JCT  Vol.1 No.2 , June 2010
Mechanisms and Immune Dysregulation in Arsenic Skin Carcinogenesis
Abstract: Long-term exposure to arsenic is associated with cancers of lung, urinary bladder, kidney, liver and skin. Arsenic car-cinogenesis might result from oxidative stress, altered growth factors, chromosomal abnormality, immune dysregula-tion, and aberrant epigenetic regulations. Bowen’s disease (As-BD) is the most common form of arsenic-induces skin cancers and is characterized by chronicity, multiplicity, and predisposition in sun-spare skin. However, only about 1% of the population exposed to arsenic developped skin cancers, indicating the host immune response plays an important modulatory role in skin carcinogenesis. In this review, we review the pathomechanisms of arsenic skin carcinogenesis and the immune interactions. Arsenic affects innate and adaptive immune responses through CD4+ T cells, monocytes, macrophages, and Langerhans cells. In skin of As-BD, CD4+ T cells undergo selective and differential apoptosis via Fas-FasL interaction. Numbers and dendrites of Langerhans cells are reduced in As-BD lesions. There is a defective homeostasis and aberrant trafficking of Langerhans cells. Such information is essential to understand the molecular mechanism for arsenic carcinogenesis in both skin and in internal organs.
Cite this paper: nullC. Lee, W. Liao and H. Yu, "Mechanisms and Immune Dysregulation in Arsenic Skin Carcinogenesis," Journal of Cancer Therapy, Vol. 1 No. 2, 2010, pp. 76-86. doi: 10.4236/jct.2010.12013.

[1]   T. Gebel, “Confounding Variables in the Environmental Toxicology of Arsenic,” Toxicology, Vol. 144, No. 1-3, 3 April 2000, pp. 155-162.

[2]   H. S. Yu, C. H. Lee, S. H. Jee, C. K. Ho and Y.L.Guo, “Environmental and Occupational Skin Diseases in Tai-wan,” Journal of Dermatology, Vol. 28, No. 11, Novem-ber 2001, pp. 628-631.

[3]   J. C. States, S. Srivastava, Y. Chen and A. Barchowsky, “Arsenic and Cardiovascular Disease,” Toxicol Sci, Vol. 107, No. 2, February 2009, pp. 312-323.

[4]   M. M. Moore, K. Harrington-Brock and C. L. Doerr, “Relative Genotoxic Potency of Arsenic and Its Methylated Metabolites,” Mutation Research, Vol. 386, No. 3, June 1997, pp. 279-290.

[5]   J. P. Buchet, R. Lauwerys and H. Roels, “Urinary Excre-tion of Inorganic Arsenic and Its Metabolites after Re-peated Ingestion of Sodium Metaarsenite by Volunteers,” International Archives of Occupational and Environmental Health, Vol. 48, No. 2, 1981, pp. 111-118.

[6]   Y. K. Huang, Y. L. Huang, Y. M. Hsueh, J. T. Wang, M. H. Yang and C. J. Chen, “Changes in Urinary Arsenic Methylation Profiles in a 15-Year Interval after Cessation of Arsenic Ingestion in Southwest Taiwan,” Environmental Health Perspectives, Vol. 117, No. 12, December 2009, pp. 1860-1866.

[7]   H. Yamauch and B. A. Fowler, “Toxicity and Metabolism of Inorganic and Methylated Arsenicals,” In: J. Q. Nriagu Ed., Arsenic in the Environment. Part II: Human Health and Ecosystem Effects, John Wiley and Sons, New York, 1994, pp. 35-53.

[8]   Y. M. Hsueh, Y. L. Huang, C. C. Huang, W. L. Wu, H. M. Chen, M. H. Yang, L. C. Lue and C. J. Chen, “Urinary Levels of Inorganic and Organic Arsenic Metabolites among Residents in an Arseniasis-Hyperendemic Area in Taiwan,” Journal of Toxicology and Environmental Health A, Vol. 54, No. 6, 24 July 1998, pp. 431-444.

[9]   C. Kojima, D.C.Ramirez, E. J. Tokar, S. Himeno, Z. Drobna, M. Styblo, R. P. Mason and M. P. Waalkes, “Requirement of Arsenic Biomethylation for Oxidative DNA Damage,” Journal of the National Cancer Institute, Vol. 101, No. 24, 16 December 2009, pp. 1670-1681.

[10]   K. Yamanaka, M. Hoshino, M. Okamoto, R. Sawamura, A. Hasegawa and S. Okada, “Induction of DNA Damage by Dimethylarsine, a Metabolite of Inorganic Arsenics, Is for the Major Part Likely Due to Its Peroxyl Radical,” Bi-ochemical and Biophysical Research Communications, Vol. 168, No. 1, 16 April 1990, pp. 58-64.

[11]   M. J. Mass, A. Tennant, B. C. Roop, W. R. Cullen, M. Styblo, D. J. Thomas and A. D. Kligerman, “Methylated Trivalent Arsenic Species Are Genotoxic,” Chemical Re-search Toxicology, Vol. 14, No. 4, April 2001, pp. 355- 361.

[12]   U. K. Chowdhury, B. K. Biswas, T. R. Chowdhury, G. Samanta, B. K. Mandal, G. C. Basu, C. R. Chanda, D. Lodh, K. C. Saha, S. K. Mukherjee, et al., “Groundwater Arsenic Contamination in Bangladesh and West Bengal, India,” Environmental Health Perspectives, Vol. 108, No. 5, May 2000, pp. 393-397.

