Doi:10.1016/j.mrgentox.2008.09.020

Biomarkers of oxidative stress and damage in human populations exposed toarsenic Andrea De Vizcaya-Ruiz , Olivier Barbier , Ruben Ruiz-Ramos , Mariano E. Cebrian a Sección Externa de Toxicología, Centro de Investigación y Estudios Avanzados del I.P.N., Avenida Instituto Politécnico Nacional 2508, México, D.F., 07360 Mexicob Centro de Investigación en Salud Poblacional INSP, Cuernavaca, Morelos, Mexico Arsenic (As) is an ubiquitous element in the environment for which the main route of human exposure is through consumption of drinking water. Reactive oxygen species generation (ROS) associated with As exposure is known to play a fundamental role in the induction of adverse health effects and disease (cancer, diabetes, hypertension, and cardiovascular and neurological diseases). However, the precise mechanismsof oxidative stress and damage from As exposure are not fully understood and moreover the use of non- invasive methods of measuring ROS generation and oxidative damage footprints in humans is no easy task. Although As induces adverse health effects not all exposed individuals develop degenerative chronic diseases or even manifest adverse effects or symptoms, suggesting that genetic susceptibility is an impor- tant factor involved in the human response to As exposure. This mini-review summarizes the literaturedescribing the molecular mechanisms affected by As, as well as the most used biomarkers of oxidativestress and damage in human populations. The most reported biomarkers of oxidative DNA damage are theurinary excretion of 8-OHdG and the comet assay in lymphocytes, and more recently DNA repair mecha-nism markers from the base and nuclear excision repair pathways (BER and NER). Genetic heterogeneityin the oxidative stress pathways involved in As metabolism are important causative factors of disease.
Thus further refinement of human exposure assessment is needed to reinforce study design to evaluateexposure–response relationships and study gene–environment interactions. The use of microarray-basedgene expression analysis can provide better insights of the underlying mechanisms involved in As-induceddiseases and could help to identify target genes that can be modulated to prevent disease.
2008 Elsevier B.V. All rights reserved.
Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Arsenic, oxidative stress and their biological implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Arsenic-induced ROS generation and oxidative damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The antioxidant response and arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
(CH3)2As•, Dimethylarsinic radical; (CH3)2AsOO•, Dimethylarsinic peroxyl; •OH, Hydroxyl radical; 1O2, Singlet oxygen; 8-OHdG, 8-Hydroxy-2 - deoxyguanosine; 8-oxo-G, 8-Hydroxy-guanine; 8-oxy-Guo, 8-Hydroxyguanosine; AGEs, Advanced glycation end-products; AP-1, Activator protein 1; ARE, Antioxidantresponse element; As, Arsenic; BCC, Basal cell carcinomas; BER, Base-excision repair; CAT, Catalase; CCL20, Chemokine (C–C Motif) ligand 20; CO, Carbon monoxide; COX-2,Cyclooxygenase 2; Creat, Creatinine; DCFH-DA, 6-Carboxy-2 ,7 -dichlorodihydrofluorescein diacetate; DMA, Dimethylarsenic acid; DMPO, 5 5-Dimethyl-1-pyrroline-N-oxide;DNA, Deoxyribonucleic acid; EGF, Epithelial growth factor; ER-␣, Estrogen receptor-␣; ERK, Extracellular signal-regulated kinases; ESR, Electron spin resonance; GPx, Glu-tathione peroxidase; GSH, Glutathione; GST, Glutathione S-transferase; GSTM1, Glutathione S-transferase M1; H2O2, Hydrogen peroxide; HIF-1, Hypoxia-inducible factor 1;HNE, 4-Hydroxy-2-nonenal; HO-1, Heme oxygenase-1; JNK, C-Jun N-terminal kinases; Keap1, Kelch-like ECH-associated protein 1; LOO•, Peroxyl radical; LPO, Lipid perox-ides; MAP Kinases, Mitogen-activated protein kinases; MDA, Malondialdehyde; MMA, Monomethylarsonic acid; NADPH, Nicotinamide adenine dinucleotide phosphate; NER,Nucleotide-excision repair; NF-kB, Nuclear factor-kappa B; Nrf-2, NF-E2-related factor-2; O , Superoxide anion; OGG1, 8-Oxoguanine DNA-glycosylase 1; Pb, Lead; PBMC, Peripheral blood mononuclear cells; PDGF, Platelet-derived growth factor; PHA, Poly-hydroxy fatty acid; PI3-kinase, Phosphatidylinositol 3-kinase; PKC, Proteinkinase C; PLA2, Phospholipase A2; PLC, Phospholipase C; POL b, Polymerase b; ROS, Reactive oxygen species; SCC, Squamous cell carcinomas; SOD, Superoxide dismutase;TNF, Tumor necrosis factors; TRX, Thioredoxin; UC, Urothelial carcinoma; XPA, Xeroderma pigmentosum, complementation group A; XRCC1, X-ray repair complementingdefective repair in chinese hamster cells 1.
∗ Corresponding author at: Sección Externa de Toxicología, Centro de Investigación y Estudios Avanzados del I.P.N., P.O. Box 14-740, México, D.F., 07360 Mexico.
Tel.: +52 55 57473309; fax: +52 55 57473395.
E-mail address: (M.E. Cebrian).
1383-5718/$ – see front matter 2008 Elsevier B.V. All rights reserved.
A. De Vizcaya-Ruiz et al. / Mutation Research 674 (2009) 85–92 Biomarkers of oxidative stress, damage and antioxidant capacity in human populations exposed to arsenic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Levels of reactive oxidants and lipid peroxidation end-products in plasma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
The use of fluorescent probes and electron spin resonance (ESR) for ROS measurement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Oxidative DNA damage associated to arsenic exposure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Guanine oxidation products . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Comet assay . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Effects of arsenic on ROS defense mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Base excision DNA repair (BER) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Nucleotide excision DNA repair (NER) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Effects of arsenic on the antioxidant response . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
oxidative stress and its formation leads to a cascade of secondaryROS such as H2O2 and •OH induces a rapid decline of Arsenic (As) is ubiquitous in the environment, but the major mitochondrial membrane potential, altering the activity of mito- route of human exposure for inorganic As is through consump- chondrial enzymes, promoting dramatic morphologic changes and tion of contaminated drinking water. Arsenic is a well-known the loss of mitochondrial internal organization. A deflection of elec- ROS inducer, and generation of these species associated with As trons from the respiratory chain has been suggested as a possible exposure has been shown to play a fundamental role in the induc- cause of the mitochondrial alterations, thus implicating mitochon- tion of adverse health effects nder pathological conditions dria as the main site where As-induced ROS are generated increased intracellular ROS content contributes to cellular impair- In addition, ROS may be formed by cytosolic enzymes having per- ment and metabolic remodeling through oxidative damage that oxidase activity, such as cytochrome P-450, which sequentially may lead to physiological dysfunctions and degenerative chronic transfer two electrons from NADPH to molecular oxygen diseases. Arsenic exposure has been associated with different types Another mechanism is the generation of H2O2 during the oxida- of cancer (skin, bladder, liver, kidney and lung) diabetes tion of As(III) to As(V) in the course of formation of intermediary rteriosclerosis and cardiovascular diseases ypertension arsine species such as dimethylarsinic peroxyl [(CH3)2AsOO•] and neurological diseases (Alzheimer and Parkinson) Although As has been proven to induce adverse health effects, not thermore, As increases oxygen cell consumption contributing to all exposed individuals develop degenerative chronic As-related increased ROS production and oxidative stress ther mecha- diseases or even manifest adverse effects or symptoms related to nism of ROS generation by As is the involvement of hepatic and renal the exposure, suggesting that genetic susceptibility is an important heme oxygenase isoform 1 (HO-1), as shown in rodents, resulting factor involved in the human response to As exposure.
