefore be an important contribution to the field of adductomics where unique transitions are essential when identifying a range of adducts within biological samples. Precursor‐product ion scans are more suited to adductomics studies than MRM scans as the latter require the precursors and products to be known . The methods were applied to CT‐DNA samples and treatment with MDA resulted in a dose‐response relationship as expected.…”

Catalysis of a 1,3-dipolar reaction by distorted DNA incorporating a heterobimetallic platinum(ii) and copper(ii) complex

“…As a control experiment, we mixed 1a with 5′-GMP and the resulting complex was analyzed by MALDI-TOF mass spectrometry. 35 , 36 We observed an ensemble of high mass-to-charge ( m / z ) signals distributed around a value of m / z ≈ 1042 a.u., as shown in Fig. 4a .…”