[13]   IARC Monographs on The Evaluation of The Carcinogenic Risk of Chemicals to Man-Overall Evaluations of Carcinogenicity: An Update of IARC Monograph 1 to 42: Arsenic and Arsenic Compound, IARC, Lyon, 1987.

[14]   K. T. Kitchin, “Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites,” Toxicology and Applied Pharma-cology, Vol. 172, No. 3, 1 May 2001, pp. 249-261.

[15]   P. B. Tchounwou, A. K. Patlolla and J. A. Centeno, “Car-cinogenic and Systemic Health Effects Associated with Arsenic Exposure-A Critical Review,” Toxicologic Pa-thology, Vol. 31, No. 6, November-December 2003, pp. 575-588.

[16]   T. G. Rossman, A. N. Uddin and F. J. Burns, “Evidence that Arsenite Acts as a Cocarcinogen in Skin Cancer,” Toxicology and Applied Pharmacology, Vol. 198, No. 3, 1 August 2004, pp. 394-404.

[17]   M. P. Waalkes, J. Liu, D. R. Germolec, C. S. Trempus, R. E. Cannon, E. J. Tokar, R. W. Tennant, J. M. Ward and B. A. Diwan, “Arsenic Exposure in Utero Exacerbates Skin Cancer Response in Adulthood with Contempora-neous Distortion of Tumor Stem Cell Dynamics,” Cancer Research, Vol. 68, No. 20, 15 October 2008, pp. 8278- 8285.

[18]   M. Vahter, “Health Effects of Early Life Exposure to Arsenic,” Basic Clinical Pharmacology and Toxicology, Vol. 102, No. 2, February 2008, pp. 204-211.

[19]   E. T. Snow, “Metal Carcinogenesis: Mechanistic Implica-tions,” Pharmacology & Therapeutics, Vol. 53, No. 1, 1992, pp. 31-65.

[20]   M. Lu, H. Wang, Z. Wang, X. F. Li and X. C. Le, “Identi-fication of Reactive Cysteines in a Protein Using Arsenic Labeling and Collision-Induced Dissociation Tandem Mass Spectrometry,” Journal of Proteome Research, Vol. 7, No. 8, August 2008, pp. 3080-3090.

[21]   C. O. Abernathy, Y. P. Liu, D. Longfellow, H. V. Apo-shian, B. Beck, B. Fowler, R. Goyer, R. Menzer, T. Rossman, C. Thompson, et al., “Arsenic: Health Effects, Mechanisms of Actions and Research Issues,” Environ-mental Health Perspectives, Vol. 107, No. 7, July 1999, pp. 593-597.

[22]   D. Zhang, J. Li, J. Gao and C. Huang, “c-Jun/AP-1 Path-way-Mediated Cyclin D1 Expression Participates in Low Dose Arsenite-Induced Transformation in Mouse Epi-dermal JB6 Cl41 Cells,” Toxicology and Applied Phar-macology, Vol. 235, No. 1, 15 February 2009, pp. 18-24.

[23]   F. G. Burleson, P. P. Simeonova, D. R. Germolec and M. I. Luster, “Dermatotoxic Chemical Stimulate of c-jun and c-fos Transcription and AP-1 DNA Binding in Human Keratinocytes,” Research Communications in Molecular Pathology & Pharmacology, Vol. 93, No. 2, August 1996, pp. 131-148.

[24]   M. Cavigelli, W. W. Li, A. Lin, B. Su, K. Yoshioka and M. Karin, “The Tumor Promoter Arsenite Stimulates AP-1 Activity by Inhibiting a JNK Phosphatase,” EMBO Journal, Vol. 15, No. 22, 15 November 1996, pp. 6269- 6279.

[25]   H. S. Yu, K. S. Chiou, G. S. Chen, R. C. Yang and S. F. Chang, “Progressive Alterations of Cytokeratin Expres-sions in the Process of Chronic Arsenism,” Journal of Dermatology, Vol. 20, No. 12, December 1993, pp. 741- 745.

[26]   M. Matsui, C. Nishigori, S. Toyokuni, J. Takada, M. Aka-boshi, M. Ishikawa, S. Imamura and Y. Miyachi, “The Role of Oxidative DNA Damage in Human Arsenic Carcinogenesis: Detection of 8-Hydroxy-2’-Deoxyguanosine in Arsenic-Related Bowen's Disease,” Journal of Investigative Dermatology, Vol. 113, No. 1, July 1999, pp. 26-31.

[27]   M. Yamamoto, S. Hirano, C. F. Vogel, X. Cui and F. Matsumura, “Selective Activation of NF-Kappab and E2F By Low Concentration of Arsenite in U937 Human Mo-nocytic Leukemia Cells,” Journal of Biochemical and Molecular Toxicology, Vol. 22, No. 2, 2008, pp. 136-146.

[28]   A. Barchowsky, E. J. Dudek, M. D. Treadwell and K. E. Wetterhahn, “Arsenic Induces Oxidant Stress and NF-Kappa B Activation in Cultured Aortic Endothelial Cells,” Free Radical Biology and Medicine, Vol. 21, No. 6, 1996, pp. 783-790.

[29]   C. Huang, J. Li, M. Ding, L. Wang, X. Shi, V. Castranova, V. Vallyathan, G. Ju and M.Costa, “Arsenic- Induced Nfkappab Transactivation Through Erks- and Jnks- Dependent Pathways in Mouse Epidermal Jb6 Cells,” Molecular and Cellular Biochemistry, Vol. 222, No. 1-2, June 2001, pp. 29-34.