in the production of additional free iron, CO and biliverdin Oxidative stress is among the more documented mechanisms Free iron can participate in a Fenton type reaction, in which H2O2 of As toxicity and carcinogenicity. The term in essence refers to is reduced to OH− and •OH. Alternatively, H2O2 can participate in a serious imbalance between production of reactive species and + H2O2 → O2 + •OH + OH−), that com- antioxidant defense, encompassing a broad spectrum of conditions bines a Fenton reaction and the reduction of Fe(III) by O •− that alter cellular redox status Notwithstanding the exper- imental evidence linking As exposure and oxidative stress, the •OH, the generally assumed critical reactive species directly attack- precise mechanisms by which As induces oxidative stress are not yet fully understood. This limitation has had implications in rela- Under physiological conditions, intracellular ROS levels play an tion to the selection of useful biomarkers of oxidative stress and important role in regulating cell functions, such as intracellular Ca2+ damage that could be associated both with exposure and adverse and glucose homeostasis pathways and autophagy ene expression hypoxic and inflammatory responses This mini-review summarizes the molecular mechanisms OS signaling also participates in maintaining cell integrity known to be affected by As and the effects of As exposure on by regulating cell adhesion apoptosis and cell proliferation molecules that can be used as biomarkers of oxidative stress and OS act as second messengers through activation/inactivation damage in human populations. The studies here described are of many signaling factors by oxidation of thiol groups by recent approaches related to: (1) measuring ROS directly in biolog- altering the intracellular redox state consequently inducing cell ical samples; (2) measuring oxidative damage and oxidative DNA signaling pathways, downstream gene expression and cell pro- damage; and (3) investigating the presence of polymorphisms and liferation or death And in consequence influencing signaling their influence on the effects of As on both DNA repair and the molecules including protein tyrosine kinases and phosphatases expression of members of the antioxidant response in As-exposed (e.g. EGF, insulin and PDGF receptors), protein serine/threonine kinases and phosphatases (e.g. MAP Kinases such as JNK, p38or ERK, Akt, PKC, PHA, calcineurin PP2B), small G proteins (e.g.
2. Arsenic, oxidative stress and their biological implications
Ras), lipid signaling (PLC, PLA2, PI3-kinase), Ca2+ signaling (inos-itol (1,4,5)-trisphosphate receptor [Ins(1,4,5)P3 R], Ca2+-ATPase, 2.1. Arsenic-induced ROS generation and oxidative damage Ca2+/Na+ exchanger) and transcription factors (e.g. AP-1, NF-␬B,Nrf-2, HIF-1 or p53) alterations also occur by biochemical The main actors of oxidative stress and oxidative signaling are reactions like glycation, resulting in reactive and unstable com- ), hydroxyl radical (•OH), hydrogen per- plex products known as advanced glycation end-products (AGEs) oxide (H2O2), singlet oxygen (1O2) and peroxyl radical (LOO•).
and protein oxidation, leading to formation of disulphides between Superoxide anion is considered the primary species in As-induced oxidized cysteine and methionine residues peroxidation A. De Vizcaya-Ruiz et al. / Mutation Research 674 (2009) 85–92 cyclization of polyunsaturated fatty acid residues of phos- tion or alterations in antioxidant activity by affecting their structure pholipids forming malondialdehyde (MDA), 4-hydroxy-2-nonenal (oxidation/reduction of thiol groups and displacement of essential (HNE) and other exocyclic DNA adducts, and nucleic acid oxidation metals). The use of antioxidants has been an efficient strategy to protect cells from oxidative injury and are currently used as pre- Cell disturbances involved in As-induced oxidative stress closely ventive and therapeutic agents against oxidative damage occurring associated with cancer include: DNA damage, DNA hypomethy- during As exposure or example, preventing changes in lation and hypermethylation, and alterations in the regulatory the expression of molecules participating in mitogenic signaling mechanisms of cell proliferation, apoptosis and necrosis pathways activated by As, such as increased COX-2 expression DNA damage observed during As exposure is not directly due tothe metalloid since it does not covalently bind to DNA structures 3. Biomarkers of oxidative stress, damage and antioxidant
but results indirectly from ROS induction which generates DNA capacity in human populations exposed to arsenic
adducts, DNA strand breaks, cross links and chromosomal aber-rations •OH seems to be responsible for the main DNA Adverse health outcomes resultant from As exposure are a damage. The four DNA bases, including the sugar backbone, can be function of both duration and intensity of exposure and to bet- oxidatively modified, thymidine being the most susceptible. The ter understand the dose–response relationships involved in disease participation of oxidative stress induced by As has been clearly development, exposure data needs to be collected. Assessment of implicated in cancer development by several studies focused on exposure usually considers the measurement of As levels in envi- bladder cancer models, such as UROtsa cells in vivo mod- ronmental media (water and soil) and/or the use of biomarkers els t has also been reported that the binding of arsenite or of exposure (blood, urine and nails). Oxidative stress and damage monomethylarsonic acid (MMA) to tubulin can lead to several of the resultant from metal exposure has been extensively reviewed genetic effects (aneuploidy, polyploidy and mitotic arrest) observed The DNA molecule and cell components, such as polyunsaturated after As exposure Arsenic exposure alters the methylation fatty acid residues of phospholipids, aminoacids, peptides and pro- state of cellular DNA by modifying the amount and activities of teins are susceptible targets of metal-induced ROS attack. The use of DNA methylation enzymes, both de novo (DNA methyltransferases non-invasive methods for measuring ROS generation and oxidative 3a and 3b) and maintenance methylation (DNA methyltransferase- damage footprints in humans is not an easy task, since the prob- 1). These effects can occur directly through As-thiol enzyme lems related with sample limitation, technical difficulties and data interaction, indirectly through ROS-enzyme interaction and/or by interpreting have not yet been completely solved.
