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DNA adduct

A DNA adduct is a segment of DNA covalently bound to a chemical moiety, typically derived from environmental carcinogens, endogenous metabolites, or reactive oxygen species, resulting in a stable modification that can distort DNA structure and impair replication or transcription.^[1] These adducts form when electrophilic species, often generated through metabolic activation by enzymes like cytochrome P450, react with nucleophilic sites on DNA bases, such as the N7 or C8 positions of guanine.^[1] If not repaired by cellular mechanisms like nucleotide excision repair, they can induce mutations during DNA replication, contributing to carcinogenesis.^[2] DNA adducts arise from diverse sources, including exogenous exposures to polycyclic aromatic hydrocarbons (PAHs) in tobacco smoke or aflatoxins in contaminated food, and endogenous processes like lipid peroxidation producing malondialdehyde.^[1] Notable examples include the benzopyrene diol epoxide adduct at the N2 position of deoxyguanosine, associated with lung cancer through G-to-T transversions in the p53 gene, and the aflatoxin B1-N7-guanine adduct linked to hepatocellular carcinoma via G-to-T mutations.^[2] Aristolochic acid adducts, such as the N6-deoxyadenosine form, exemplify how herbal remedies can cause urothelial cancers through A-to-T transversions.^[1] These modifications serve as critical biomarkers of genotoxic exposure, reflecting the "exposome" of chemical insults over time.^[2] The biological consequences of DNA adducts extend beyond mutagenesis to include stalled replication forks, genomic instability, and altered gene expression, all of which elevate cancer risk.^[1] In humans, adduct levels in tissues like lung or liver correlate with exposure history and predict disease susceptibility, as seen in smokers with elevated PAH adducts.^[2] Detection methods have evolved from radiolabeled techniques like 32P-postlabeling, which identifies one adduct per 10^10 nucleotides, to advanced liquid chromatography-mass spectrometry (LC-MS/MS) for sensitive, multiplexed analysis in biospecimens such as blood or archived tissues.^[1] Emerging fields like DNA adductomics aim to profile the full spectrum of adducts comprehensively, enhancing molecular epidemiology and personalized risk assessment.^[2]

Definition and Formation

Definition of DNA Adducts

A DNA adduct is a covalent modification of the DNA molecule resulting from the chemical binding of an electrophilic group or metabolite to nucleophilic sites on DNA bases, deoxyribose sugars, or phosphate groups in the backbone. These modifications typically occur at highly reactive positions, such as the N7 atom of guanine (the most nucleophilic site in DNA) or the O6 position of guanine, which lies in the major groove and is prone to alkylation. This binding alters the structural integrity and functional properties of DNA, potentially interfering with replication, transcription, and repair processes if not addressed.^[1] Representative examples illustrate the diversity of DNA adducts. Simple alkyl adducts, such as O6-methylguanine, form when methylating agents attach a small alkyl group to the O6 position of guanine, leading to base mispairing during replication. In contrast, bulky adducts arise from polycyclic aromatic hydrocarbons (PAHs), like the diol epoxide metabolite of benzopyrene, which covalently links to the exocyclic amino group (N2) of guanine, causing significant helical distortion due to the large size of the attached moiety. These examples highlight how adduct structure influences their biological impact, with smaller modifications often being more readily repaired while bulkier ones persist longer.^[1]^[3] DNA adducts are distinguished from other DNA lesions, such as strand breaks or interstrand crosslinks, by their nature as isolated chemical additions derived primarily from reactive xenobiotics or their metabolites, rather than physical disruptions or linkages between DNA strands or proteins. While breaks involve cleavage of the phosphodiester backbone and crosslinks covalently join two nucleophilic sites (e.g., on opposing strands), adducts represent stable, point-specific attachments that do not inherently fragment the DNA chain but can block enzymatic processes. This specificity makes DNA adducts key biomarkers of chemical exposure.^[1] The recognition of DNA adducts as critical molecular entities emerged in the 1960s through pioneering studies on alkylating agents, including mustard gas, where researchers demonstrated their formation via covalent attachment to purine bases like guanine. This work, building on earlier observations, established adducts as central to understanding chemical carcinogenesis.^[4]

Mechanisms of Formation

DNA adducts form primarily through the electrophilic attack of reactive metabolites on nucleophilic sites within DNA bases, such as the exocyclic amino groups of purines or the N7 position of guanine.^[5] These reactions typically proceed via nucleophilic substitution mechanisms, including SN1 (unimolecular, involving a carbocation intermediate) for secondary or tertiary electrophiles and SN2 (bimolecular, concerted backside attack) for primary or methyl electrophiles.^[5] The general chemical reaction can be represented as:

\text{R-X} + \text{DNA-Nu} \rightarrow \text{DNA-Nu-R} + \text{X}^-

where R-X is the electrophilic species (e.g., an alkyl halide or epoxide), DNA-Nu is the nucleophilic site on DNA, and X is the leaving group.^[5] Many procarcinogens require metabolic activation to generate these ultimate electrophiles, often through enzymatic pathways involving cytochrome P450 (CYP) enzymes. For instance, polycyclic aromatic hydrocarbons (PAHs) like benzopyrene are oxidized by CYP1A1 or CYP1B1 to form reactive epoxides, such as the 7,8-diol-9,10-epoxide (BPDE), which then covalently bind to DNA nucleophiles, predominantly at the N2 position of guanine.^[6] This bioactivation occurs in phase I metabolism, where CYP enzymes introduce oxygen across aromatic rings or double bonds, yielding unstable intermediates that drive adduct formation.^[1] The efficiency of adduct formation is modulated by several factors, including cellular pH, which influences the stability and reactivity of electrophiles and nucleophiles; higher nucleophile concentrations, such as those of guanine residues, that favor binding at electron-rich sites; and DNA accessibility, particularly during replication when the double helix unwinds, exposing bases to reactive species.^[1] These elements collectively determine the rate and site specificity of adduction, with major groove positions generally more reactive due to reduced steric hindrance.^[5]

Sources of DNA Adducts

Exogenous Sources

Exogenous sources of DNA adducts primarily arise from environmental contaminants, lifestyle choices, dietary exposures, and occupational hazards that introduce genotoxic chemicals into the body. These agents often require metabolic activation to form reactive intermediates capable of binding to DNA. Polycyclic aromatic hydrocarbons (PAHs), such as benzopyrene (BP), are prominent environmental pollutants generated from incomplete combustion processes, including vehicle exhaust, industrial emissions, and biomass burning, with ambient air concentrations ranging from 1–30 ng/m³ in urban areas and higher in polluted sites like road tunnels.^[6] Grilled or charred meats also contribute PAHs through high-temperature cooking, leading to BP levels in food that can result in DNA adduct formation after hepatic metabolism to the reactive diol epoxide, which covalently binds to the N² position of deoxyguanosine (BPDE-dG).^[6] Aromatic amines, another class of environmental pollutants, stem from industrial processes like dye manufacturing and combustion byproducts, where compounds such as 4-aminobiphenyl undergo N-hydroxylation to form nitrenium ions that generate C8-guanine adducts in exposed tissues.^[7] Lifestyle factors significantly contribute to exogenous DNA adduct formation, particularly through tobacco smoke and alcohol consumption. Tobacco smoke contains multiple PAHs, including BP at levels up to 20–40 ng per cigarette, which is metabolically activated to BPDE, forming stable BPDE-N²-dG adducts detectable in lung and buccal cells of smokers at approximately 3.1 adducts per 10¹¹ nucleotides—roughly double the levels in nonsmokers.^[8] Alcohol metabolism produces acetaldehyde, a Group 1 carcinogen, which directly alkylates DNA to form adducts like N²-ethyl-2'-deoxyguanosine (N²-Et-dG) and 1,N²-propano-deoxyguanosine (PdG); salivary acetaldehyde levels reach 50–150 μM after moderate intake (0.5 g/kg ethanol), with elevated N²-Et-dG observed in white blood cells of alcoholics.^[9] Dietary exposures introduce genotoxins through contaminated or processed foods. Heterocyclic aromatic amines (HAAs), such as 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), form during high-temperature cooking of meats (150–250°C) via Maillard reactions, reaching concentrations of 1–500 ng/g in well-done beef; these are activated by cytochrome P450 1A2 to N-hydroxy derivatives that produce C8-guanine adducts (e.g., dG-C8-PhIP) in colon and mammary tissues.^[10] Aflatoxins, mycotoxins produced by Aspergillus fungi, contaminate staples like peanuts and corn in humid regions, with aflatoxin B1 (AFB1) levels exceeding 12 μg/kg in some samples; AFB1 is oxidized to a reactive epoxide that binds N7-guanine, forming the aflatoxin-N7-guanine adduct, a urinary biomarker of exposure in high-risk populations.^[11] Occupational exposures in industries like rubber manufacturing and plastics production introduce specific genotoxins leading to DNA adducts. Benzene, used as a solvent in rubber production, is metabolized to benzene oxide and other reactive species like muconaldehyde, forming adducts such as 7-phenylguanine in bone marrow DNA of exposed workers, with levels correlating to cumulative exposure above 0.5–1 ppm-years.^[12] Vinyl chloride, a monomer in polyvinyl chloride plastics manufacturing, is bioactivated by CYP2E1 to chloroethylene oxide, generating promutagenic etheno adducts including 1,N⁶-ethenodeoxyadenosine (εdA) and 3,N⁴-ethenodeoxycytidine (εdC) in liver DNA, observed at elevated levels in workers historically exposed above 50 ppm.^[13] Aromatic amines, such as o-toluidine in dye and rubber industries, similarly form C8-deoxyguanosine adducts via nitrenium ion intermediates following occupational inhalation or dermal contact.^[7]

