DNA adducts: Formation, biological effects, and new biospecimens for mass spectrometric measurements in humans

Abstract

Hazardous chemicals in the environment and diet or their electrophilic metabolites can form adducts with genomic DNA, which can lead to mutations and the initiation of cancer. In addition, reactive intermediates can be generated in the body through oxidative stress and damage the genome. The identification and measurement of DNA adducts are required for understanding exposure and the causal role of a genotoxic chemical in cancer risk. Over the past three decades, P-postlabeling, immunoassays, gas chromatography/mass spectrometry, and liquid chromatography/mass spectrometry (LC/MS) methods have been established to assess exposures to chemicals through measurements of DNA adducts. It is now possible to measure some DNA adducts in human biopsy samples, by LC/MS, with as little as several milligrams of tissue. In this review article, we highlight the formation and biological effects of DNA adducts, and highlight our advances in human biomonitoring by mass spectrometric analysis of formalin-fixed paraffin-embedded tissues, untapped biospecimens for carcinogen DNA adduct biomarker research.

Urinary DNA adductomics – A novel approach for exposomics

“…With the exception perhaps of 32 P-postlabelling (Jones 2012), the overwhelming majority of the literature describes the use of targeted analysis of DNA damage, measuring single, or a few, DNA adducts simultaneously (Hwa Yun et al 2018). While of value, this approach fails to reflect the totality of adducts, both expected and unexpected (aka.…”

“…Initially, adductomics approaches focused upon proteins, and specific amino acid modifications as biomarkers of exposure (Rappaport et al 2002), due to their abundance, and persistence (Rappaport et al 2012). More recently, DNA adductomics has emerged to assess the totality of DNA adducts in treated, free 2’-deoxyribonucleosides (2’-dN) (Claereboudt et al 1990), and in cellular DNA, often from cultured cells (Singh et al 2010; Stornetta et al 2017), or animal models (Hwa Yun et al 2018), or, more rarely, human tissue (Kanaly et al 2006; Kanaly et al 2007). Given the role of DNA damage in pathogenesis, in particular cancer, this approach is critical to characterizing the role of DNA adducts in disease risk identification and prevention.…”

“…However, use of human samples presently represents a severe challenge due to the need for high sensitivity, to detect multiple adducts. Recent advances in linear ion trap and Orbitrap instruments offer improved sensitivity (Hwa Yun et al 2018), but the availability of such instrumentation is limited, not least due to cost. Furthermore, cellular DNA adductomics requires a significant amount of DNA (20–500 μg, depending on adduct frequency), and therefore sufficient cells/tissue must be obtained.…”

A simplified method for detection of N‐terminal valine adducts in patients receiving treosulfan

“…Utilization of the Poroshell column technology enables adduct analysis without the need for adduct enrichment such as the FI R E assay, immunoaffinity purification or modified Edman degradation and gas chromatography . The simplicity of the applied method suggests that it can be expanded to unbiased adduct profiling, using the next generation of more sensitive and specific mass spectrometers …”

“…16,19,[28][29][30][31][32] The simplicity of the applied method suggests that it can be expanded to unbiased adduct profiling, using the next generation of more sensitive and specific mass spectrometers. [33][34][35]…”