depletion of S-adenosyl-methionine pool(s), the methyl donorrequired for As- and DNA-methylation processes Global 3.1. Levels of reactive oxidants and lipid peroxidation DNA hypomethylation has been shown to occur during As-induced malignant transformation leading to cancer. Such a state of DNAmethylation imbalance could conceivably disrupt appropriate gene Lipid peroxidation generates a variety of relatively stable expression, as occurs during As-induced malignant transforma- decomposition end-products, mainly ␣,␤-unsaturated reactive tion in rodent liver cells, where As-induced aberrant expression aldehydes, such as MDA, HNE and 2-propenal (acrolein) and iso- of cytokines, steroid-, apoptosis- and cell cycle-related genes was prostanes, which can be measured in plasma and urine as indirect observed. In particular, the marked increase in the expression of indicators of oxidative stress A study conducted in Tai- estrogen receptor-␣ (ER-˛) and cyclin D1 genes suggested that DNA wan showed that As concentration in whole blood of exposed hypomethylation is a non-genotoxic mechanism of carcinogenesis individuals (9.6 ± 9.9 ␮g As/L) was positively associated with the acting by facilitating aberrant gene expression The inhi- concentration of reactive oxidants and negatively associated with bition of apoptotic pathways via MAP-kinases by As-induced ROS the antioxidant capacity of plasma relationship between seems to be an important mechanism of As carcinogenicity chronic As exposure from drinking water and oxidative stress inhumans was also explored in Inner Mongolia, China Their 2.2. The antioxidant response and arsenic results indicated that the mean serum level of lipid peroxides(LPO) was significantly higher in highly exposed individuals hav- The antioxidant response is one of the most efficient mech- ing 360 ± 173 ␮g As/L in their urine, as compared with less exposed anisms of cell defense and is also a vulnerable target for toxic subjects (71 ± 13 ␮g As/L), without significant differences in blood compounds, transforming itself in a factor for redox imbalance and SOD activity. Elevated serum LPO concentrations were correlated oxidative stress. Numerous enzymatic and non-enzymatic factors with blood levels of inorganic As and its methylated metabolites.
participate in cell protection by clearing and scavenging ROS to In addition, there was an inverse correlation with non-protein maintain low intracellular levels oxide dismutase (SOD), sulfhydryl levels in whole blood. Both studies provided evidence catalase (CAT), glutathione transferase (GST), glutathione peroxi- that chronic As exposure via drinking water results in induction of dase (GPx) and HO-1 are among the main enzymatic mechanisms oxidative stress in humans, in agreement with the solid evidence involved in the antioxidant response to As. In the case of non- enzymatic antioxidants, vitamins C and E, carotenoids, flavonoids,oligoelements, such as zinc and selenium, amino-acids (taurine, 3.2. The use of fluorescent probes and electron spin resonance methionine, cystein) and thiol compounds like glutathione (GSH), N-acetylcysteine, alpha-lipoic acid and thioredoxin (TRX) mustbe mentioned Alterations in the antioxidant cell system Arsenic exposure induces oxidative stress in humans but in have been reported in many pathologies involving metal-induced order to evaluate its magnitude, the measurement of ROS in bio- oxidative stress The antioxidant response to As seems to logical media of exposed individuals needs to be performed. The be time dependent since SOD and CAT activities were shown to more useful techniques are fluorescent probes to detect ROS or increase initially but later declined after prolonged exposure the use of ESR to identify oxygen radicals. Fluorescent probes are Arsenic-induced damage in the antioxidant system involves sev- tools with high sensitivity for detecting 1O eral mechanisms such as altered SOD, CAT and GPx expression in human samples Dihydro-compounds such as 6-carboxy- modification of cellular antioxidant uptake, GSH and vitamin deple- 2 ,7 -dichlorodihydrofluorescein diacetate (DCFH-DA) were used A. De Vizcaya-Ruiz et al. / Mutation Research 674 (2009) 85–92 to detect ROS generation in peripheral blood mononuclear cells lia, China, showed that MMA was significantly higher in subjects (PBMC) from individuals chronically exposed to As and pre- presenting arsenical dermatosis than in those without the dis- senting skin lesions (204 ± 102 ␮g As/L in drinking water and ease, despite no significant differences in the average As levels in 535 ± 346 ␮g As/L in urine), as compared with less exposed indi- well water. Urinary As species and metabolites were significantly viduals (6 ± 1 and 27 ± 11 ␮g As/L, respectively). A significantly associated with 8-OHdG, suggesting a link between As exposure, higher amount of ROS was detected in highly exposed individ- oxidative DNA lesions and the presence of As-induced dermatosis uals (611 ± 48 arbitrary units) as compared with less exposed individuals (350 ± 51 arbitrary units). High As exposure signifi- In addition, evidence linking 8-oxoguanine oxidation products cantly reduced the mitochondrial membrane potential, increased with precancerous and cancerous lesions with As exposure has the release of cytochrome c to the cytosol, damaged DNA, lowered been reported. Studies in Inner Mongolia, China reported on the Bcl-2 expression, up-regulated Bax expression and caused cell cycle effects of chronic As exposure via drinking water on 8-oxoguanine- arrest at G1 in PBMC owever, the limitations of fluorescent DNA glycosylase (OGG1) expression. OGG1 encodes 8-oxoguanine probes to measure intracellular ROS generation in human samples DNA glycosylase, the main enzyme responsible for removing 8- should be considered since they tend to react with a wide variety oxoguanine from DNA. The induction of OGG1 expression has of ROS and are not completely photostable been shown to correlate with the repair capacity of 8-oxoguanine Another widely used approach to determine ROS generation The expression of OGG1 was positively associated with in human samples is ESR which allows measurement of sev- As concentrations in water, reaching its maximum expression at eral types of radical species induced by oxidative stressors. ESR 149 ␮g As/L. OGG1 expression was also significantly associated with allows the detection of unpaired electrons and since radical species nail As concentrations but inversely associated with nail selenium have an extremely short half-life (t1/2 = 10−9–10 s), spin trapping levels. In addition, OGG1 expression showed a significant dose- agents to immobilize and measure them are commonly used. The dependent increased risk of skin hyperkeratosis in men (OR = 2.98 measurement of oxygen species using ESR has shown that As(III) for the highest category of OGG1 expression) but not in women oxidation to As(V) in cells generates O •− authors concluded that OGG1 expression may be a use- As(III) into dimethylarsine was accompanied by the production of ful biomarker for assessing oxidative stress from As exposure. A and •OH in cellular systems ESR spectroscopy stud- hospital-based case–control study was conducted in Taiwan to ies using 5 5-dimethyl-1-pyrroline-N-oxide (DMPO) suggested that evaluate the relationships among urinary levels of 8-OHdG, the pro- the DNA-damaging activity of DMA(III) is an indirect genotoxic file of As species in urine and the presence of urothelial carcinoma effect mediated by a hydroxyl radical-adduct formed concomitantly (UC). The mean urinary concentration of total As was significantly with the oxidation of DMA(III) to DMA(V) mmunodetection of higher in UC patients (37.6 ± 2.9 ␮g/g creat) than in healthy controls spin trapping agents, combining the specificity and sensitivity of (21.1 ± 0.7 ␮g/g creat) and that urinary 8-OHdG levels correlated spin trapping and antigen–antibody interactions, is an alternative with total As urinary concentrations. Multiple linear regression approach to overcome the need for large amounts of radicals and analyses revealed that high urinary 8-OHdG levels were associated protein levels to detect the formation of protein-derived radicals with increased total As, inorganic arsenite, MMA and dimethylarse- owever, these techniques have not been used for detecting nate (DMA) concentrations, as well as the primary methylation radicals resultant from As exposure in humans. Considering the index even after adjusting for age, gender and UC status. The results possible sequence of events: As → superoxide anions → hydrogen suggest that oxidative DNA damage was associated with As expo- peroxide → hydroxyl radicals → genotoxicity/toxicity t would sure, even at low urinary As levels, and that 8-OHdG may be a good be interesting to establish their feasibility and usefulness for studies The associations between urinary concentrations of As, Cr and Ni and the level of oxidative DNA damage were studied in school chil- 3.3. Oxidative DNA damage associated to arsenic exposure dren exposed to emissions from a coal-fired power plant in Taiwan.