Endogenous Sources

Endogenous sources of DNA adducts arise from normal physiological processes and metabolic activities within cells, contributing to baseline levels of DNA damage that accumulate with age and under pathological conditions. These internal origins include reactive species generated during cellular respiration, lipid metabolism, hormone processing, and immune responses, leading to the formation of various adducts without external exposure. Unlike exogenous factors, these sources are unavoidable and linked to fundamental biology, with their impact modulated by antioxidant defenses and repair mechanisms. Oxidative stress represents a primary endogenous source, where reactive oxygen species (ROS) produced mainly in mitochondria during aerobic respiration react with DNA bases. Key adducts include 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), formed by oxidation of guanine, and thymine glycol, resulting from hydroxyl radical attack on thymine. These lesions arise from the imbalance between ROS generation and scavenging, with 8-oxodG levels estimated at 1–10 per 10^6 bases in human cells under normal conditions, promoting transversion mutations if unrepaired.^[14]^[15] Lipid peroxidation, another intracellular process exacerbated by oxidative stress, generates bifunctional aldehydes such as malondialdehyde (MDA) and 4-hydroxynonenal (HNE) from the breakdown of polyunsaturated fatty acids in cell membranes. These electrophiles covalently bind to DNA nucleobases, forming exocyclic etheno adducts like 1,N^6-ethenodeoxyadenosine (εdA) and 3,N^4-ethenodeoxycytidine (εdC), which distort the DNA helix and impair replication. Such adducts have been detected in human tissues at levels of approximately 1–5 per 10^8 normal bases, associating with chronic inflammation and aging-related damage.^[16]^[17] Estrogen metabolism contributes through the oxidation of endogenous estrogens to catechol estrogens, particularly 4-hydroxyestradiol, which are further converted to reactive quinones by enzymes like cytochrome P450. These quinones act as Michael acceptors, reacting primarily with the N7 position of guanine and N3 of adenine in DNA to form depurinating adducts that release the modified base and leave apurinic sites, potentially leading to mutations. Elevated levels of these adducts are observed in high-risk tissues like breast, correlating with unbalanced estrogen metabolism.^[18]^[19] Inflammation-induced nitrosative stress, stemming from nitric oxide (NO) produced by inducible nitric oxide synthase in activated macrophages and other cells, generates reactive nitrogen species like peroxynitrite (ONOO^-) upon reaction with superoxide. Peroxynitrite nitrates DNA bases to form adducts such as 8-nitro-2'-deoxyguanosine and causes deamination (e.g., guanine to xanthine), contributing to genomic instability in chronic inflammatory states. These modifications occur at sites of persistent inflammation, with adduct levels rising in conditions like ulcerative colitis. DNA repair pathways, including base excision repair, mitigate these endogenous adducts to prevent their accumulation.^[20]^[21]

Types of DNA Adducts

Bulky Adducts

Bulky DNA adducts are covalent modifications of DNA resulting from the binding of large, sterically hindering chemical groups to nucleobases, primarily guanine or adenine, which distort the DNA helix and impede normal cellular processes.^[1] These adducts typically involve polycyclic aromatic hydrocarbons (PAHs) or other voluminous electrophiles that attach at sites such as the C8 or N2 position of guanine and the N6 position of adenine, creating a bulky lesion that protrudes into the DNA groove.^[22] Formation of bulky adducts occurs through metabolic activation of environmental carcinogens or therapeutic agents into reactive intermediates, such as epoxides, which covalently bind to DNA bases via nucleophilic attack.^[1] A hallmark of these adducts is their ability to induce significant helical distortion, including DNA bending of up to 45 degrees in the case of certain PAH-derived lesions, which disrupts base pairing and stacking.^[23] Prominent examples include the (+)-anti-benzopyrene-7,8-diol 9,10-epoxide (BPDE) adduct, formed from the PAH benzopyrene found in tobacco smoke and grilled meats, which binds primarily to the N2 position of deoxyguanosine (dG-N²-BPDE), leading to G to T transversions.^[24] Aristolochic acid adducts, derived from plants used in traditional medicines, form at the N6 position of deoxyadenosine (dA-AL-I) and are highly nephrotoxic, contributing to Balkan endemic nephropathy and upper urinary tract cancers through A to T transversions.^[25] Cyclophosphamide metabolites, employed in chemotherapy, generate bulky adducts and interstrand crosslinks at the N7 position of guanine, enhancing their cytotoxic effects.^[26] These adducts exhibit considerable stability and persistence within DNA, with some, like aristolochic acid lesions, remaining detectable in renal tissues for years due to their resistance to nucleotide excision repair.^[27] Their large size poses challenges for detection methods, often requiring advanced mass spectrometry for accurate quantification.^[28]

