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Arsenic Exposure and the Induction of Human Cancers

By Victor D. Martinez, Emily A. Vucic, Daiana D. Becker-Santos, Lionel Gil and Wan L. Lam


Arsenic is a metalloid, that is, considered to be a human carcinogen. Millions of individuals worldwide are chronically exposed through drinking water, with consequences ranging from acute toxicities to development of malignancies, such as skin and lung cancer. Despite well-known arsenic-related health effects, the molecular mechanisms involved are not fully understood; however, the arsenic biotransformation process, which includes methylation changes, is thought to play a key role. This paper explores the relationship of arsenic exposure with cancer development and summarizes current knowledge of the potential mechanisms that may contribute to the neoplastic processes observed in arsenic exposed human populations

Topics: Review Article
Publisher: Hindawi Publishing Corporation
OAI identifier:
Provided by: PubMed Central

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  1. (2005). A Field Guide for Detection, Management, and Surveillance of Arsenicosis Cases, World Health Organization, Regional Office of South-East Asia,
  2. (2002). A novel S-adenosylL-methionine:arsenic(III) methyltransferase from rat liver cytosol,”
  3. (2011). A prospective study of the synergistic effects of arsenic exposure and smoking, sun exposure, fertilizer use, and pesticide use on risk of premalignant skin lesions in Bangladeshi men,”
  4. A.D.Kligerman,S.I.Malik,andJ.A.Campbell,“Cytogenetic insights into DNA damage and repair of lesions induced by a monomethylated trivalent arsenical,”
  5. (1999). Academy Press,
  6. (1998). Activation of MAPKs in human bronchial epithelial cells exposed to metals,”
  7. (2008). Acute promyelocytic leukemia: from highly fatal to highly curable,”
  8. Agency for Toxic Substances and Disease Registry (ATSDR), Arsenic Toxicity, U.S. Department of Health and Human Services,
  9. (2007). Agency for Toxic Substances and Disease Registry (ATSDR), Toxicological Profile for Arsenic,
  10. (2011). An emerging role for epigenetic dysregulation in arsenic toxicity and carcinogenesis,” Environmental Health Perspectives,
  11. and GSTM1 genetic polymorphisms in lung cancer populations exposed to arsenic in drinking water,”
  12. (1997). Arsenic alters cytosine methylation patterns of the promoter of the tumor suppressor gene p53 in human lung cells: a model for a mechanism of carcinogenesis,”
  13. (2002). Arsenic calamity in the Indian subcontinent: what lessons have been learned?”
  14. (1981). Arsenic dose in patients with cutaneous carcinomata and hepatic haemangio-endothelioma after environmental and occupational exposure,”
  15. (2008). Arsenic in drinking water and lung cancer: a systematic review,”
  16. (2001). Arsenic in drinking water and skin cancers: cell-type specificity (Taiwan,
  17. (2008). Arsenic in drinking-water and risk for cancer in Denmark,” Environmental Health Perspectives,
  18. (1992). Arsenic ingestion and internal cancers: a review,”
  19. Arsenic promotes centrosome abnormalities and cell colony formationinp53compromisedhumanlungcells,”Toxicology andAppliedPharmacology,vol.225,no.2,pp.162–170,2007.