The children with higher urinary As and Cr levels (21.3 ± 4.3 and 3.7 ± 0.5 ␮g/g creat, respectively) had the highest urinary 8-OHdG Several products of guanine oxidation in position 8 and excreted levels in urine, followed by those with low As and high Cr levels, and in urine have been used as oxidative DNA damage markers in those with low levels of both elements. The authors concluded that human studies, among them are 8-hydroxy-guanine (8-oxo-G), 8- exposure to As and Cr may play an important role in oxidative DNA hydroxyguanosine (8-oxy-Guo) and 8-hydroxy-2 -deoxyguanosine damage to children and that the role of exposure to other metals (8-OHdG). The analytical methods to detect these markers are tech- should be further investigated study in six villages from Ari- nically challenging since the initial products of the free radical zona (USA) and Sonora (Mexico) studied the relationship between attack on purines, pyrimidines and deoxyribose suffer transforma- As exposure from ≤5 to 40 ␮g As/L in tap water and urinary 8-OHdG tion into stable end products whose relative amounts are highly concentration. There were no significant associations between uri- dependent on reaction conditions and artifactual DNA damage may nary As (13–79 ␮g As/g creat) and 8-OHdG levels, suggesting that occur during isolation is one of the more abundant higher exposures are required to produce oxidative DNA damage base modifications and has attracted special attention because it available evidence supports the idea that 8-OHdG in As- causes G-to-T transversions and its presence may lead to mutagen- exposed human populations is a reliable marker of oxidative DNA esis. Moreover, the repair process of the 8-OHdG-inflicted damage damage at medium and high exposure levels. Thus, it remains to be results in the excised 8-OHdG adduct being excreted in urine, established if the methodologies applied have enough sensitivity to and because of its easy collection it is regarded as a suitable detect low levels of 8-oxodG induced by exposure to low As levels.
oxidative DNA damage biomarker In relation to studies onAs-exposed populations, a study in a Cambodian population chron- ically exposed to As in groundwater (<1–886 ␮g As/L) showed that The single-cell gel electrophoresis or comet assay is based on subjects with elevated levels of As in urine (2.2–119 ng/mg creat) the ability of negatively charged DNA fragments to be resolved in had higher levels of urinary 8-OHdG suggesting that induction of an agarose gel in response to an electric field, the extent of DNA oxidative DNA damage was caused by chronic As exposure migration is directly proportional to the DNA damage present in the A cross-sectional study in an As-affected village in Inner Mongo- cells. The assay is widely used to measure DNA damage and repair A. De Vizcaya-Ruiz et al. / Mutation Research 674 (2009) 85–92 alterations in primary human lymphocytes induced by oxidative ant allele whereas 78% presented the high-risk XRCC1 wild-type 194 species by measuring strand breaks and apurinic sites. Glass work- Trp/Trp genotype. The authors concluded that individuals may have ers from Hyderabad, India chronically exposed to As (12.3 ± 2.3 inherently different odds for developing skin lesions based in part years) had significantly higher blood As concentrations (56.7 ␮g/L) on their genetic profile for BER and their As exposure history when compared with controls (11.7 ␮g/L). The workers had a sig- A study on Bangladeshi healthy women reported a novel interac- nificantly higher level of basal DNA damage, as measured by mean tion between As and GSTM1 genotype in association with urinary tail length (14.9 ␮m) in the comet assay, as compared with controls 8-OHdG. Urinary 8-OHdG concentration increased in response to (8.2 ␮m). The workers also had a significantly higher frequency of high total urinary As concentrations only among women with micronuclei (1.5%) when compared with controls (0.2%). They also the GSTM1 null genotype. These results suggested that individu- showed a significant positive correlation of As levels in whole blood als lacking a functional GSTM1 enzyme cannot properly detoxify with both parameters of lymphocyte genotoxicity Another As, resulting in increased oxidative stress. In addition, the APE1 study comparing workers from three Polish copper smelters hav- 148 Glu allele was associated with decreases in urinary 8-OHdG, ing mean urinary total As levels of 57.0 ± 50.3 ␮g As/L with control suggesting that the polymorphism affects the repair of this adduct individuals having 12.6 ± 20.0 ␮g As/L found significant increases oth studies contribute to a growing body of evidence that in DNA damage, measured as median tail moment, and in oxidative As is associated with oxidative stress and alterations in the repair DNA damage, as measured with the formamidopyrimidine glyco- of oxidative damage, and that the measurement of changes in the sylase digestion method in leukocytes. Although inorganic As was expression of BER genes holds great promise as a susceptibility present in air and urine samples from workers, no clear association biomarker of oxidative DNA damage in human populations exposed with DNA damage was found. The authors suggested that the DNA to oxidant stressors such as As. The data also suggest the increasing damage was caused not only by exposure to As but also to other importance of considering genetic heterogeneity in the pathways agents present in the environment of copper smelters study involved in oxidative stress, and As metabolism as a contributing on children exposed simultaneously to lead and As assessed DNA factor to explain discrepancies in results across studies.
damage and DNA repair ability in lymphocytes by means of thecomet assay and the hydrogen peroxide challenge. Most children 3.4.2. Nucleotide excision DNA repair (NER) (93%) had urinary As concentrations above 50 ␮g/L and 65% had BER enzymes recognize specific lesions in DNA and only repair blood lead levels above 10 ␮g/L. The DNA damage and decreased damaged bases whereas NER participating enzymes identify bulky repair ability in all children were more severe than that reported distortions in the shape of the DNA double helix and initiate the for healthy non-exposed Mexican children. However, multivariate process by removing a short single-stranded DNA segment that analysis did not show significant associations between DNA basal includes the lesion, creating a single-strand gap in the DNA damage and lead or As levels, or evidence of Pb and As interac- The next step involves the correction by DNA polymerase using the tions. Children responding to the peroxide challenge showed that undamaged strand as a template. Arsenic inhibits NER by block- repair ability at 60 min was negatively associated with urinary As ing the ligation and incision steps. One product of NER action is levels. No significant association with Pb or evidence of interac- 8-oxo-7,8-dihydro-2 -deoxyguanosine (8-oxo-dGuo) which could tions between As and Pb was found aken together, the data be identified in urine A study in Taiwanese semiconduc- summarized above contribute to the evidence that oxidative stress tor workers reported a relationship between As exposure and plays a major role in As-induced DNA-damage and that exposure NER pathway products showing a significantly elevated urinary to other contaminants requires further study.