Small and Oxidative Adducts

Small alkyl adducts involve the addition of compact alkyl groups, such as methyl or ethyl, to DNA bases, primarily guanine, without causing significant helical distortion.^[29] A prominent example is O⁶-methylguanine (O⁶-MeG), formed when N-nitrosodimethylamine (NDMA), a nitrosamine found in tobacco smoke and processed foods, is metabolically activated by cytochrome P450 enzymes to generate methyldiazonium ions that alkylate the O⁶ position of guanine.^[30] This adduct is highly mutagenic because it mispairs with thymine during DNA replication, leading to G:C to A:T transitions if not repaired.^[30] Another key alkyl adduct is N⁷-ethylguanine (N⁷-EtG), produced by ethylating agents like N-nitrosodiethylamine (NDEA) or N-ethyl-N-nitrosourea (ENU), which target the N⁷ position of guanine via Sₙ1 mechanisms; this lesion is less directly mutagenic but can cause depurination and replication stalling.^[29] Levels of N⁷-EtG have been detected at approximately 0.084 adducts per 10⁷ nucleotides in human liver DNA and 1.0 per 10⁷ in lymphocytes.^[29] Oxidative adducts arise from the reaction of endogenous reactive oxygen species (ROS), generated during normal cellular metabolism, with DNA bases.^[15] The most studied is 8-oxo-7,8-dihydroguanine (8-oxoG or 8-oxo-dG), formed by oxidation of guanine at the C8 position, often by hydroxyl radicals.^[15] This lesion adopts a syn conformation that allows it to pair with adenine instead of cytosine during replication, resulting in G:C to T:A transversions.^[15] Background levels of 8-oxoG in human lymphocyte DNA are around 0.5 lesions per megabase pair, reflecting its abundance as a marker of oxidative stress.^[15] Compared to bulky adducts, small alkyl and oxidative lesions occur more frequently due to both exogenous exposures and routine endogenous processes like lipid peroxidation and mitochondrial respiration, though each causes subtler base modifications rather than large-scale structural changes.^[31] These adducts are primarily addressed by base excision repair pathways, such as those involving OGG1 for 8-oxoG removal.^[15]

Biological Effects

Impact on DNA Structure and Function

DNA adducts covalently modify DNA bases or the sugar-phosphate backbone, leading to local structural perturbations that disrupt normal base pairing and helical integrity. For instance, O6-methylguanine (O6-meG), a common alkylated adduct, alters the hydrogen bonding pattern of guanine, favoring wobble base pairing with thymine instead of cytosine during replication, which compromises Watson-Crick fidelity. Bulky adducts, such as those formed by polycyclic aromatic hydrocarbons like benzopyrene, induce significant helix distortions by protruding into the major or minor groove, widening the helix or causing kinks that hinder the smooth progression of DNA-binding enzymes. These structural changes reduce the stability of the DNA duplex and impair the recognition of correct base pairs by polymerases. Such modifications profoundly affect DNA replication by stalling high-fidelity DNA polymerases at the lesion site, particularly during S-phase, as the enzyme active site cannot accommodate the distorted geometry. Prolonged polymerase stalling can trigger replication fork collapse, where the unwound DNA strands form aberrant structures or double-strand breaks if the fork cannot restart. In transcription, adducts interfere with RNA polymerase II elongation, causing arrest at the blocking lesion and resulting in truncated transcripts or reduced mRNA production, which dysregulates gene expression. Bulky adducts tend to cause more pronounced stalling in both processes due to their steric bulk. The presence of DNA adducts also elicits immediate cellular responses through activation of DNA damage checkpoints. Specifically, stalled replication forks generate single-stranded DNA regions that recruit the ATR kinase, initiating the ATR-CHK1 pathway to halt cell cycle progression and allow time for damage resolution. Similarly, helix-distorting adducts can activate the ATM kinase via indirect sensing of structural stress, coordinating broader damage signaling to prevent propagation of errors. These checkpoint activations help maintain genomic stability by pausing proliferation until the structural disruptions are addressed.

