Mutation Research 674 (2009) 85–92 Contents lists available at ScienceDirect Mutation Research/Genetic Toxicology and Environmental Mutagenesis journal homepage: www.elsevier.com/locate/gentox Community address: www.elsevier.com/locate/mutres Mini-review Biomarkers of oxidative stress and damage in human populations exposed to arsenic Andrea De Vizcaya-Ruiz a , Olivier Barbier a , Ruben Ruiz-Ramos b , Mariano E. Cebrian a,∗ a Sección Externa de Toxicología, Centro de Investigación y Estudios Avanzados del I.P.N., Avenida Instituto Politécnico Nacional 2508, México, D.F., 07360 Mexico b Centro de Investigación en Salud Poblacional INSP, Cuernavaca, Morelos, Mexico article info Article history: Received 25 September 2008 Accepted 29 September 2008 Available online 15 October 2008 Keywords: Arsenic Oxidative stress 8-OHdG Antioxidant response abstract 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 mechanisms of 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 literature describing the molecular mechanisms affected by As, as well as the most used biomarkers of oxidative stress and damage in human populations. The most reported biomarkers of oxidative DNA damage are the urinary 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 heterogeneity in 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 evaluate exposure–response relationships and study gene–environment interactions. The use of microarray-based gene expression analysis can provide better insights of the underlying mechanisms involved in As-induced diseases and could help to identify target genes that can be modulated to prevent disease. © 2008 Elsevier B.V. All rights reserved. Contents 1. Introduction .......................................................................................................................................... 86 2. Arsenic, oxidative stress and their biological implications .......................................................................................... 86 2.1. Arsenic-induced ROS generation and oxidative damage ..................................................................................... 86 2.2. The antioxidant response and arsenic ........................................................................................................ 87 Abbreviations: (CH3)2As • , Dimethylarsinic radical; (CH3)2AsOO • , Dimethylarsinic peroxyl; • OH, Hydroxyl radical; 1 O2, 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, Antioxidant response 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; O2, Oxygen; O2 •- , 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, Protein kinase 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 complementing defective 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: mcebrian@cinvestav.mx (M.E. Cebrian). 1383-5718/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.mrgentox.2008.09.020