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The concept of the exposome is the encompassing of all the environmental exposures, both exogenous and endogenous, across the life course. Many, if not all, of these exposures can result in the generation of reactive species, and/or the modulation of cellular processes, that can lead to a breadth of modifications of DNA, the nature of which may be used to infer their origin. Because of their role in cell function, such modifications have been associated with various major human diseases, including cancer, and so their assessment is crucial. Historically, most methods have been able to only measure one or a few DNA modifications at a time, limiting the information available. With the development of DNA adductomics, which aims to determine the totality of DNA modifications, a far more comprehensive picture of the DNA adduct burden can be gained. Importantly, DNA adductomics can facilitate a "top-down" investigative approach whereby patterns of adducts may be used to trace and identify the originating exposure source. This, together with other 'omic approaches, represents a major tool for unraveling the complexities of the exposome and hence allow a better a understanding of the environmental origins of disease., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Marcus Cooke reports financial support was provided by National Institutes of Health. Chiung-Wen Hu reports financial support was provided by National Institutes of Health. Marcus Cooke reports a relationship with National Institutes of Health that includes: funding grants. Chiung-Wen Hu reports a relationship with National Institutes of Health that includes: funding grants. MSC is currently a guest editor of this special edition of Environmental Toxicology and Pharmacology, entitled "Environmental pollutants and genetic toxicity: from mechanisms to human studies" The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Exposure to endogenous and exogenous factors can result in the formation of a wide variety of DNA adducts, and these may lead to gene mutations, thereby contributing to the development of cancer. DNA adductomics, a novel tool for exposomics, aims to detect the totality of DNA adducts. Liquid chromatography-high resolution mass spectrometry (LC-HRMS) is the state-of-the-art method for DNA adductomic analysis, although its high cost has limited widespread use. In this study, we compared the analytical performance between HRMS and the more popular/accessible triple-quadrupole MS (QqQ-MS). We initially developed and optimized a hybrid quadrupole-linear ion trap-orbitrap MS (Q-LIT-OT-MS) method, considering the detection of both purine and pyrimidine adducts. LC-Q-LIT-OT-MS and LC-QqQ-MS methods were compared by non-targeted screening of formaldehyde-induced DNA adducts. Using the results from Q-LIT-OT-MS as the gold standard, QqQ-MS successfully detected 12 out of 18 formaldehyde-induced DNA adducts/inter-strand crosslinks (ICLs). QqQ-MS however also produced nine false-positive results owing to the inherent instrumental mass resolution limits. To discriminate the false-positive results from the accurate ones, we firstly introduced a statistical analysis, partial least squares-discriminant analysis, which efficiently excluded the false signals. Six DNA adducts/ICLs were not detected by QqQ-MS, due to insufficient sensitivity. This could be overcome by employing a selected reaction monitoring scan mode with multiple injections. Overall, this study demonstrated that high resolution may not be a strict requirement for MS-based DNA adductomics. LC-QqQ-MS with statistical analysis, could also provide a comparable performance as HRMS for pre-screening purposes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The exposome is a concept that encompasses the totality of internal and external environmental exposures, from conception onwards. Evaluation of the exposome, across the lifecourse represents a significant challenge, e.g., methods/technology may simply not exist to comprehensively assess all exposures, or they may not be applicable to human populations, or may have insufficient sensitivity. Cellular DNA adductomics aims to determine the totality of DNA adducts in the cellular genome. However, application to human populations requires the necessarily invasive sampling of tissue, to obtain sufficient DNA for sensitive analysis, which can represent a logistical and IRB challenge, particularly when investigating vulnerable populations. To circumvent this, we recently applied DNA adductomics to urine, detecting a range of expected and unexpected 2'-deoxyribonucleoside DNA adducts. However, base excision repair, the main DNA repair pathway for non-bulky DNA adducts, and processes such as spontaneous depurination, generate nucleobase adducts. Herein we propose a strategy to simultaneously assess 2'-deoxyribonucleoside and nucleobase adducts, using a widely used mass spectrometic platform (i.e., triple quadrupole tandem mass spectrometry). This will provide a much needed DNA adductomic approach for non-invasively, biomonitoring environmental exposures, through assessing the totality of DNA adducts; contributing to the evaluation of the exposome, across the life-course., (Published by Elsevier Ltd.)