Role in Mutagenesis and Carcinogenesis

DNA adducts contribute to mutagenesis primarily through interference with DNA replication, leading to error-prone translesion synthesis (TLS) by specialized polymerases. During replication, bulky or distorting adducts stall high-fidelity replicative polymerases, prompting recruitment of Y-family TLS polymerases such as DNA polymerase η (Pol η). Pol η can insert nucleotides opposite the adduct, but this process is often mutagenic, particularly for certain lesions like those formed by benzopyrene diol epoxide (BPDE), where it promotes G to T transversions by misinserting adenine opposite the damaged guanine.^[32] In contrast, for platinum-DNA adducts from cisplatin, Pol η facilitates more accurate bypass, reducing mutation rates compared to Pol η-deficient cells, which exhibit 2- to 2.5-fold higher mutagenesis at the HPRT locus.^[33] This error-prone bypass converts stable adducts into permanent mutations, amplifying genetic instability.^[34] In oncogenic pathways, DNA adducts preferentially accumulate in critical genomic regions, such as proto-oncogenes like RAS and tumor suppressor genes like TP53, driving clonal expansion of mutated cells. For instance, adducts from tobacco-specific nitrosamines like NNK induce G to A transitions at codon 12 of the K-ras oncogene in lung tissues, activating oncogenic signaling and promoting tumor initiation.^[1] Similarly, polycyclic aromatic hydrocarbon (PAH) adducts, such as those from benzopyrene, target mutational hotspots in TP53 (e.g., codons 157, 248, and 273), resulting in loss-of-function mutations that impair DNA damage responses and apoptosis, facilitating carcinogenesis in smoking-related cancers.^[1] Accumulation of these driver mutations in key genes disrupts cellular homeostasis, enabling uncontrolled proliferation and tumor progression.^[1] The mutagenic risk exhibits a dose-response relationship, where higher adduct levels correlate with increased mutation frequencies, though tissue-specific factors influence efficiency. In experimental models, low levels of DNA adducts can lead to detectable elevations in mutation rates, with the dose-response relationship varying by tissue. This correlation underscores how even moderate exposure can elevate cancer risk by exceeding repair capacity and promoting heritable changes. Animal models provide compelling evidence for the carcinogenic role of DNA adducts, exemplified by aflatoxin B1 (AFB1), which forms guanine adducts primarily in the liver. In infant B6C3F1 mice treated with AFB1, hepatic adduct levels reached up to 200 per 10^8 nucleotides, correlating with G to T transversions at hotspots like codon 249 of TP53, mirroring human hepatocellular carcinoma mutations and accelerating tumor formation.^[35] High-fidelity sequencing in AFB1-exposed mouse livers revealed distinct mutational spectra with C to A transversions enriched at non-transcribed strands, establishing AFB1 adducts as biomarkers of exposure and drivers of liver cancer hotspots.^[36] These findings confirm the mechanistic link between adduct persistence and oncogenesis in vivo.^[36]

DNA Repair Pathways

Nucleotide Excision Repair

Nucleotide excision repair (NER) is the primary DNA repair pathway responsible for removing bulky, helix-distorting DNA adducts, such as those formed by ultraviolet radiation or chemical carcinogens, which threaten genomic integrity by blocking replication and transcription.^[37] These lesions are recognized through two main subpathways: global genome repair (GG-NER), which scans the entire genome for damage, and transcription-coupled repair (TC-NER), which prioritizes actively transcribed genes to swiftly resume transcription.^[38] Defects in NER can lead to persistent adducts that promote mutagenesis, underscoring its critical role in preventing carcinogenesis.^[38] The NER mechanism initiates with damage recognition: in GG-NER, the XPC-RAD23B complex binds to the distorted DNA helix induced by bulky adducts, while in TC-NER, stalling of RNA polymerase II at the lesion recruits CSB and XPG proteins.^[37] This is followed by the assembly of a multiprotein complex, including TFIIH, which unwinds the DNA around the adduct. Dual incisions are then made by the endonucleases XPG on the 3' side (4-7 nucleotides downstream) and XPF-ERCC1 on the 5' side (16-21 nucleotides upstream), excising an oligonucleotide fragment of 22-30 nucleotides containing the damaged bases.^[37] The resulting single-strand gap is filled by DNA polymerases δ and ε, with RFC and PCNA facilitating processivity, and sealed by DNA ligase I.^[38] GG-NER and TC-NER differ in their scope and speed: GG-NER operates throughout the genome but is slower and less efficient in non-transcribed regions, whereas TC-NER rapidly targets the transcribed strand of active genes, often repairing lesions 3-5 times faster via CSB and XPG recruitment to stalled RNA polymerase II.^[37] Key proteins in NER are organized into xeroderma pigmentosum (XP) complementation groups; for instance, mutations in XPC (XP-C group) impair GG-NER recognition, while defects in XPG (XP-G) or XPF (XP-F) disrupt incisions, leading to XP syndrome characterized by extreme sensitivity to bulky adducts and elevated skin cancer risk.^[38] NER exhibits high efficiency against bulky adducts, removing over 80% of certain UV-induced lesions, such as cyclobutane pyrimidine dimers, from highly repaired sites within 8 hours post-exposure in human cells.^[39] For more distorting adducts like (6-4) photoproducts, bulk repair is often completed within 4 hours, highlighting the pathway's rapid response to maintain cellular function.^[39]