  20. (2008). Arsenic-induced changes in the gene expression of lung epithelial L2 cells: implications in carcinogenesis,”
  21. (1993). Arsenic-induced DNA-strand breaks associated with DNA-protein crosslinks in human fetal lung fibroblasts,”
  22. (2005). Arsenic: in search of an antidote to a global poison,”
  23. (1960). Arsenical skin cancer and lung cancer. A report of two cases,”
  24. (2008). Arsenicinduced health effects and genetic damage in keratotic individuals: involvement of p53 arginine variant and chromosomal aberrations in arsenic susceptibility,”
  25. (2010). Arsenicrelated DNA copy-number alterations in lung squamous cell carcinomas,”
  26. (1997). Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression,”
  27. (2000). Basal cell carcinoma in chronic arsenicism occurring in Queensland, Australia, after ingestion of an asthma medication,”
  28. (1996). Bladder cancer mortality associated with arsenic in drinking water in
  29. (1986). C h e n ,Y .C .C h u a n g ,a n dS .L .Y o u ,“ Ar e t r o s p e c t i v e study on malignant neoplasms of bladder, lung and liver in blackfoot disease endemic area in Taiwan,”
  30. (1995). C h e n ,Y .M .H s u e h ,M .S .L a ie ta l . ,“ I n c r e a s e dp r e v -alence of hypertension and long-term arsenic exposure,”
  31. (2001). c-Jun N-terminal kinase on p53-independent GADD45 induction by arsenite,”
  32. (1992). Cancer risks from arsenic in drinking water,”
  33. (2006). Carcinogen exposure and epigenetic silencing
  34. (2002). Chromatin modification and epigenetic reprogramming in mammalian development,”
  35. (2007). Chromatin modifications and their function,”
  36. (2004). Chronic health effects in people exposed to arsenic via the drinking water: dose-response relationships in review,”
  37. (2006). Chronic oral exposure to inorganic arsenate interferes with methylation status of p16INK4a and RASSF1A and induces lung cancer
  38. (2000). Contamination of drinking-water by arsenic in Bangladesh: a public health emergency,”
  39. (2008). Crosstalk between calcium and redox signaling: from molecular mechanisms to health implications,”
  40. (1998). Cutaneous manifestations of chronic arsenicism: review of seventeen cases,”
  41. (2000). Diagnosis and treatment of chronic arsenic poisoning,” in United Nations Synthesis Report on Arsenic in Drinking Water,
  42. (2001). Differential effects of trivalent and pentavalent arsenicals on cell proliferation and cytokine secretion in normal human epidermal keratinocytes,”
  43. (2007). Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome,”
  44. (2006). DNA hypermethylation of promoter of gene p53 and p16 in arsenic-exposed people with and without malignancy,”
  45. (1990). Ecological correlation between arsenic level in well water and age-adjusted mortality from malignant neoplasms,”
  46. (1977). Effects and dose response relationships of skin cancer and blackfoot disease with arsenic,”
  47. (2004). Effects and interactions of low doses of arsenic and
  48. (2010). Effects of arsenic exposure on DNA methylation and epigenetic gene regulation,”
  49. (2001). Environmental Protection Agency (EPA), Technical Fact Sheet: Proposed Rule for Arsenic
  50. (2008). Epigenetic remodeling during arsenical-induced malignant transformation,” Carcinogenesis,v o l .2 9 ,n o .8 ,p p .
  51. (2009). European Food Safety Authority (EFSA) and EFSA Panel on Contaminants in the Food Chain (CONTAM), “Scientific opinion on arsenic in food,”
  52. (2004). Evidence that arsenite acts as a cocarcinogen in skin cancer,”
  53. (2007). Exposure to arsenic at levels found in U.S. drinking water modifies expressioninthemouselung,”Toxicological
  54. (2007). Fetal onset of aberrant gene expression relevant to pulmonary carcinogenesis in lung adenocarcinoma development induced by in utero arsenic exposure,”
  55. (2007). Fifty-Year study of lung and bladder cancer mortality in Chile related to arsenic in drinking water,”
  56. (2006). Free radicals, metals and antioxidants in oxidative stress-induced cancer,”
  57. (2003). G r e g o r i ,E .F u e n t e s ,M .R o j a s ,H .P i n o c h e t ,a n dM . Potin-Gautier, “Monitoring of copper, arsenic and antimony levels in agricultural soils impacted and non-impacted by mining activities, from three regions in
  58. (2008). G.Wen,G.M.Calaf,M.A.Partridgeetal.,“Neoplastictransformation of human small airway epithelial cells induced by arsenic,”
  59. (2010). Gene expression of normal human epidermal keratinocytes modulated by trivalent arsenicals,”
  60. (2006). Genomic DNA methylation: the mark and its mediators,”
  61. (1985). H.B.Nicolli,T.E.O’Connor,andJ.M.Suriano,“Geoquimica del arsenico y de otros oligoelementos en aguas subterraneas de la llanura Sudoriental de la provinda de
  62. (2010). Histone deacetylase inhibitors downregulate checkpoint kinase 1 expression to induce cell death in non-small cell lung cancer cells,”
  63. (2004). Histones and histone modifications,”
  64. (2003). Huang et al., “Determinants of inorganic arsenic methylation capability among residents of the Lanyang Basin, Taiwan: arsenic and selenium exposure and alcohol consumption,”
  65. (2009). i n g ,K .M y e r s ,S .B o t t o m l e y ,T .H e l l e d a y ,a n dH .E . Bryant, “BRCA2-dependent homologous recombination is required for repair of Arsenite-induced replication lesions in mammalian cells,”
  66. (1995). Incidence of internal cancers and ingested inorganic arsenic: a seven- yearJournal of Toxicology 11 follow-up study in
  67. Induction of DNA strand breaks, DNA-protein crosslinks and sister chromatid exchanges by arsenite in a human lung cellline,”ToxicologyinVitro,vol.20,no.3,pp.279–285,2006.