[30]   J. B. Wijeweera, A. J. Gandolfi, A. Parrish and R. C. Lantz, “Sodium Arsenite Enhances AP-1 and NFkappaB DNA Binding and Induces Stress Protein Expression in Precision-Cut Rat Lung Slices,” Toxicol Sci, Vol. 61, No. 2, June 2001, pp. 283-294.

[31]   W. T. Liao, K. L. Chang, C. L. Yu, G. S. Chen, L. W. Chang and H. S. Yu, “Arsenic Induces Human Keratino-cyte Apoptosis by the FAS/FAS Ligand Pathway, Which Correlates with Alterations in Nuclear Factor-Kappa B and Activator Protein-1 Activity,” Journal of Investigative Dermatology, Vol. 122, No. 1, January 2004, pp. 125- 129.

[32]   P. Ghosh, M. Banerjee, S. De Chaudhuri, J. K. Das, N. Sarma, A. Basu and A. K. Giri, “Increased Chromosome Aberration Frequencies in the Bowen's Patients Compared to Non-Cancerous Skin Lesions Individuals Exposed to Arsenic,” Mutation Research, Vol. 632, No. 1-2, 15 Au-gust 2007, pp. 104-110.

[33]   T. C. Lee, N. Tanaka, P. W. Lamb, T. M. Gilmer and J. C. Barrett, “Induction of Gene Amplification by Arsenic,” Science, Vol. 241, No. 4861, 1 July 1988, pp. 79-81.

[34]   J. Mahata, A. Basu, S. Ghoshal, J. N. Sarkar, A. K. Roy, G. Poddar, A. K. Nandy, A. Banerjee, K. Ray, A. T. Na-tarajan, et al., “Chromosomal Aberrations and Sister Chromatid Exchanges in Individuals Exposed to Arsenic through Drinking Water in West Bengal, India,” Mutation Research, Vol. 534, No. 1-2, 10 January 2003, pp. 133- 143.

[35]   R. N. Huang, I. C. Ho, L. H. Yih and T. C. Lee, “Sodium Arsenite Induces Chromosome Endoreduplication and In-hibits Protein Phosphatase Activity in Human Fibroblasts,” Environmental and Molecular Mutagenesis, Vol. 25, No. 3, 1995, pp. 188-196.

[36]   T. S. Kochhar, W. Howard, S. Hoffman and L. Bram-mer-Carleton, “Effect of Trivalent and Pentavalent Arsenic in Causing Chromosome Alterations in Cultured Chinese Hamster Ovary (CHO) Cells,” Toxicology Letters, Vol. 84, No. 1, January 1996, pp. 37-42.

[37]   K. Yamanaka and S. Okada, “Induction of Lung-Specific DNA Damage by Metabolically Methylated Arsenics via the Production of Free Radicals,” Environmental Health Perspectives, Vol. 102 Supplement 3, September 1994, pp. 37- 40.

[38]   L. H. Yih, and T. C. Lee, “Effects of Exposure Protocols on Induction of Kinetochore-Plus and -Minus Micronuclei by Arsenite in Diploid Human Fibroblasts,” Mutation Re-search, Vol. 440, No. 1, 15 March 1999, pp. 75-82.

[39]   A. Basu, J. Mahata, A. K. Roy, J. N. Sarkar, G. Poddar, A. K. Nandy, P. K. Sarkar, P. K. Dutta, A. Banerjee, M. Das, et al., “Enhanced Frequency of Micronuclei in Individuals Exposed to Arsenic through Drinking Water in West Bengal, India,” Mutation Research, Vol. 516, No. 1-2, 26 April 2002, pp. 29-40.

[40]   D. Tian, H. Ma, Z. Feng, Y. Xia, X. C. Le, Z. Ni, J. Allen, B. Collins, D. Schreinemachers and J. L. Mumford, “Ana-lyses of Micronuclei in Exfoliated Epithelial Cells from In-dividuals Chronically Exposed to Arsenic via Drinking Water in Inner Mongolia, China,” Journal of Toxicology and Environmental Health A, Vol. 64, No. 6, 23 November 2001, pp. 473-484.

[41]   M. L. Warner, L. E. Moore, M. T. Smith, D. A. Kalman, E. Fanning and A. H. Smith, “Increased Micronuclei in Exfoliated Bladder Cells of Individuals Who Chronically Ingest Arsenic-Contaminated Water in Nevada,” Cancer Epidemiol Biomarkers Prev, Vol. 3, No. 7, October- November 1994, pp. 583-590.

[42]   C. W. Chien, M. C. Chiang, I. C. Ho and T. C. Lee, “As-sociation of Chromosomal Alterations with Arsenite- Induced Tumorigenicity of Human Hacat Keratinocytes in Nude Mice,” Environ Health Perspect, Vol. 112, No. 17, December 2004, pp. 1704-1710.

[43]   X. J. Qin, L. G. Hudson, W. Liu, W. Ding, K. L. Cooper, and K. J. Liu, “Dual Actions Involved in Arsenite-Induced Oxidative DNA Damage,” Chemical Research Toxicology, Vol. 21, No. 9, September 2008, pp. 1806-1813.

[44]   S. F. Lee-Chen, C. T. Yu and K. Y. Jan, “Effect of Arse-nite on the DNA Repair of UV-Irradiated Chinese Hamster Ovary Cells,” Mutagenesis, Vol. 7, No. 1, January 1992, pp. 51-55.

[45]   H. K. Hamadeh, K. J. Trouba, R. P. Amin, C. A. Afshari and D. Germolec, “Coordination of Altered DNA Repair and Damage Pathways in Arsenite-Exposed Keratino-cytes,” Toxicol Sci, Vol. 69, No. 2, October 2002, pp. 306-316.