Base Excision Repair and Other Pathways

Base excision repair (BER) is a primary DNA repair mechanism that addresses small, non-bulky adducts, such as those arising from oxidation and alkylation, which cause minimal distortion to the DNA helix.^[40] These lesions, including oxidative products like 8-oxoguanine (8-oxoG), are recognized and removed by DNA glycosylases that initiate the pathway by cleaving the N-glycosidic bond between the damaged base and the sugar-phosphate backbone, generating an abasic (AP) site.^[40] For instance, 8-oxoguanine DNA glycosylase (OGG1) specifically excises 8-oxoG, a common oxidative adduct, while N-methylpurine-DNA glycosylase (MPG) targets small alkylated bases such as 3-methyladenine and 7-methylguanine.^[40] In contrast to nucleotide excision repair (NER), which removes larger oligonucleotide segments containing bulky lesions, BER focuses on precise, base-specific interventions to restore integrity with minimal structural alteration.^[40] Following base removal, apurinic/apyrimidinic endonuclease 1 (APE1) cleaves the phosphodiester backbone 5' to the AP site, creating a single-strand break with a 3'-hydroxyl group and a 5'-deoxyribose phosphate (5'-dRP) moiety.^[40] This incision enables gap-filling synthesis, which proceeds via two subpathways: short-patch BER, predominant for simple lesions, where DNA polymerase β (Pol β) inserts a single nucleotide opposite the gap and also removes the 5'-dRP block via its lyase activity; or long-patch BER, involving the synthesis of 2-10 nucleotides by Pol δ/ε in coordination with proliferating cell nuclear antigen (PCNA) and flap endonuclease 1 (FEN1) to process the displaced strand, followed by ligation with DNA ligase 1 (LIG1) or ligase 3 (LIG3).^[40] APE1 and Pol β are essential coordinators in these processes, ensuring efficient downstream repair.^[40] Beyond BER, direct reversal pathways handle certain small alkyl adducts without strand breakage. The AlkB family of Fe(II)/α-ketoglutarate-dependent dioxygenases, such as AlkB in bacteria and its human homologs ALKBH2 and ALKBH3, oxidatively demethylate N1-methyladenine and N3-methylcytosine adducts through a single-step oxidative process that restores the unmodified base.^[41] This mechanism prevents mutagenesis from small alkylation damage, particularly from endogenous sources like S-adenosylmethionine.^[41] Mismatch repair (MMR) complements these pathways by addressing replication errors induced by persistent DNA adducts. The MutSα heterodimer, composed of MSH2 and MSH6, recognizes base mismatches or small insertion/deletion loops arising when replication forks encounter unrepaired adducts, such as O6-methylguanine, triggering excision and resynthesis of the nascent strand to correct the error.^[42] This post-replicative surveillance is crucial for preventing fixation of mutations from small adducts that evade BER.^[42] Despite their efficiency, these repair pathways have limitations, particularly under high-adduct burdens where oxidative or alkylative stress overwhelms enzymatic capacity. Slow turnover rates of glycosylases like OGG1 (approximately 0.1 per minute) and competition for repair factors can lead to accumulation of AP sites and incomplete repair, exacerbating genomic instability.^[43] In such overload scenarios, persistent lesions may channel into error-prone alternatives, highlighting the pathway's vulnerability to excessive damage.^[43]

Detection and Quantification

Chromatographic and Spectroscopic Methods

Liquid chromatography-mass spectrometry (LC-MS/MS) has emerged as a cornerstone technique for the high-resolution identification and quantification of specific DNA adducts due to its ability to separate complex mixtures and provide detailed structural information through tandem mass spectrometry.^[44] In particular, LC-MS/MS with electrospray ionization enables the detection of adducts such as the benzopyrene diol epoxide-deoxyguanosine (BPDE-dG) adduct by fragmenting precursor ions and analyzing product ions, offering specificity for low-abundance modifications in biological samples.^[45] Recent advances include untargeted DNA adductomics approaches using ultra-high performance liquid chromatography-electrospray ionization-high-resolution mass spectrometry (UHPLC-ESI-HRMS), which as of 2025 allow comprehensive profiling of both known and unknown adducts without authentic standards, facilitating exposome-wide analysis.^[46] This method typically involves enzymatic digestion of DNA to nucleosides or nucleotides, followed by chromatographic separation and mass analysis, achieving sensitivities down to approximately 1 adduct per 10^9 normal bases after sample enrichment steps like solid-phase extraction.^[47] Gas chromatography-mass spectrometry (GC-MS) serves as an alternative for analyzing DNA adducts, particularly those converted to volatile derivatives via hydrolysis and derivatization, which enhances compatibility with the gas phase.^[48] For instance, after acid or enzymatic hydrolysis of DNA to release modified bases, silylation or other derivatization renders non-volatile adducts amenable to GC separation and electron impact MS detection, allowing quantification of oxidative or alkylative lesions such as 8-oxoguanine.^[1] While historically sensitive, GC-MS requires more extensive sample preparation than LC-MS/MS and is best suited for smaller, hydrolyzable adducts rather than large bulky ones.^[48] Nuclear magnetic resonance (NMR) spectroscopy provides detailed structural elucidation for purified DNA adducts, revealing conformational details at the atomic level through chemical shift analysis and coupling constants. High-field NMR, often using heteronuclear techniques like 1H-13C HSQC, has been applied to characterize stereoisomeric adducts, such as those from aromatic amines, by resolving proton and carbon environments in isolated nucleoside models.^[49] Advances in microscale NMR allow structural determination at picomole quantities, though it necessitates prior isolation via chromatography for in vitro or synthetic adducts.^[50] Fluorescence spectroscopy complements these methods for structural studies of purified adducts that exhibit native or enhanced emission properties, enabling conformational analysis through spectral shifts and quenching effects.^[51] For example, polycyclic aromatic hydrocarbon adducts like BPDE-dG display characteristic excitation and emission spectra that differ based on intercalation or external binding modes within oligonucleotide duplexes, as observed in line-narrowed fluorescence experiments.^[52] This technique is particularly useful for bulky adducts with conjugated systems, providing insights into adduct-DNA interactions without the need for ionization.^[53] Overall, these chromatographic and spectroscopic approaches require DNA enrichment—such as immunoaffinity purification or offline fractionation—to achieve the necessary sensitivity for trace-level detection in genomic DNA, often reaching limits of 1 adduct per 10^9 bases.^[54]