  68. (1995). Ingested arsenic and internal cancer: a historical cohort study followed for 33years,”
  69. (2004). Ingested arsenic, cigarette smoking, and lung cancer risk: a follow-up study in arseniasis-endemic areas in
  70. (2004). International Agency for Cancer Research (IARC), “Some drinking-water disinfectants and contaminants, including arsenic,”
  71. (1995). Involvement of preferential formation of apurinic/apyrimidinicsitesindimethylarsenic-inducedDNA strand breaks and DNA-protein crosslinks in cultured alveolar epithelial cells,”
  72. (2003). K.C.Saha,“Diagnosisofarsenicosis,”JournalofEnvironment a lS c i e n c ea n dH e a l t hP a r tA ,
  73. (2004). Kelsey,“Lowdoseexposuretosodiumarsenitesynergistically interacts with UV radiation to induce mutations and alter DNA repair in human cells,” Mutagenesis,v o l .1 9 ,n o .2 ,p p .
  74. (2011). KRAS-mutated non-small cell lung cancer cells are responsive to either cotreatment with erlotinib or gefitinib and histone deacetylase inhibitors or single treatment with lapatinib,” Oncology Reports,
  75. (1997). L.M.DelRazo,G.G.Garc´ ıa-Vargas,H.Vargasetal.,“Altered profile of urinary arsenic metabolites in adults with chronic arsenicism. A pilot study,”
  76. (1998). Lung and kidney cancer mortality associated with arsenic in drinking water in Cordoba,
  77. (2000). Lung cancer and arsenic concentrationsindrinkingwaterinChile,”Epidemiology,vol.
  78. (2008). Lung cancer and exposure to arsenic in rural
  79. (2000). M o r a l e s ,L .R y a n
  80. (1998). Marked increase in bladder and lung cancer mortality in a region of northern Chile due to arsenic in drinking water,”
  81. (2002). Mechanisms of arsenic biotransformation,”
  82. (2000). Mechanisms of arsenic carcinogenicity: genetic or epigenetic mechanisms?”
  83. (2008). Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?”
  84. Medicinal arsenic and internal malignancies,”
  85. (1999). Merkel cell carcinoma and chronic arsenicism,”
  86. (2010). Merkel cell carcinoma,”
  87. (1997). Metabolic methylation is a possible genotoxicity-enhancing process of inorganic arsenics,”
  88. (1980). Metals and Metallic Compounds,”
  89. (2006). MicroRNA responses to cellular stress,”
  90. (2006). MicroRNA signatures in human cancers,”
  91. (2008). Modulation of DNA polymerase beta-dependent base excision repair in cultured human cells after low dose exposure to arsenite,”
  92. (2007). Morimura et al., “Carcinogenicity of dimethylarsinic acid
  93. (1998). Mortality by cancer in groups of the Belgian population with a moderately increased intake of arsenic,”
  94. (1999). Mortality for certain diseasesinareaswithhighlevelsofarsenicindrinkingwater,”
  95. (1953). Multiple arsenical cancers of skin and internal organs,” Cancer,v o l .6 ,n o .2 ,p p .