[46]   J. H. Li and T. G. Rossman, “Inhibition of DNA Ligase Activity by Arsenite: A Possible Mechanism of Its Com-utagenesis,” Molecular Toxicology, Vol. 2, No. 1, Winter 1989, pp. 1-9.

[47]   Y. Hu, L. Su and E. T. Snow, “Arsenic Toxicity Is En-zyme Specific and Its Affects on Ligation Are Not Caused by the Direct Inhibition of DNA Repair Enzymes,” Muta-tion Research, Vol. 408, No. 3, 11 September 1998, pp. 203-218.

[48]   S. Lynn, H. T. Lai, J. R. Gurr and K. Y. Jan, “Arsenite retards DNA Break Rejoining by Inhibiting DNA Liga-tion,” Mutagenesis, Vol. 12, No. 5, September 1997, pp. 353-358.

[49]   J. W. Yager and J. K. Wiencke, “Inhibition of Poly (ADP-Ribose) Polymerase by Arsenite,” Mutation Re-search, Vol. 386, No. 3, June 1997, pp. 345-351.

[50]   T. G. Rossman, “Mechanism of Arsenic Carcinogenesis: An Integrated Approach,” Mutation Research, Vol. 533, No. 1-2, 10 December 2003, pp. 37-65.

[51]   T. C. Lee, M. Oshimura, and J. C. Barrett, , “Comparison of Arsenic-Induced Cell Transformation, Cytotoxicity, Mutation and Cytogenetic Effects in Syrian Hamster Embryo Cells in Culture,” Carcinogenesis, Vol. 6, No. 10, October 1985, pp. 1421-1426.

[52]   T. C. Lee, K. C. Lee, Y. J. Tzeng, R. Y. Huang and K. Y. Jan, “Sodium Arsenite Potentiates the Clastogenicity and Mutagenicity of DNA Crosslinking Agents,” Environ-mental Mutagenesis, Vol. 8, No. 1, 1986, pp. 119-128.

[53]   J. L. Yang, M. F. Chen, C. W. Wu and T. C. Lee, “Post-treatment with Sodium Arsenite Alters the Mutational Spectrum Induced by Ultraviolet Light Irradiation in Chi-nese Hamster Ovary Cells,” Environmental and Molecular Mutagenesis, Vol. 20, No. 3, 1992, pp. 156-164.

[54]   X. Zhou, H. Sun, T. P. Ellen, H. Chen and M. Costa, “Arsenite Alters Global Histone H3 Methylation,” Car-cinogenesis, Vol. 29, No. 9, September 2008, pp. 1831- 1836.

[55]   H. Chen, S. Li, J. Liu, B. A. Diwan, J. C. Barrett and M. P. Waalkes, “Chronic Inorganic Arsenic Exposure Induces Hepatic Global and Individual Gene Hypomethylation: Im-plications for Arsenic Hepatocarcinogenesis,” Carcinoge-nesis, Vol. 25, No. 9, September 2004, pp. 1779- 1786.

[56]   S. Chanda, U. B. Dasgupta, D. Guhamazumder, M. Gupta, U. Chaudhuri, S. Lahiri, S. Das, N. Ghosh and D. Chat-terjee, “DNA Hypermethylation of Promoter of Gene p53 and p16 in Arsenic-Exposed People with and without Ma-lignancy,” Toxicol Sci, Vol. 89, No. 2, February 2006, pp. 431-437.

[57]   J. F. Reichard, M. Schnekenburger and A. Puga, “Long term Low-Dose Arsenic Exposure Induces Loss of DNA Methylation,” Biochemical and Biophysical Research Communication, Vol. 352, No. 1, 5 January 2007, pp. 188-192.

[58]   Y. Xie, J. Liu, L. Benbrahim-Tallaa, J. M. Ward, D. Logsdon, B. A. Diwan and M. P. Waalkes, “Aberrant DNA Methylation and Gene Expression in Livers of Newborn Mice Transplacentally Exposed to a Hepatocar-cinogenic Dose of Inorganic Arsenic,” Toxicology, Vol. 236, No. 1-2, 1 July 2007, pp. 7-15.

[59]   J. A. Centeno, F. G. Mullick, L. Martinez, N. P. Page, H. Gibb, D. Longfellow, C. Thompson and E. R. Ladich, “Pathology Related to Chronic Arsenic Exposure,” Envi-ronmental Health Perspectives, Vol. 110 Supplement 5, October 2002, pp. 883-886.

[60]   S. Yeh, “Skin Cancer in Chronic Arsenicism,” Human Pathology, Vol. 4, No. 4, December 1973, pp. 469-485.

[61]   G. Alain, J. Tousignant and E. Rozenfarb, “Chronic Ar-senic Toxicity,” International Journal of Dermatology, Vol. 32, No. 12, December 1993, pp. 899-901.

[62]   W. P. Tseng, H. M. Chu, S. W. How, J. M. Fong, C. S. Lin and S. Yeh, “Prevalence of Skin Cancer in an Endemic Area of Chronic Arsenicism in Taiwan,” Journal of the National Cancer Institute, Vol. 40, No. 3, March 1968, pp. 453-463.

[63]   D. N. Guha Mazumder, R. Haque, N. Ghosh, B. K. De, A. Santra, D. Chakraborty and A. H. Smith, “Arsenic Le-vels in Drinking Water and the Prevalence of Skin Lesions in West Bengal, India,” International Journal of Epidemiology, Vol. 27, No. 5, October 1998, pp. 871-877.

[64]   S. Yeh, S. W. How and C. S. Lin, “Arsenical Cancer of Skin. Histologic Study with Special Reference to Bowen's Disease,” Cancer, Vol. 21, No. 2, Febuary 1968, pp. 312- 339.