Immunological and Radiolabeling Techniques

Immunological techniques for detecting DNA adducts primarily rely on monoclonal antibodies that specifically recognize modified nucleosides or bases formed by carcinogen exposure. Enzyme-linked immunosorbent assay (ELISA) employs these antibodies to quantify adducts in DNA extracts, offering high sensitivity for screening purposes without requiring extensive sample purification. For instance, monoclonal antibodies against benzopyrene diol epoxide (BPDE)-DNA adducts have been used in ELISA to measure polycyclic aromatic hydrocarbon (PAH)-derived lesions in human lung tissue, enabling detection in biopsy samples from smokers or environmentally exposed individuals.^[55]^[56] Immunohistochemistry (IHC) extends this approach by visualizing adduct distribution in intact tissues, using the same antibodies conjugated to enzymes or fluorophores for microscopic localization. In lung cancer studies, anti-BPDE antibodies applied via IHC have revealed focal adduct accumulation in bronchial epithelial cells, correlating with PAH exposure sites and aiding in histopathological assessment. These methods are particularly valuable for high-throughput analysis of archived paraffin-embedded samples, though cross-reactivity with structurally similar adducts can occur.^[56]^[57] The 32P-postlabeling assay represents a cornerstone radiolabeling technique for DNA adduct detection, involving enzymatic digestion of DNA to 3'-nucleotides, followed by polynucleotide kinase-mediated transfer of 32P from ATP to the 5'-hydroxyl groups of adducted nucleotides. The labeled adducts are then separated by thin-layer chromatography (TLC) and quantified via autoradiography, allowing detection of total bulky adducts at levels as low as one per 10^9-10^10 normal nucleotides without needing authentic standards. Developed in the early 1980s by Randerath and colleagues, this method was initially optimized for monitoring PAH-DNA adducts in animal models and human tissues exposed to environmental pollutants.^[58] Accelerator mass spectrometry (AMS) is an ultra-sensitive isotopic technique for quantifying DNA adducts, particularly those formed from 14C- or 3H-labeled carcinogens, by directly measuring isotope ratios in combusted DNA samples. AMS achieves detection limits as low as 1 adduct per 10^12 normal nucleotides, making it ideal for low-dose exposure studies and human dosimetry, though it requires specialized facilities and labeled analytes.^[59] Key advantages of 32P-postlabeling include its cost-effectiveness, simplicity, and broad applicability to diverse adduct types, making it suitable for large-scale epidemiological screening of occupational or smoking-related exposures. However, it lacks structural specificity, as TLC spots represent aggregate modifications that require confirmatory techniques like mass spectrometry for identification, and radiolabeling introduces handling and disposal challenges.^[60]^[61]