8-oxo-dGuo excretion in exposed workers in comparison with non-exposed workers (9.6 ± 5.1 ␮g/L vs. 3.3 ± 2.3 ␮g/L). The strongest 3.4. Effects of arsenic on ROS defense mechanisms correlation observed was between the urinary levels of 8-oxo-dGuo and MMA monomethylarsonic acid urthermore, genes 3.4.1. Base excision DNA repair (BER) involved in NER, such as the excision repair cross-complement 1 DNA repair systems reduce mutations and chromosomal aber- (ERCC1), have also been identified to be altered in As exposure in rations, remove DNA adducts, correct DNA sequence and rejoin humans. ERCC1 is essential for nucleotide repair and it is known to strand breaks, and BER is the predominant repair pathway for remove 3 single-stranded flaps from DNA ends and cleaves the 5 ROS-induced DNA lesions olymorphisms in XRCC1, APE1 and side of a bubble in NER to excise the lesion. Incision by ERCC1-XPF hOGG1 have been shown to reduce the capacity to repair oxidative creates a 3 OH group that is used to prime DNA synthesis to replace damage. XRCC1 is a scaffolding protein that interacts with enzy- excised bases and it is also involved in homologous recombina- matic components during DNA repair, including polymerase b (POL tion and repair of double-strand breaks and interstrand crosslinks.
b), hOGG1 and APE. It can also repair single strand breaks from the A study carried out in New Hampshire, USA and Sonora, Mex- BER process itself or damage to deoxyribose. APE1 is essential for ico showed that individuals exposed to As concentrations higher apurinic/apyrimidinic excision sites generated during glycosylase than 6 ␮g/L in drinking water had lower ERCC1 expression than initiation of the repair of a damaged base process; it also helps those exposed to less than 6 ␮g/L at both locations. In the New to recruit POL b to facilitate the repair process. hOGG1 is a DNA Hampshire population, ERCC1 expression decreased with increased glycosylase protein that specifically removes adducts from oxida- urinary inorganic As levels and low levels of ERCC1 protein were tively damaged DNA, which mainly acts onto the G:C pair, and, also found in individuals exposed to As concentrations higher than together with hOGG2, removes 8-OHdG and incise the resulting 5 ␮g/L in drinking water. In addition, residents exposed to high As apurinic/apyrimidinic (AP) site by its accompanying AP-lyase activ- levels in water (13–93 ␮g/L) had higher levels of DNA damage as ity through ␤-elimination mechanism. A study on an As exposed indicated by larger olive tail moments than residents exposed to population (6 ␮g/g ± 8.32 in toenail) conducted in Bangladesh with lower levels (<0.7 ␮g/L) ability of As to react with thiols the purpose of investigating effect modifiers of the association of the zinc binding structures present in NER enzymes, such as the between As exposure and skin lesions, explored some polymor- Zn finger proteins XPA and XPD seems to be a plausible explana- phisms in BER genes (XRCC1 Arg399Gln, XRCC1 Arg194Trp, hOGG1 tion for the DNA damage induced by As involvement Ser326Cys and APE1 Asp148Glu). The study provided evidence that of XPA protein in As-induced NER alterations is also supported by a APE1 and XRCC1 were associated with As-induced skin lesions. Only study focused on NER genetic polymorphisms XPA (A23G) and XPD 6% of the population was homozygous for the high-risk APE1 vari- (Asp 312 Asn and Lys 751 Gln) and basal (BCC) and squamous cell A. De Vizcaya-Ruiz et al. / Mutation Research 674 (2009) 85–92 carcinomas (SCC) in an As-exposed population in New Hampshire, gested that the robust and persistent up-regulation of HO-1 could USA. For XPA subjects with homozygous wild-type genotypes and have an important role in cellular adaptation to chronic As expo- high As exposure (>286 ␮g/g in nails) there was an elevated risk sure n addition, a genome-wide expression study aimed to for BCC compared with the homozygous wild-type with lower As explore alterations due to As exposure and As-induced toxicity (OR = 1.8). Variations in XPD at both loci (Asp 312 Asn and Lys 751 in an exposed human population in Bangladesh, showed down- Gln) occurred less frequently (OR = 0.8) in both types of cancer com- regulation in SOD2 expression in individuals with skin lesions, pared with controls. However, in the individuals having a variant indicating an increased vulnerability to ROS generated by As in indi- for both XPD polymorphisms, there was an increased OR (2.2) for viduals with manifest As toxicity. A down-regulated TNF expression was also observed among affected individuals along with down-regulated expression of CCL20, providing support for the idea that 3.5. Effects of arsenic on the antioxidant response As suppresses a chemokine response pathway and is associatedwith deficient wound healing in the exposed individuals Recent studies have indicated that As stimulated defense elements against As-induced oxidative stress, such as HO-1, a 4. Conclusions
cytoprotective enzyme important in heme catabolism, whoseexpression is regulated through transcription of Nrf-2 by the Arsenic is a strong disruptor of cell signaling pathways by stim- antioxidant response element (ARE) Arsenic toxicity in the context of disruptions in the signal transduction cascade, tran- species later on transformed to the more reactive oxygenated scription factors involved and As biotransformation has recently species H2O2 and •OH. The interaction of these species with been reviewed The authors emphasized that alterations in macromolecules leads to oxidative stress, DNA damage, DNA transcription factors such as inhibition of NF-␬B, and activation hypomethylation and hypermethylation, lipid peroxidation and of AP-1 and Nrf-2 during As exposure may occur through: (i) alterations in regulatory mechanisms of cell proliferation and ROS production and/or (ii) an electrophilic metabolite of As (e.g., death. Furthermore, various enzymatic and non-enzymatic ele- MMeAs(III)) that reacts readily with the reactive thiols of Keap1 ments in response to oxidative stress are altered by As exposure, and suggested that Nrf-2 antioxidant genes, such as HO-1 could among these are SOD, CAT, GPx and HO-1.
be an effective molecular target to counteract As induced-toxicity.