[65]   C. H. Lee, C. L. Yu, W. T. Liao, Y. H. Kao, C.Y. Chai, G.S. Chen and H. S. Yu, “Effects and Interactions of Low Doses of Arsenic and UVB on Keratinocyte Apoptosis,'” Chemical Research Toxicology, Vol. 17, No. 9, September 2004, pp. 1199-1205.

[66]   Y. Miki, T. Kawatsu, K. Matsuda, H. Machino and K. Kubo, “Cutaneous and Pulmonary Cancers Associated with Bowen's Disease,” Journal of the American Academy of Dermatology, Vol. 6, No. 1, January 1982, pp. 26-31.

[67]   H. J. Kim, H. G. Min and E. S. Lee, “Bowen's Diseases and Basal Cell Carcinomas in a Patient,” Journal of Der-matology, Vol. 26, No. 10, October 1999, pp. 695-697.

[68]   E. Koh, N. Kondoh, H. Kaihara, H. Fujioka and K. Kita-mura, “Ureteral Tumor with Multiple Bowen's Disease Forty-Two Years after Exposure to Arsenic,” European Urology, Vol. 16, No. 5, 1989, pp. 398-400.

[69]   R.C.Yu, K.H.Hsu, C.J.Chen, , and J.R.Froines, “Arsenic methylation Capacity and Skin Cancer,” Cancer Epidemi-ology, Biomarkers & Prevention, Vol. 9, No. 11, No-vember 2000, pp. 1259-1262.

[70]   L. Lee and G. Bebb, “A Case of Bowen’s Disease and Small-Cell Lung Carcinoma: Long-Term Consequences of Chronic Arsenic Exposure in Chinese Traditional Medicine,” Environmental Health Perspectives, Vol. 113, No. 2, February 2005, pp. 207-210.

[71]   T. Yoshida, H. Yamauchi and G. Fan Sun, “Chronic Health Effects in People Exposed to Arsenic via the Drinking Water: Dose-Response Relationships in Review,” Toxicology and Applied Pharmacology, Vol. 198, No. 3, 1 August 2004, pp. 243-252.

[72]   T. T. Kuo, S.Hu, S. K. Lo and H. L. Chan, “p53 Expres-sion and Proliferative Activity in Bowen's Disease with or without Chronic Arsenic Exposure,” Human Pathology, Vol. 28, No. 7, July 1997, pp. 786-790.

[73]   C. H. Chang, R. K. Tsai, G. S. Chen, H. S. Yu and C. Y. Chai, “Expression of bcl-2, p53 and Ki-67 in Arsenical Skin Cancers,” Journal of Cutaneous Pathology, Vol. 25, No. 9, October 1998, pp. 457-462.

[74]   E. V. Komissarova and T. G. Rossman, “Arsenite Induced Poly(ADP-Ribosyl)ation of Tumor Suppressor P53 in Human Skin Keratinocytes as a Possible Mechanism for Carcinogenesis Associated with Arsenic Exposure,” Tox-icology and Applied Pharmacology, Vol. 243, No. 3, 15 March 2010, pp. 399-404.

[75]   L. H. Yih and T. C. Lee, “Arsenite Induces P53 Accumu-lation through an ATM-Dependent Pathway in Human Fibroblasts,” Cancer Research, Vol. 60, No. 22, 15 No-vember 2000, pp. 6346-6352.

[76]   D. Menendez, G. Mora, A. M. Salazar and P. Ostrosky- Wegman, “ATM Status Confers Sensitivity to Arsenic Cytotoxic Effects,” Mutagenesis, Vol. 16, No. 5, Sep-tember 2001, pp. 443-448.

[77]   C. Y. Chai, H. S. Yu, H. T. Yen, K. B. Tsai, G. S. Chen and C. L. Yu, “The Inhibitory Effect of UVB Irradiation on the Expression of P53 and Ki-67 Proteins in Arsen-ic-Induced Bowen's Disease,” Journal of Cutaneous Pa-thology, Vol. 24, No. 1, January 1997, pp. 8-13.

[78]   L. L. Hsieh, H. J. Chen, J. T. Hsieh, S. H. Jee, G. S. Chen and C. J. Chen, “Arsenic-related Bowen's Disease and Paraquat-Related Skin Cancerous Lesions Show No De-tectable Ras and P53 Gene Alterations,” Cancer Letter, Vol. 86, No. 1, 28 October 1994, pp. 59-65.

[79]   C. H. Hsu, S. A. Yang, J. Y. Wang, H. S. Yu and S. R. Lin, “Mutational Spectrum of P53 Gene in Arsenic-Related Skin Cancers from the Blackfoot Disease Endemic Area of Taiwan,” British Journal of Cancer, Vol. 80, No. 7, June 1999, pp. 1080-1086.

[80]   L. H. Yih, S. W. Hsueh, W. S. Luu, T. H. Chiu and T. C. Lee, “Arsenite Induces Prominent Mitotic Arrest via Inhi-bition of G2 Checkpoint Activation in CGL-2 Cells,” Carcinogenesis, Vol. 26, No. 1, January 2005, pp. 53-63.

[81]   L. H. Yih, Y. Y. Tseng, Y. C. Wu and T. C. Lee, “Induc-tion of Centrosome Amplification During Arsenite-Induced Mitotic Arrest In CGL-2 Cells,” Cancer Res, Vol. 66, No. 4, 15 February 2006, pp. 2098-2106.