Objectives: The objective of this study was to assess sperm quality and deoxyribonucleic acid (DNA) integrity of coke oven workers exposed to polycyclic aromatic hydrocarbons (PAHs) as compared to control subjects., Material and Methods: The coke oven workers (N = 52) and administrative staff (N = 35) of a steel plant served as the exposed and control groups, respectively. Exposure to PAHs was assessed by measuring 1-hydroxypyren. Analysis of sperm quality (concentration, motility, vitality, and morphology) was performed simultaneously with sperm DNA integrity analysis, including DNA fragmentation, denaturation, bulky DNA adducts, and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dGuo). A questionnaire was conducted to collect demographic and potential confounding data., Results: The coke oven workers had lower percentages of sperm motility, vitality and normal morphology than the control group, but the difference was not significant. For DNA integrity, the coke oven workers had significantly higher concentrations of bulky DNA adducts and 8-oxo-dGuo than the control subjects (p = 0.009 and p = 0.048, respectively). However, DNA fragmentation percentages did not significantly increase as compared to those in the subjects from the control group (p = 0.232). There was no correlation between sperm quality parameters and DNA integrity indicators., Conclusions: Occupational exposure of the coke oven workers to PAHs was associated with decreased sperm DNA integrity. Int J Occup Med Environ Health 2016;29(6):915-926., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)

Over the years, betel quid chewing and tobacco use have attracted considerable interest as they are implicated as the most likely causative risk factors of oral and esophageal cancers. Although areca nut use and betel quid chewing may lead to apoptosis, chronic exposure to areca nut and slaked lime may promote pre-malignant and malignant transformation of oral cells. The putative mutagenic and carcinogenic mechanisms may involve endogenous nitrosation of areca and tobacco alkaloids as well as the presence of direct alkylating agents in betel quid and smokeless tobacco. Metabolic activation of carcinogenic N-nitrosamines by phase-I enzymes is required not only to elicit the genotoxicity via the reactive intermediates but also to potentiate the mutagenicity with the sporadic alkylations of nucleotide bases, resulting in the formation of diverse DNA adducts. Persistent DNA adducts provides the impetus for genetic and epigenetic lesions. The genetic and epigenetic factors cumulatively influence the development and progression of disorders such as cancer. Accumulation of numerous genetic and epigenetic aberrations due to long-term betel quid (with or without tobacco) chewing and tobacco use culminates into the development of head and neck cancers. We review recent evidence that supports putative mechanisms for mutagenicity and carcinogenicity of betel quid chewing along with tobacco (smoking and smokeless) use. The detailed molecular mechanisms of the extent of accumulation and patterns of genetic alterations, indicative of the prior exposure to carcinogens and alkylating agents because of BQ chewing and tobacco use, have not yet been elucidated.

Abstract: A rapid, highly specific and sensitive liquid chromatographic–tandem mass spectrometric (LC–MS/MS) method was developed for measuring urinary N3-methyladenine (N3-MeA). With the use of an isotope internal standard (d3-N3-MeA) and on-line solid-phase extraction (SPE), urine samples can be directly analyzed within 12min without prior sample purification. The detection limit of this method was estimated as 0.035ng/mL on-column (11.7fmol). Intra- and inter-day imprecision (CV) were <7.4% and <10.8%, respectively. Mean recovery of N3-MeA in urine was 97–101%. This method was further applied to study the methylating agents exposure arising from cigarette smoke. Eighty-six volunteers were recruited including 41 regular smokers and 45 nonsmokers. The results showed that the urinary levels of N3-MeA observed in smokers (10.9±13.2ng/mg creatinine) were significantly higher than those in nonsmokers (4.1±4.3ng/mg creatinine; P <0.001). It was further noted that the urinary level of N3-MeA was found to be highly associated with cotinine for smokers (Spearman correlation coefficients, r =0.69, P <0.001), implying that cigarette smoking resulted in increased DNA methylation, followed by depurination and excretion of N3-MeA in urine. As a result of the on-line SPE system, this method is capable of routine high-throughput analysis and accurate quantification of N3-MeA, and would be a useful tool for the surveillance of methylating agent exposure and its associated cancer risk. [Copyright &y& Elsevier]