The advances in oxidative stress measurement techniques Furthermore, the expression of HO-1 involving ERK/MAPK acti- have not yet been fully exploited to improve the monitoring of vation and ROS generation in human keratinocyte HaCaT cells populations exposed to environmental contaminants, particularly exposed to arsenite (0–30 ␮M) was reported and the authors sug- regarding the relationship between oxidative stress and disease Table 1
Biomarkers of effects and damage in human populations exposed to arsenic.
power plant exposed to As and Cr– Taiwan 30.6 ± 13.2 ␮g As/L in urine-A;46.6 ± 21.7 ␮g As/L in urine-M A. De Vizcaya-Ruiz et al. / Mutation Research 674 (2009) 85–92 outcomes. However, the more extensively used biomarkers of [17] Y. Higaki, T. Mikami, N. Fujii, M.F. Hirshman, K. Koyama, T. Seino, K. Tanaka, L.J.
oxidative DNA damage in As-exposed populations are the urinary Goodyear, Oxidative stress stimulates skeletal muscle glucose uptake through aphosphatidylinositol-3-kinase-dependent pathway, Am. J. Physiol. Endocrinol.
excretion of 8-OHdG and the comet assay in lymphocytes. More recently DNA repair mechanism markers from the BER and NER [18] Y. Chen, E. McMillan-Ward, J. Kong, S.J. Israels, S.B. Gibson, Oxidative stress pathways have also been successfully used as indicators of oxida- induces autophagic cell death independent of apoptosis in transformed andcancer cells, Cell Death Differ. 15 (2008) 171–182.
tive stress and repair of oxidative damage associated to As exposure [19] S. Xu, R.M. Touyz, Reactive oxygen species and vascular remodelling in hyper- tension: still alive, Can. J. Cardiol. 22 (2006) 947–951.
Gene–gene and gene–environment interactions, including diet, [20] J. Pouyssegur, F. Mechta-Grigoriou, Redox regulation of the hypoxia-inducible are involved in As-induced health effects, including genomic insta- factor, Biol. Chem. 387 (2006) 1337–1346.
[21] J.M. Cook-Mills, Hydrogen peroxide activation of endothelial cell-associated bility and oxidative stress. Thus, genetic heterogeneity in the MMPs during VCAM-1-dependent leukocyte migration, Cell. Mol. Biol. (Noisy- pathways involved in oxidative stress and As metabolism appear to be an important contributing factor to disease outcomes. Fur- [22] Bharathi, R. Ravid, K.S. Rao, Role of metals in neuronal apoptosis: challenges associated with neurodegeneration, Curr. Alzheimer Res. 3 (2006) 311–326.
ther refinement of human exposure assessment is needed since [23] J.V. Cross, D.J. Templeton, Regulation of signal transduction through protein this is often the weakest link when designing studies to evalu- cysteine oxidation, Antioxid Redox Signal 8 (2006) 1819–1827.
ate exposure–response relationships and study gene–environment [24] I. Dalle-Donne, A. Milzani, N. Gagliano, R. Colombo, D. Giustarini, R.
Rossi, Molecular mechanisms and potential clinical significance of S- interactions. Further studies using microarray-based gene expres- glutathionylation, Antioxid Redox Signal 10 (2008) 445–473.
sion analysis are needed to characterize the molecular profile of As [25] M.E. Goetz, A. Luch, Reactive species: a cell damaging rout assisting to chemical exposure and its relationship with As-induced diseases. The genes carcinogens, Cancer Lett. 266 (2008) 73–83.
[26] R. Franco, O. Schoneveld, A.G. Georgakilas, M.I. Panayiotidis, Oxidative stress, identified from this analysis may provide insights into the under- DNA methylation and carcinogenesis, Cancer Lett. 266 (2008) 6–11.
lying mechanisms of disease and may aid to identify target genes [27] B. Halliwell, Oxidative stress and cancer: have we moved forward? Biochem. J.
susceptible to be modulated to prevent disease.
[28] K.E. Eblin, M.E. Bowen, D.W. Cromey, T.G. Bredfeldt, E.A. Mash, S.S. Lau, A.J.
Gandolfi, Arsenite and monomethylarsonous acid generate oxidative stress Conflict of interest statement
response in human bladder cell culture, Toxicol. Appl. Pharmacol. 217 (2006)7–14.
[29] S.M. Cohen, T. Ohnishi, L.L. Arnold, X.C. Le, Arsenic-induced bladder cancer in The authors declare that there are no conflicts of interest.
an animal model, Toxicol. Appl. Pharmacol. 222 (2007) 258–263.
[30] K.T. Kitchin, K. Wallace, The role of protein binding of trivalent arsenicals in arsenic carcinogenesis and toxicity, J. Inorg. Biochem. 102 (2008) 532–539.
References
[31] H. Chen, S. Li, J. Liu, B.A. Diwan, J.C. Barrett, M.P. Waalkes, Chronic inorganic arsenic exposure induces hepatic global and individual gene hypomethyla- [1] Y. Kumagai, D. Sumi, Arsenic: signal transduction, transcription factor, and bio- tion: implications for arsenic hepatocarcinogenesis, Carcinogenesis 25 (2004) transformation involved in cellular response and toxicity, Annu. Rev. Pharmacol.
[32] Y. Kumagai, J. Pi, Molecular basis for arsenic-induced alteration in nitric oxide [2] H. Shi, X. Shi, K.J. Liu, Oxidative mechanism of arsenic toxicity and carcinogen- production and oxidative stress: implication of endothelial dysfunction, Toxicol.
esis, Mol. Cell. Biochem. 255 (2004) 67–78.
Appl. Pharmacol. 198 (2004) 450–457.
[3] A.D. Kligerman, A.H. Tennant, Insights into the carcinogenic mode of action of [33] S. Hirano, Y. Kobayashi, X. Cui, S. Kanno, T. Hayakawa, A. Shraim, The accumula- arsenic, Toxicol. Appl. Pharmacol. 222 (2007) 281–288.
tion and toxicity of methylated arsenicals in endothelial cells: important roles [4] A. Szymanska-Chabowska, J. Antonowicz-Juchniewicz, R. Andrzejak, The con- of thiol compounds, Toxicol. Appl. Pharmacol. 198 (2004) 458–467.
centration of selected cancer markers (TPA, TPS, CYFRA 21-1, CEA) in workers [34] M. Valko, D. Leibfritz, J. Moncol, M.T. Cronin, M. Mazur, J. Telser, Free radicals occupationally exposed to arsenic (As) and some heavy metals (Pb, Cd) dur- and antioxidants in normal physiological functions and human disease, Int. J.
ing a two-year observation study, Int. J. Occup. Med. Environ. Health 20 (2007) Biochem. Cell. Biol. 39 (2007) 44–84.
[35] D. Beyersmann, A. Hartwig, Carcinogenic metal compounds: recent insight into [5] A. Diaz-Villasenor, A.L. Burns, M. Hiriart, M.E. Cebrian, P. Ostrosky-Wegman, molecular and cellular mechanisms, Arch. Toxicol. 82 (2008) 493–512.
Arsenic-induced alteration in the expression of genes related to type 2 diabetes [36] D. Nandi, R.C. Patra, D. Swarup, Effect of cysteine, methionine, ascorbic acid mellitus, Toxicol. Appl. Pharmacol. 225 (2007) 123–133.
and thiamine on arsenic-induced oxidative stress and biochemical alterations [6] A. Navas-Acien, A.R. Sharrett, E.K. Silbergeld, B.S. Schwartz, K.E. Nachman, T.A.
in rats, Toxicology 211 (2005) 26–35.