[82]   S. Kawara, M. Takata and K. Takehara, “High Frequency of DNA Aneuploidy Detected by DNA Flow Cytometry in Bowen's Disease,” Journal of Dermatological Science, Vol. 21, No. 1, September 1999, pp. 23-26.

[83]   M. Faris, N. Kokot, K. Latinis, S. Kasibhatla, D. R. Green, G. A. Koretzky and A. Nel, “The c-Jun N-terminal Kinase Cascade Plays a Role in Stress-Induced Apoptosis in Jur-kat Cells by Up-Regulating Fas Ligand Expression,” Journal of Immunology, Vol. 160, No. 1, 1 January 1998, pp. 134-144.

[84]   A. Zagariya, S. Mungre, R. Lovis, M. Birrer, S. Ness, B. Thimmapaya and R. Pope, “Tumor Necrosis Factor Alpha Gene Regulation: Enhancement of C/Ebpbeta-Induced Ac-tivation by c-Jun,” Molecular and Cellular Biology, Vol. 18, No. 5, May 1998, pp. 2815-2824.

[85]   A. Kolbus, I. Herr, M. Schreiber, K. M. Debatin, E. F. Wagner and P. Angel, “c-Jun-dependent CD95-L Expres-sion Is a Rate-Limiting Step in the Induction of Apoptosis by Alkylating Agents,” Molecular and Cellular Biology, Vol. 20, No. 2, January 2000, pp. 575-582.

[86]   A. C. Hermann and C. H. Kim, “Effects of Arsenic on Zebrafish Innate Immune System,” Marine Biotechnology, NY, Vol. 7, No. 5, September-October 2005, pp. 494-505.

[87]   D. Ghosh, S. Bhattacharya and S. Mazumder, “Perturba-tions in the Catfish Immune Responses by Arsenic: Organ and Cell Specific Effects,” Comp Biochem Physiol C Toxicol Pharmacol, Vol. 143, No. 4, August 2006, pp. 455-463.

[88]   M. Di Gioacchino, N. Verna, L. Di Giampaolo, F. Di Claudio, M. C. Turi, A. Perrone, C. Petrarca, R. Mariani- Costantini, E. Sabbioni and P. Boscolo, “Immunotoxicity and Sensitizing Capacity of Metal Compounds Depend on Speciation,” International Journal of Immunopathology and Pharmacology, Vol. 20, No. 2 Supplement 2, April- June 2007, pp. 15-22.

[89]   B. Hernandez-Castro, L.M. Doniz-Padilla, M. Salgado-Bustamante, D. Rocha, M. D. Ortiz-Perez, M. E. Jimenez- Capdeville, D. P. Portales-Perez, A. Quintanar-Stephano and R. Gonzalez-Amaro, “Effect of arsenic on regulatory T cells,” Journal of Clinical Immunology, Vol. 29, No. 4, July 2009, pp. 461-469.

[90]   T. Yoshida, T.Shimamura and S. Shigeta, “Enhancement of the Immune Response in Vitro by Arsenic,” International Journal of Immunopharmacology, Vol. 9, No. 3 1987, pp. 411-415.

[91]   R. Raqib, S. Ahmed, R. Sultana, Y. Wagatsuma, D. Mondal, A. M. Hoque, B. Nermell, M. Yunus, S. Roy, L. A. Persson, et al., “Effects of in Utero Arsenic Exposure on Child Immunity and Morbidity in Rural Bangladesh,” Toxicology Letter, Vol. 185, No. 3, 28 March 2009, pp. 197-202.

[92]   C. D. Kozul, K. H. Ely, R. I. Enelow and J. W. Hamilton, , “Low-dose Arsenic Compromises the Immune Response to Influenza a Infection in Vivo,” Environmental Health Perspectives, Vol. 117, No. 9, September 2009, pp. 1441- 1447.

[93]   C. D. Kozul, T. H. Hampton, J. C. Davey, J. A. Gosse, A. P. Nomikos, P. L. Eisenhauer, D. J. Weiss, J. E. Thorpe, M. A. Ihnat and J. W. Hamilton, “Chronic Exposure to Arsenic in the Drinking Water Alters the Expression of Immune Response Genes in Mouse Lung,” Environmental Health Perspectives, Vol. 117, No. 7, July 2009, pp. 1108-1115.

[94]   H. S. Yu, K. L. Chang, C. L. Yu, C. S. Wu, G. S. Chen and J. C. Ho, “Defective IL-2 Receptor Expression in Lymphocytes of Patients with Arsenic-Induced Bowen's Disease,” Archives Dermatological Research, Vol. 290, No. 12, December 1998, pp. 681-687.

[95]   R. Patterson, L. Vega, K. Trouba, C. Bortner and D. Germolec, “Arsenic-induced Alterations in the Contact Hypersensitivity Response in Balb/C Mice,” Toxicology and Applied Pharmacology, Vol. 198, No. 3, 1 August 2004, pp. 434-443.

[96]   H. S. Yu, K. L. Chang, C. M. Wang and C. L. Yu, “Alte-rations of Mitogenic Responses of Mononuclear Cells by Arsenic in Arsenical Skin Cancers,” Journal of Derma-tology, Vol. 19, No. 11, November 1992, pp. 710-714.

[97]   H.S.Yu, , W.T.Liao, , K.L. Chang, , C.L. Yu and G.S.Chen, “Arsenic Induces Tumor Necrosis Factor Alpha Release and Tumor Necrosis Factor Receptor 1 Signaling in T Helper Cell Apoptosis,” Journal of Investigative Dermatology, Vol. 119, No. 4, October 2002, pp. 812-819.