  96. (2006). Nucleolin links to arsenic-induced stabilization of GADD45{alpha} mRNA,”
  97. (1963). o b so na n dA.M.J ell i ffe, “Medicinal arsenic poisoning and lung cancer,”
  98. (2001). Oral administration of dimethylarsinic acid, a main metabolite of inorganic arsenic, in mice promotes skin tumorigenesis initiated by dimethylbenz(a)anthracene with or without ultraviolet B as a promoter,”
  99. (1993). Organization (WHO), WHO Guidelines for Drinking-Water Quality,
  100. (2004). Oxidative mechanism of arsenic toxicity and carcinogenesis,”
  101. (2003). Oxidative stress as a possible modeofaction forarseniccarcinogenesis,”
  102. (2006). Parvez et al., “Modification of risk of arsenic-induced skin lesions by sunlight exposure, smoking, and occupational exposures in
  103. (2002). Public health. Worldwide occurrences of arsenic in ground water,”
  104. (2010). Rathouzetal.,“ Arsenicexposurefrom drinking water, and all-cause and chronic-disease mortalities in Bangladesh (HEALS): a prospective cohort study,”
  105. (2001). Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites,”
  106. (2006). Regulation of the Wnt/beta-catenin pathway by redox signaling,”
  107. (2005). Retinoic acid and arsenic for treating acute promyelocytic leukemia,”
  108. (2011). Reversal and prevention ofarsenic-inducedhumanbronchialepithelialcellmalignant transformation by microRNA-200b,” Toxicological Sciences,
  109. (2006). Role of oxidative stress in arsenic-induced toxicity,”
  110. (2000). Salud Antofagasta (Unidad de Registro de Cancer),
  111. (2003). Samanta et al., “Arsenic in drinking water and skin lesions: dose-response data from WestBengal,India,”Epidemiology,vol.14,no.2,pp.174–182,
  112. (1978). Selective multiplication of dihydrofolate reductase genes in methotrexate-resistant variants of cultured murine cells,”
  113. (1997). Serum betacarotene level, arsenic methylation capability, and incidence of skin cancer,”
  114. (2010). Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data,”
  115. (2002). Skin manifestations of arsenicosis in two villages in
  116. (2005). Smoking habit and genetic factors associated with lung cancer in a population highly exposed to arsenic,”
  117. (2009). Sodium arsenite induces ROS generation, DNA oxidative damage, HO-1 and c-Myc proteins, NF-kappaB activation and cell proliferation in human breast cancer MCF-7 cells,”
  118. (2005). Specific induction of oxidative stress in terminal bronchiolar Clara cells during dimethylarsenic-induced lungJournal of Toxicology 13 tumor promoting process in mice,”
  119. (2001). systemic toxicity of arsenic,”
  120. (1984). The reaction of methylarsenicals with thiols: some biological implications,”
  121. (2002). The role of biomethyl-ation in toxicity and carcinogenicity of arsenic: a research update,”
  122. (2000). The role of orally administered dimethylarsinicacid,amainmetaboliteofinorganicarsenics, in the promotion and progression of UVB-induced skin tumorigenesis in hairless mice,”
  123. (1999). The role of oxidative DNA damage in human arsenic carcinogenesis: Detectionof8-hydroxy-2 -deoxyguanosineinarsenic-related Bowen’s disease,”
  124. (2009). Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia,”
  125. (2001). Utility of recent studies to assess the National Research Council
  126. (1998). V¨ ah¨ akangas,
  127. (1994). Vascular effects of chronic arsenic exposure: a review,” Epidemiologic Reviews,
  128. (2007). W a t s o n ,R .J .d e L e e u w ,D .E .H o r s m a n ,J .A .S q u i r e , a n dW .L .L a m ,“ C y t o g e n e t i c a l l yb a l a n c e dt r a n s l o c a t i o n s are associated with focal copy number alterations,”
  129. (1989). W u ,T .L .K u o ,Y .H .H w a n g ,a n dC .J .C h e n ,“ D o s e -responserelationbetweenarsenicconcentrationinwellwater and mortality from cancers and vascular diseases,”
  130. (2008). X.Zhou,H.Sun,T.P.Ellen,H.Chen,andM.Costa,“Arsenite alters global histone H3 methylation,”
  131. (2000). Y u ,K .H .H s u ,C .J .C h e n ,a n dJ .R .F r o i n e s ,“ A r s e n i c methylation capacity and skin cancer,” Cancer Epidemiology Biomarkers and Prevention,
  132. (2004). Y.An,Z.Gao,Z.Wangetal.,“Immunohistochemicalanalysis of oxidative DNA damage in arsenic-related human skin samples from arsenic-contaminated area of
  133. Y.Cui,Z.Han,H.Yietal.,“MicroRNA-181bandmicroRNA9mediatearsenic-inducedangiogenesisviaNRP1,”Journalof Cellular Physiology.

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