Burke, E. Guallar, Arsenic exposure and cardiovascular disease: a systematic [37] Y.H. Han, S.H. Kim, S.Z. Kim, W.H. Park, Apoptosis in arsenic trioxide-treated review of the epidemiologic evidence, Am. J. Epidemiol. 162 (2005) 1037– Calu-6 lung cells is correlated with the depletion of GSH levels rather than the changes of ROS levels, J. Cell. Biochem. 104 (2008) 862–878.
[7] W.C. Prozialeck, J.R. Edwards, D.W. Nebert, J.M. Woods, A. Barchowsky, W.D.
[38] S.J. Flora, Arsenic-induced oxidative stress and its reversibility following com- Atchison, The vascular system as a target of metal toxicity, Toxicol. Sci. 102 bined administration of N-acetylcysteine and meso 2,3-dimercaptosuccinic acid in rats, Clin. Exp. Pharmacol. Physiol. 26 (1999) 865–869.
[8] E.M. Schmuck, P.G. Board, A.K. Whitbread, N. Tetlow, J.A. Cavanaugh, A.C. Black- [39] E. Garcia-Chavez, I. Jimenez, B. Segura, L.M. Del Razo, Lipid oxidative damage burn, A. Masoumi, Characterization of the monomethylarsonate reductase and distribution of inorganic arsenic and its metabolites in the rat nervous and dehydroascorbate reductase activities of Omega class glutathione trans- system after arsenite exposure: influence of alpha tocopherol supplementation, ferase variants: implications for arsenic metabolism and the age-at-onset of Neurotoxicology 27 (2006) 1024–1031.
Alzheimer’s and Parkinson’s diseases, Pharmacogenet. Genomics 15 (2005) [40] K.E. Eblin, T.G. Bredfeldt, S. Buffington, A.J. Gandolfi, Mitogenic signal trans- duction caused by monomethylarsonous acid in human bladder cells: role in [9] A. Vahidnia, G.B. van der Voet, F.A. de Wolff, Arsenic neurotoxicity—a review, arsenic-induced carcinogenesis, Toxicol. Sci. 95 (2007) 321–330.
Hum. Exp. Toxicol. 26 (2007) 823–832.
[41] M. Valko, C.J. Rhodes, J. Moncol, M. Izakovic, M. Mazur, Free radicals, metals [10] B. Halliwell, M. Whiteman, Measuring reactive species and oxidative damage and antioxidants in oxidative stress-induced cancer, Chem. Biol. Interact. 160 in vivo and in cell culture: how should you do it and what do the results mean? Br. J. Pharmacol. 142 (2004) 231–255.
[42] M.M. Wu, H.Y. Chiou, T.W. Wang, Y.M. Hsueh, I.H. Wang, C.J. Chen, T.C. Lee, Asso- [11] J. Pourahmad, M. Rabiei, F. Jokar, P.J. O’Brien, A comparison of hepatocyte cyto- ciation of blood arsenic levels with increased reactive oxidants and decreased toxic mechanisms for chromate and arsenite, Toxicology 206 (2005) 449–460.
antioxidant capacity in a human population of northeastern Taiwan, Environ.
[12] S. Jana, J. Paliwal, Molecular mechanisms of cytochrome p450 induction: poten- Health Perspect. 109 (2001) 1011–1017.
tial for drug–drug interactions, Curr. Protein Pept. Sci. 8 (2007) 619–628.
[43] J. Pi, H. Yamauchi, Y. Kumagai, G. Sun, T. Yoshida, H. Aikawa, C. Hopenhayn- [13] K. Yamanaka, S. Okada, Induction of lung-specific DNA damage by metaboli- Rich, N. Shimojo, Evidence for induction of oxidative stress caused by chronic cally methylated arsenics via the production of free radicals, Environ. Health exposure of Chinese residents to arsenic contained in drinking water, Environ.
Perspect. 102 (Suppl. 3) (1994) 37–40.
Health Perspect. 110 (2002) 331–336.
[14] A. Barchowsky, L.R. Klei, E.J. Dudek, H.M. Swartz, P.E. James, Stimulation of [44] R. Kadirvel, K. Sundaram, S. Mani, S. Samuel, N. Elango, C. Panneerselvam, Sup- reactive oxygen, but not reactive nitrogen species, in vascular endothelial cells plementation of ascorbic acid and alpha-tocopherol prevents arsenic-induced exposed to low levels of arsenite, Free Radic. Biol. Med. 27 (1999) 1405–1412.
protein oxidation and DNA damage induced by arsenic in rats, Hum. Exp. Toxi- [15] S.X. Liu, M. Athar, I. Lippai, C. Waldren, T.K. Hei, Induction of oxyradicals by arsenic: implication for mechanism of genotoxicity, Proc. Natl. Acad. Sci. U.S.A.
[45] A. Kinoshita, H. Wanibuchi, M. Wei, T. Yunoki, S. Fukushima, Elevation of 8- hydroxydeoxyguanosine and cell proliferation via generation of oxidative stress [16] K.T. Kitchin, S. Ahmad, Oxidative stress as a possible mode of action for arsenic by organic arsenicals contributes to their carcinogenicity in the rat liver and carcinogenesis, Toxicol. Lett. 137 (2003) 3–13.
bladder, Toxicol. Appl. Pharmacol. 221 (2007) 295–305.
A. De Vizcaya-Ruiz et al. / Mutation Research 674 (2009) 85–92 [46] P. Wardman, Fluorescent and luminescent probes for measurement of oxidative [61] J. Méndez-Gómez, G.G. García-Vargas, L. López-Carrillo, E.S. Calderón-Aranda, and nitrosative species in cells and tissues: progress, pitfalls, and prospects, Free A. Gómez, E. Vera, M. Valverde, M.E. Cebrián, E. Rojas, Genotoxic Effects of envi- Radic. Biol. Med. 43 (2007) 995–1022.
ronmental exposure to arsenic and lead on children in region Lagunera, Mexico, [47] N. Banerjee, M. Banerjee, S. Ganguly, S. Bandyopadhyay, J.K. Das, A. Bandyopad- hay, M. Chatterjee, A.K. Giri, Arsenic-induced mitochondrial instability leading [62] C.L. Powell, J.A. Swenberg, I. Rusyn, Expression of base excision DNA repair to programmed cell death in the exposed individuals, Toxicology 246 (2008) genes as a biomarker of oxidative DNA damage, Cancer Lett. 229 (2005) [48] N. Soh, Recent advances in fluorescent probes for the detection of reactive [63] C.V. Breton, W. Zhou, M.L. Kile, E.A. Houseman, Q. Quamruzzaman, M. Rahman, oxygen species, Anal. Bioanal. Chem. 386 (2006) 532–543.