[98]   L. Vega, P. Ostrosky-Wegman, T. I. Fortoul, C. Diaz, V. Madrid and R. Saavedra, “Sodium Arsenite Reduces Pro-liferation of Human Activated T-Cells by Inhibition of the Secretion of Interleukin-2,” Immunopharmacology and Immunotoxicology, Vol. 21, No. 2, May 1999, pp. 203- 220.

[99]   R. Biswas, P. Ghosh, N. Banerjee, J. K. Das, T. Sau, A. Banerjee, S. Roy, S. Ganguly, M. Chatterjee, A. Mukher-jee, et al., “Analysis of T-cell Proliferation and Cytokine Secretion in the Individuals Exposed to Arsenic,” Human & Experimental Toxicology, Vol. 27, No. 5, May 2008, pp. 381-386.

[100]   G. A. Soto-Pena, A. L. Luna, L. Acosta-Saavedra, P. Conde, L. Lopez-Carrillo, M. E. Cebrian, M. Bastida, E. S. Calderon-Aranda and L. Vega, “Assessment of Lympho-cyte Subpopulations and Cytokine Secretion in Children Exposed to Arsenic,” Journal of the Federation of Amer-ican Societies for Experimental Biology, Vol. 20, No. 6, April 2006, pp. 779-781.

[101]   S. W. Burchiel, L. A. Mitchell, F. T. Lauer, X. Sun, J. D. McDonald, L. G. Hudson and K. J. Liu, “Immunotoxicity and Biodistribution Analysis of Arsenic Trioxide in C57Bl/6 Mice Following a 2-week Inhalation Exposure,” Toxicology and Applied Pharmacology, Vol. 241, No. 3, 15 December 2009, pp. 253-259.

[102]   A. Lemarie, C. Morzadec, E. Bourdonnay, O. Fardel and L. Vernhet, “Human Macrophages Constitute Targets for Immunotoxic Inorganic Arsenic,” Journal of Immunology, Vol. 177, No. 5, 1 September 2006, pp. 3019-3027.

[103]   N. Banerjee, S. Banerjee, R. Sen, A. Bandyopadhyay, N. Sarma, P. Majumder, J. K. Das, M. Chatterjee, S. N. Kabir and A. K. Giri, “Chronic Arsenic Exposure Impairs Macrophage Functions in the Exposed Individuals,” Journal of Clinical Immunology, Vol. 29, No. 5, Septem-ber 2009, pp. 582-594.

[104]   A. L. Luna, L. C. Acosta-Saavedra, L. Lopez-Carrillo, P. Conde, E. Vera, A. De Vizcaya-Ruiz, M. Bastida, M. E. Cebrian and E. S. Calderon-Aranda, “Arsenic Alters Mo-nocyte Superoxide Anion and Nitric Oxide Production in Environmentally Exposed Children,” Toxicology and Ap-plied Pharmacology, 11 March 2010.

[105]   F. Antoine, J. Ennaciri and D. Girard, “Syk is a Novel Target of Arsenic Trioxide (ATO) and is Involved in the Toxic Effect of ATO in Human Neutrophils,” Toxicology in Vitro, Vol. 24, No. 3, April 2010, pp. 936-941.

[106]   S. Gupta, L. Yel, D. Kim, C. Kim, S. Chiplunkar and S. Gollapudi, “Arsenic Trioxide Induces Apoptosis in Peri-pheral Blood T Lymphocyte Subsets by Inducing Oxida-tive Stress: A Role of Bcl-2,” Molecular Cancer Thera-peutics, Vol. 2, No. 8, August 2003, pp. 711-719.

[107]   M. E. Gonsebatt, L. Vega, L. A.Herrera, R. Montero, E. Rojas, M. E. Cebrian and P. Ostrosky-Wegman, “Inor-ganic Arsenic Effects on Human Lymphocyte Stimulation and Proliferation,” Mutation Research, Vol. 283, No. 2, October 1992, pp. 91-95.

[108]   D. A. Eastmond and D. Pinkel, “Detection of Aneuploidy and Aneuploidy-Inducing Agents in Human Lymphocytes Using Fluorescence in Situ Hybridization with Chromo-some-Specific DNA Probes,” Mutation Research, Vol. 234, No. 5, October 1990, pp. 303-318.

[109]   L. Vega, M. E. Gonsebatt and P. Ostrosky-Wegman, “Aneugenic Effect of Sodium Arsenite on Human Lym-phocytes in Vitro: An Individual Susceptibility Effect Detected,” Mutation Research, Vol. 334, No. 3, June 1995, pp. 365-373.

[110]   Y. H. Hsu, S. Y. Li, H. Y. Chiou, P. M. Yeh, J. C. Liou, Y. M. Hsueh, S. H. Chang and C. J. Chen, “Spontaneous and Induced Sister Chromatid Exchanges and Delayed Cell Proliferation in Peripheral Lymphocytes of Bowen’s Disease Patients and Matched Controls of Arsenia-sis-Hyperendemic Villages in Taiwan,” Mutation Research, Vol. 386, No. 3, June 1997, pp. 241-251.

[111]   W. N. Wen, T. L. Lieu, H. J. Chang, S. W. Wuu, M. L. Yau and K. Y. Jan, “Baseline and Sodium Arsenite- Induced Sister Chromatid Exchanges in Cultured Lym-phocytes from Patients with Blackfoot Disease and Healthy Persons,” Human Genetics, Vol. 59, No. 3, 1981, pp. 201-203.

[112]   D. Lerda, “Sister-Chromatid Exchange (SCE) among Individuals Chronically Exposed to Arsenic in Drinking Water,” Mutation Research, Vol. 312, No. 2, April 1994, pp. 111-120.