Applications as Biomarkers

Exposure and Risk Assessment

DNA adducts function as molecular dosimeters, offering a direct assessment of the internal dose of genotoxic agents by measuring the biologically effective dose at the cellular level, unlike external exposure metrics or biomarkers such as urinary metabolites that primarily reflect recent or aggregate exposure levels.^[62] For instance, while urinary polycyclic aromatic hydrocarbon (PAH) metabolites like 1-hydroxypyrene indicate systemic uptake, DNA adducts capture the covalent binding of reactive metabolites to DNA, providing insight into the potential for genotoxic damage that persists beyond transient exposure markers.^[63] This makes them valuable for evaluating the actual risk from environmental or occupational carcinogens, as they integrate factors like absorption, distribution, and metabolic activation.^[64] Elevated DNA adduct levels correlate with increased mutation rates and subsequent cancer risk, serving as predictive indicators of genotoxic potential. Quantitative analyses have shown that higher adduct burdens lead to greater mutagenic efficiency, with the slope of the dose-response curve linking total adducts to mutant frequencies in model systems.^[65] In humans, for example, benzopyrene diol epoxide (BPDE)-DNA adduct levels exceeding 10 per 10^8 nucleotides in lung tissue have been associated with elevated lung cancer risk among smokers, reflecting the propensity for these bulky adducts to induce nucleotide misincorporation during replication.^[66] Such correlations underscore the role of adducts in bridging exposure to adverse health outcomes, though the exact threshold varies by adduct type and tissue.^[67] Prospective cohort studies have validated DNA adducts as predictors of cancer incidence, aligning with frameworks from the International Agency for Research on Cancer (IARC) that emphasize biomarkers of genotoxic effects in risk assessment. In the Physicians' Health Study, individuals with high leukocyte DNA adduct levels had a nearly 3-fold increased risk of lung cancer compared to those with low levels (odds ratio 2.98, 95% CI: 1.05–8.42), particularly among current smokers, demonstrating the prognostic value of baseline measurements.^[68] Similarly, IARC evaluations of PAH-DNA adducts in white blood cells or lung tissue confirm their utility as risk markers, with elevated levels prospectively linked to higher lung cancer incidence in multiple populations.^[69] These findings support the integration of adduct data into epidemiological models for early risk stratification.^[70] Challenges in exposure and risk assessment arise from inter-individual variability in DNA adduct formation, largely driven by genetic polymorphisms in metabolic enzymes such as cytochrome P450 1A1 (CYP1A1). Variants like CYP1A1*2 enhance the activation of procarcinogens to reactive intermediates, leading to 2- to 10-fold higher BPDE-DNA adduct levels in lungs of susceptible smokers compared to those without the variant.^[71] This variability complicates uniform risk predictions, necessitating personalized approaches that account for genotype alongside adduct measurements to refine exposure estimates.^[72]

Case Studies in Human Populations

Studies of tobacco exposure have demonstrated elevated levels of polycyclic aromatic hydrocarbon (PAH) DNA adducts in the lungs of smokers compared to non-smokers, with increases ranging from 2- to 10-fold depending on the specific adduct and study population.^[73]^[68] These adducts serve as biomarkers of exposure and are associated with the development of lung cancer, contributing to approximately 25-30% of all cancer deaths worldwide attributable to tobacco use.^[74] In prospective cohort analyses, individuals with higher PAH-DNA adduct levels in white blood cells showed a 3- to 4.6-fold increased risk of lung cancer diagnosis.^[68] Dietary exposure to aflatoxin B1, a mycotoxin contaminating staple foods like maize and peanuts in high-risk regions, leads to the formation of aflatoxin-N7-guanine DNA adducts that correlate strongly with hepatocellular carcinoma (HCC) incidence in sub-Saharan African populations.^[75] In these areas, where chronic hepatitis B virus co-infection is prevalent, aflatoxin adducts in liver tissue and urinary biomarkers are detected at elevated levels, accounting for 25,000 to 155,000 HCC cases annually globally, with the majority in Africa.^[76] Molecular epidemiological studies have identified aflatoxin-specific mutations, such as in the TP53 gene, in up to 50% of HCC tumors from these high-exposure groups, underscoring the adduct's role as a direct biomarker of carcinogenic risk.^[77] Environmental exposure to airborne fine particulate matter (PM2.5), prevalent in urban settings due to traffic and industrial emissions, induces bulky DNA adducts in the respiratory and systemic tissues of city dwellers.^[78] Cross-sectional studies in urban populations have shown positive associations between personal PM2.5 exposure levels and PAH-derived bulky adducts in blood cells, with higher adduct burdens in individuals residing in high-pollution areas.^[79] These findings highlight PM2.5 as a key inducer of genotoxic damage, contributing to increased cancer risks in densely populated cities. Investigations into dietary heterocyclic amines (HCAs), formed during high-temperature cooking of beef and other meats, reveal elevated HCA-DNA adducts in human subjects with high consumption of well-done red meat.^[80] In cohort studies, individuals reporting frequent intake of grilled or barbecued beef exhibited detectable levels of PhIP (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) and other HCA adducts in blood and tissues, correlating with oxidative stress and potential colorectal cancer risk.^[81] These adducts are modulated by cooking methods and intake frequency, with biomarker assays confirming their presence as indicators of dietary genotoxic exposure.^[82] Post-2020 research on severe COVID-19 has linked the associated systemic inflammation to increased oxidative DNA adducts, particularly 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxo-dG), in intensive care unit (ICU) patients.^[83] Clinical studies report significantly higher serum and urinary 8-oxo-dG levels in critically ill COVID-19 patients compared to mild cases or controls, with elevations up to 2-fold in those requiring mechanical ventilation, reflecting heightened oxidative stress from viral-induced inflammation.^[84] These adducts have been proposed as prognostic biomarkers, associating with disease severity and outcomes in ICU settings.^[85]

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