G. Mahiuddin, D.C. Christiani, Susceptibility to arsenic-induced skin lesions [49] S. Nesnow, B.C. Roop, G. Lambert, M. Kadiiska, R.P. Mason, W.R. Cullen, M.J.
from polymorphisms in base excision repair genes, Carcinogenesis 28 (2007) Mass, DNA damage induced by methylated trivalent arsenicals is mediated by reactive oxygen species, Chem. Res. Toxicol. 15 (2002) 1627–1634.
[64] C.V. Breton, M.L. Kile, P.J. Catalano, E. Hoffman, Q. Quamruzzaman, M. Rahman, [50] R.P. Mason, Using anti-5,5-dimethyl-1-pyrroline N-oxide (anti-DMPO) to detect G. Mahiuddin, D.C. Christiani, GSTM1 and APE1 genotypes affect arsenic- protein radicals in time and space with immuno-spin trapping, Free Radic. Biol.
induced oxidative stress: a repeated measures study, Environ. Health 6 (2007) [51] R.H. Wong, C.Y. Kuo, M.L. Hsu, T.Y. Wang, P.I. Chang, T.H. Wu, S. Huang, Increased [65] J.H. Hoeijmakers, Genome maintenance mechanisms for preventing cancer, levels of 8-hydroxy-2-deoxyguanosine attributable to carcinogenic metal expo- sure among schoolchildren, Environ. Health Perspect. 113 (2005) 1386–1390.
[66] M.S. Cooke, M.D. Evans, R. Dove, R. Rozalski, D. Gackowski, A. Siomek, J. Lunec, [52] R. Kubota, T. Kunito, T. Agusa, J. Fujihara, I. Monirith, H. Iwata, A. Subrama- R. Olinski, DNA repair is responsible for the presence of oxidatively damaged nian, T.S. Tana, S. Tanabe, Urinary 8-hydroxy-2’-deoxyguanosine in inhabitants DNA lesions in urine, Mutat. Res. 574 (2005) 58–66.
chronically exposed to arsenic in groundwater in Cambodia, J. Environ. Monit.
[67] C.W. Hu, C.H. Pan, Y.L. Huang, M.T. Wu, L.W. Chang, C.J. Wang, M.R. Chao, Effects of arsenic exposure among semiconductor workers: a cautionary note on uri- [53] Y. Fujino, X. Guo, J. Liu, I.P. Matthews, K. Shirane, K. Wu, H. Kasai, M. Miy- nary 8-oxo-7,8-dihydro-2’-deoxyguanosine, Free Radic. Biol. Med. 40 (2006) atake, K. Tanabe, T. Kusuda, T. Yoshimura, Chronic arsenic exposure and urinary 8-hydroxy-2’-deoxyguanosine in an arsenic-affected area in Inner Mongolia, [68] A.S. Andrew, J.L. Burgess, M.M. Meza, E. Demidenko, M.G. Waugh, J.W. Hamilton, China, J. Expo. Anal. Environ. Epidemiol. 15 (2005) 147–152.
M.R. Karagas, Arsenic exposure is associated with decreased DNA repair in vitro [54] S. Kondo, S. Toyokuni, T. Tanaka, H. Hiai, H. Onodera, H. Kasai, M. Imamura, and in individuals exposed to drinking water arsenic, Environ. Health Perspect.
Overexpression of the hOGG1 gene and high 8-hydroxy-2’-deoxyguanosine (8- OHdG) lyase activity in human colorectal carcinoma: regulation mechanism of [69] K. Piatek, T. Schwerdtle, A. Hartwig, W. Bal, Monomethylarsonous acid destroys the 8-OHdG level in DNA, Clin. Cancer Res. 6 (2000) 1394–1400.
a tetrathiolate zinc finger much more efficiently than inorganic arsenite: mech- [55] D.J. Smart, J.K. Chipman, N.J. Hodges, Activity of OGG1 variants in the repair anistic considerations and consequences for DNA repair inhibition, Chem. Res.
of pro-oxidant-induced 8-oxo-2’-deoxyguanosine, DNA Repair (Amst) 5 (2006) [70] K.M. Applebaum, M.R. Karagas, D.J. Hunter, P.J. Catalano, S.H. Byler, S. Mor- [56] J. Mo, Y. Xia, T.J. Wade, M. Schmitt, X.C. Le, R. Dang, J.L. Mumford, Chronic arsenic ris, H.H. Nelson, Polymorphisms in nucleotide excision repair genes, arsenic exposure and oxidative stress: OGG1 expression and arsenic exposure, nail sele- exposure, and non-melanoma skin cancer in New Hampshire, Environ. Health nium, and skin hyperkeratosis in Inner Mongolia, Environ. Health Perspect. 114 [71] H.O. Pae, E.C. Kim, H.T. Chung, Integrative survival response evoked by heme [57] C.J. Chung, C.J. Huang, Y.S. Pu, C.T. Su, Y.K. Huang, Y.T. Chen, Y.M. Hsueh, Uri- oxygenase-1 and heme metabolites, J. Clin. Biochem. Nutr. 42 (2008) 197–203.
nary 8-hydroxydeoxyguanosine and urothelial carcinoma risk in low arsenic [72] K.L. Cooper, K.J. Liu, L.G. Hudson, Contributions of reactive oxygen species exposure area, Toxicol. Appl. Pharmacol. 226 (2008) 14–21.
and mitogen-activated protein kinase signaling in arsenite-stimulated [58] J.L. Burgess, M.M. Meza, A.B. Josyula, G.S. Poplin, M.J. Kopplin, H.E. McClellen, S. Sturup, R.C. Lantz, Environmental arsenic exposure and urinary 8-OHdG in arizona and sonora, Clin. Toxicol. (Phila) 45 (2007) 490–498.
[73] M. Argos, M.G. Kibriya, F. Parvez, F. Jasmine, M. Rakibuz-Zaman, H. Ahsan, Gene [59] S.B. Vuyyuri, M. Ishaq, D. Kuppala, P. Grover, Y.R. Ahuja, Evaluation of micronu- expression profiles in peripheral lymphocytes by arsenic exposure and skin cleus frequencies and DNA damage in glass workers exposed to arsenic, Environ.
lesion status in a Bangladeshi population, Cancer Epidemiol. Biomarkers Prev.
[60] J. Palus, D. Lewinska, E. Dziubaltowska, M. Stepnik, J. Beck, K. Rydzynski, R. Nils- [74] H. Yamauchi, Y. Aminaka, K. Yoshida, G. Sun, J. Pi, M.P. Waalkes, Eval- son, DNA damage in leukocytes of workers occupationally exposed to arsenic uation of DNA damage in patients with arsenic poisoning: urinary in copper smelters, Environ. Mol. Mutagen. 46 (2005) 81–87.
8-hydroxydeoxyguanine, Toxicol. Appl. Pharmacol. 198 (2004) 291–296.

Source: http://toxicologia.cinvestav.mx/Portals/0/SiteDocs/Publicaciones/De%20Vizcaya/De%20vizcaya%20review.pdf