[113]   G. A. Soto-Pena and L. Vega, “Arsenic Interferes with the Signaling Transduction Pathway of T Cell Receptor Ac-tivation by Increasing Basal and Induced Phosphorylation of Lck and Fyn in Spleen Cells,” Toxicology and Applied Pharmacology, Vol. 230, No. 2, 15 July 2008, pp. 216- 226.

[114]   A. D. Kligerman, C. L. Doerr and A. H. Tennant, “Oxida-tion and Methylation Status Determine the Effects of Ar-senic on the Mitotic Apparatus,” Molecular and Cellular Biochemistry, Vol. 279, No. 1-2, November 2005, pp. 113-121.

[115]   T. Ramirez, V. Garcia-Montalvo, C. Wise, R. Cea-Olivares, L. A. Poirier and L. A. Herrera, “S-adenosyl-L-methionine is Able to Reverse Micronucleus Formation Induced by Sodium Arsenite and Other Cytoskeleton Disrupting Agents in Cultured Human Cells,” Mutation Research, Vol. 528, No. 1-2, 25 July 2003, pp. 61-74.

[116]   G. Tabellini, P. L. Tazzari, R. Bortul, C. Evangelisti, A. M. Billi, T. Grafone, G. Martinelli, M. Baccarani and A. M. Martelli, “Phosphoinositide 3-kinase/Akt Inhibition Increases Arsenic Trioxide-Induced Apoptosis of Acute Promyelocytic and T-cell Leukaemias,” British Journal of Haematology, Vol. 130, No. 5, September 2005, pp. 716- 725.

[117]   Y. Zheng, H. Yamaguchi, C. Tian, M. W. Lee, H. Tang, H. G. Wang and Q. Chen, “Arsenic Trioxide (As(2)O(3)) Induces Apoptosis through Activation of Bax in Hemato-poietic Cells,” Oncogene, Vol. 24, No. 20, 5 May 2005, pp. 3339-3347.

[118]   M. E. El-Sabban, R. Nasr, G. Dbaibo, O. Hermine, N. Abboushi, F. Quignon, J. C. Ameisen, F. Bex, H. de The and A. Bazarbachi, “Arsenic-interferon-alpha-triggered Apoptosis in HTLV-I Transformed Cells is Associated with Tax Down-Regulation and Reversal of NF-kappa B Activation,” Blood, Vol. 96, No. 8, 15 October 2000, pp. 2849-2855.

[119]   K. Ishitsuka, S. Hanada, K. Uozumi, A. Utsunomiya and T. Arima, “Arsenic Trioxide and the Growth of Human T-cell Leukemia Virus Type I Infected T-cell Lines,” Leukemia and Lymphoma, Vol. 37, No. 5-6, May 2000, pp. 649-655.

[120]   D. R. Germolec, J. Spalding, H. S. Yu, G. S. Chen, P. P. Simeonova, M. C. Humble, A. Bruccoleri, G. A. Boorman, J. F. Foley, T. Yoshida, et al., “Arsenic Enhancement of Skin Neoplasia by Chronic Stimulation of Growth Fac-tors,” American Journal of Pathology, Vol. 153, No. 6, December 1998, pp. 1775-1785.

[121]   D. R. Germolec, T. Yoshida, K. Gaido, J. L. Wilmer, P. P. Simeonova, F. Kayama, F. Burleson, W. Dong, R. W. Lange and M. I. Luster, “Arsenic Induces Overexpression of Growth Factorsin Human Keratinocytes,” Toxicology and Applied Pharmacology, Vol. 141, No. 1, November 1996, pp. 308-318.

[122]   H. T. Yen, L. C. Chiang, K. H. Wen, S. F. Chang, C. C. Tsai, C. L. Yu and H. S. Yu, “Arsenic Induces Interleu-kin-8 Expression in Cultured Keratinocytes,” Archives Dermatological Research, Vol. 288, No. 11, October 1996, pp. 716-717.

[123]   L.Vega, , M. Styblo, R. Patterson, W. Cullen, C. Wang and D. Germolec, “Differential Effects of Trivalent and Pentavalent Arsenicals on Cell Proliferation and Cytokine Secretion in Normal Human Epidermal Keratinocytes,” Toxicology and Applied Pharmacology, Vol. 172, No. 3, 1 May 2001, pp. 225-232.

[124]   W. T. Liao, C. L. Yu, E. L. Cheng-Che, C. H. Lee, C. S. Chang, L. W. Chang, H. L. You and H. S. Yu, “Differen-tial Effects of Arsenic on Cutaneous and Systemic Im-munity: Focusing on CD4+ Cell Apoptosis in Patients with Arsenic-Induced Bowen's Disease,” Carcinogenesis, 17 April 2009.

[125]   T. S. Griffith, T. Brunner, S. M. Fletcher, D. R. Green, and T. A. Ferguson, “Fas Ligand-Induced Apoptosis as a Mechanism of Immune Privilege,” Science, Vol. 270, No. 5239, 17 November 1995, pp. 1189-1192.

[126]   G. F. Murphy, P. A. Krusinski, L. A. Myzak and W. B. Ershler, “Local Immune Response in Basal Cell Carcinoma: Characterization by Transmission Electron Microscopy and Monoclonal Anti-T6 Antibody,” Journal of the American Academy of Dermatology, Vol. 8, No. 4, April 1983, pp. 477-485.

[127]   G. M. Woods, R. C. Malley and H. K. Muller, “The Skin Immune System and the Challenge of Tumour Immuno-surveillance,” European Journal of Dermatology, Vol. 15, No. 2, March-April 2005, pp. 63-69.