Bioanalytical and Mass Spectrometric Methods for Aldehyde Profiling in Biological Fluids
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toxics Review Bioanalytical and Mass Spectrometric Methods for Aldehyde Profiling in Biological Fluids Romel P. Dator , Morwena J. Solivio , Peter W. Villalta * and Silvia Balbo * Masonic Cancer Center, University of Minnesota, 2231 6th Street SE, Minneapolis, MN 55455, USA; [email protected] (R.P.D.); [email protected] (M.J.S.) * Correspondence: [email protected] (P.W.V.); [email protected] (S.B.); Tel.: +1-612-626-8165 (P.W.V.); +1-612-624-4240 (S.B.) Received: 22 March 2019; Accepted: 22 May 2019; Published: 4 June 2019 Abstract: Human exposure to aldehydes is implicated in multiple diseases including diabetes, cardiovascular diseases, neurodegenerative disorders (i.e., Alzheimer’s and Parkinson’s Diseases), and cancer. Because these compounds are strong electrophiles, they can react with nucleophilic sites in DNA and proteins to form reversible and irreversible modifications. These modifications, if not eliminated or repaired, can lead to alteration in cellular homeostasis, cell death and ultimately contribute to disease pathogenesis. This review provides an overview of the current knowledge of the methods and applications of aldehyde exposure measurements, with a particular focus on bioanalytical and mass spectrometric techniques, including recent advances in mass spectrometry (MS)-based profiling methods for identifying potential biomarkers of aldehyde exposure. We discuss the various derivatization reagents used to capture small polar aldehydes and methods to quantify these compounds in biological matrices. In addition, we present emerging mass spectrometry-based methods, which use high-resolution accurate mass (HR/AM) analysis for characterizing carbonyl compounds and their potential applications in molecular epidemiology studies. With the availability of diverse bioanalytical methods presented here including simple and rapid techniques allowing remote monitoring of aldehydes, real-time imaging of aldehydic load in cells, advances in MS instrumentation, high performance chromatographic separation, and improved bioinformatics tools, the data acquired enable increased sensitivity for identifying specific aldehydes and new biomarkers of aldehyde exposure. Finally, the combination of these techniques with exciting new methods for single cell analysis provides the potential for detection and profiling of aldehydes at a cellular level, opening up the opportunity to minutely dissect their roles and biological consequences in cellular metabolism and diseases pathogenesis. Keywords: aldehydes; genotoxicity; cancer; diseases; oxidative stress; exposure biomarkers; high-resolution mass spectrometry; data-dependent profiling; derivatization; biological fluids; isotope labeling 1. Introduction Sources of Human Exposure to Aldehydes Aldehydes are characterized by the presence of a –HC = O reactive site and often exist in combination with other functional groups. They are ubiquitous in the environment, originating from man-made sources, as well as through natural processes (Figure1). The hydroxyl radical mediated-photochemical oxidation of hydrocarbons generates aldehydes in the atmosphere [1–3]. For instance, formaldehyde is produced from the oxidation of methane and naturally occurring compounds, such as terpenoids and isoprenoids from tree foliage [2]. In industrialized areas, the Toxics 2019, 7, 32; doi:10.3390/toxics7020032 www.mdpi.com/journal/toxics Toxics 2019, 7, 32 2 of 35 Toxics 2019, 7, x FOR PEER REVIEW 2 of 34 majority of aldehydes are produced from motor vehicle exhaust (internal diesel engine combustion), whichyields eitheraldehydes directly or yieldsgenerates aldehydes hydrocarbons, or generates which hydrocarbons, are eventua whichlly converted are eventually to aldehydes converted by to aldehydesphotochemical by photochemical oxidation reactions oxidation [1,4–8]. reactions Formaldehyde, [1,4–8]. Formaldehyde, acetaldehyde, acetaldehyde,and acrolein are and significant acrolein arecontributors significant to contributors the overall tosummed the overall risk summedof mobile risk sources of mobile of air sources toxicants of air according toxicants to according the United to theStates United Environmental States Environmental Protection Protection Agency Agency(U.S. EPA) (U.S. EPA)[1]. [Other1]. Other sources sources of ofaldehydes aldehydes include agricultural andand forestforest fires, fires, incinerators, incinerators, and and coal-based coal-based power power plants plants [9– [9–13].13]. Additionally, Additionally, humans humans are exposedare exposed to aldehydes to aldehydes in residential in residential and occupational and occupational settings settings where aldehydeswhere aldehydes are present are inpresent confined in spacesconfined [14 spaces] due to[14] the due release to the of release fumes fromof fumes indoor from furniture, indoor furniture, carpets, fabrics, carpets, household fabrics, household cleaning agents,cleaning cosmetic agents, products, cosmetic and products, paints [ 12and,15 –paints18]. Aldehydes [12,15–18]. are Aldehydes also widely are used also as fumigants widely used and foras biologicalfumigants specimen and for biological preservation specimen [1]. Another preservation major source [1]. Another of aldehyde major exposure source of comes aldehyde from exposure cigarette smoke.comes from Mainstream cigarette tobaccosmoke. Mainstream smoke (MTS) tobacco is composed smoke of(MTS) significant is composed amounts of significant of acetaldehyde amounts as theof acetaldehyde major component, as the followedmajor component, by acrolein, followed formaldehyde, by acrolein, and formaldehyde, crotonaldehyde and [19 crotonaldehyde–26]. Similarly, popular[19–26]. devicesSimilarly, such popular as e-cigarettes, devices such which as e-cigarettes, are advocated which as safer are alternativesadvocated as to safer tobacco, alternatives have been to foundtobacco, to have generate been high found concentrations to generate high of aldehydes concentrations [27–37 ].of Aldehydes aldehydes are[27–37]. also presentAldehydes in food are also and beveragespresent in (asfood flavorings), and beverages and in (as alcoholic flavorings), drinks and either in alcoholic as congeners drinks or, ineither the caseas congeners of acetaldehyde, or, in the as thecase oxidative of acetaldehyde, by-product as ofthe ethanol oxidative [38– 40by-product]. Biotransformation of ethanol is[38–40]. another Biotransformation source of aldehyde is exposure. another Thissource includes of aldehyde metabolism exposure. of a sizeable This includes number ofmetabolism environmental of a agents,sizeable such number as drugs, of tobaccoenvironmental smoke, alcohol,agents, andsuch other as drugs, forms tobacco of xenobiotics smoke, [41 alcohol,–43]. Of note,and other exposure forms also of comes xenobiotics from the [41–43]. metabolism Of note, of a numberexposure of also widely comes used from anticancer the metabolism drugs such of asa number cyclophosphamide, of widely used ifosfamide, anticancer and drugs misonidazole such as ascyclophosphamide, well as other drugs ifosfamide, used for and the treatmentmisonidazole of diseases as well suchas other as epilepsy drugs used and for HIV-1 the infectiontreatment [1of]. Thediseases production such as of epilepsy aldehydes and is HIV-1 proposed infection to be an[1]. important The production contributor of aldehydes to the toxicity is proposed and undesirable to be an sideimportant effects contributor of treatment to with the toxicity these drugs. and undesirable side effects of treatment with these drugs. Inflammation 1 O2 Metabolism/ Food/Beverages Lipid Peroxidation .- . O2 H2O2 OH Air Pollution Smoking/Vaping Drugs Figure 1. Exogenous and endogenous sources of human exposure to aldehydes. Finally, normalnormal cellular metabolic pathways such as lipid peroxidation, Alk-B type type repair, histone demethylation,demethylation, carbohydrate carbohydrate or ascorbateor ascorb autoxidation,ate autoxidation, carbohydrate carbohydrate metabolism, metabolism, and amine and oxidase-,amine oxidase-, cytochrome cytochrome P-450-, andP-450-, myeloperoxidase-catalyzed and myeloperoxidase-catalyzed metabolic metabo pathwayslic pathways produce aldehydes produce endogenouslyaldehydes endogenously [1,44,45]. The [1,44,45]. metabolism The metabolism of molecules of molecules such as amino such as acids, amino vitamins, acids, vitamins, and steroids, and tosteroids, name ato few, name also a generatesfew, also aldehydesgenerates aldehy [46]. Aldehydesdes [46]. Aldehydes are generally are formedgenerally during formed conditions during conditions of high oxidative stress. Oxidants are generated as a result of normal intracellular metabolism in the mitochondria, peroxisomes, and a number of cytosolic enzyme systems [47]. These metabolic free radicals and oxidants are referred to as reactive oxygen species (ROS). A balance Toxics 2019, 7, 32 3 of 35 of high oxidative stress. Oxidants are generated as a result of normal intracellular metabolism in the mitochondria, peroxisomes, and a number of cytosolic enzyme systems [47]. These metabolic free radicals and oxidants are referred to as reactive oxygen species (ROS). A balance between ROS production and removal by the antioxidant defense systems is essential to maintaining redox homeostasis. A disturbance in the balance favoring pro-oxidative conditions results to oxidative stress. An elevated level of ROS and the resulting oxidative stress leads to biological damage and is implicated in aging and pathologies of various conditions including cancer, cardiovascular,