Abstract
The exposure/biotransformation of inorganic arsenic (iAs) may perturb DNA methylation patterns and subsequently influence disease risk by altering the expression of key genes. Interindividual variation in patterns of DNA methylation can be explained by the influence of environmental, genetic, and stochastic factors. Here, we examined promoter DNA methylation levels with urinary arsenical concentrations and investigated the genetic and nongenetic determinants of DNA methylation in 105 samples collected from populations in Shanxi Province, China, with high levels of arsenic in drinking water. Arsenic concentrations in water were determined by atomic absorption spectrophotometry (AA-6800, Shimadzu Co., Kyoto, Japan). Urine samples were measured using an atomic absorption spectrophotometer with an arsenic speciation pretreatment system (ASA-2sp, Shimadzu Co. Kyoto, Japan) for detection. Gene-specific (CDH1, EREG, ERCC2, GSTP1, and MGMT) DNA methylation was quantified by targeted bisulfite sequencing. Single-nucleotide polymorphism (SNP) genotyping was performed using a custom-by-design 2 × 48-Plex SNPscan™ Kit. These results revealed CDH1 with promoter DNA methylation levels associated with iAs. After the exclusion of confounding factors, age was correlated with increased methylation of the CDH1 gene. The susceptibility of the CDH1 and GSTP1 gene promoters to methylation was increased in individuals carrying the DNMT3B (SNP rs2424932) GA genotype, and the susceptibility of the CDH1 gene promoters to methylation was increased in individuals carrying the DNMT3B (SNP rs6087990) TC genotype. Although the above results must still be replicated in larger samples, the findings improve our understanding of the pathogenesis of arsenic and may highlight certain DNA methylation markers as attractive surrogate markers for prevention research.
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References
Banerjee N, Banerjee S, Sen R, Bandyopadhyay A, Sarma N, Majumder P, Das JK, Chatterjee M, Kabir SN, Giri AK (2009) Chronic arsenic exposure impairs macrophage functions in the exposed individuals. J Clin Immunol 29:582–594
Smith AH, Marshall G, Yuan Y, Ferreccio C, Liaw J, von Ehrenstein O, Steinmaus C, Bates MN, Selvin S (2006) Increased mortality from lung cancer and bronchiectasis in young adults after exposure to arsenic in utero and in early childhood. Environ Health Perspect 114:1293–1296
Baylin SB, Herman JG, Graff JR et al (1998) Alterations in DNA methylation: a fundamental aspect of neoplasia. Adv Cancer Res 72:141
Zhao CQ, Young MR, Diwan BA, Coogan TP, Waalkes MP (1997) Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci U S A 94:10907–10912
IARC (2004) IARC monographs on the evaluation of the carcinogenic risk to humans. Lyon: IARC 84:39–267
Santra A, Maiti A, Das S, Lahiri S, Charkaborty SK, Guha Mazumder DN, Guha Mazumder D (2000) Hepatic damage caused by chronic arsenic toxicity in experimental animals. J Toxicol Clin Toxicol 38:395–405
Chen Y-C, Su H-JJ, Guo Y-LL et al (2003) Arsenic methylation and bladder cancer risk in Taiwan. Cancer Causes Control 14:303–310
Abernathy CO, Liu YP, Longfellow D, Aposhian HV, Beck B, Fowler B, Goyer R, Menzer R, Rossman T, Thompson C, Waalkes M (1999) Arsenic: health effects, mechanisms of actions, and research issues. Environ Health Perspect 107:593–597
Chen H, Liu J, Merrick BA et al (2015) Genetic events associated with arsenic-induced malignant transformation: applications of cDNA microarray technology†. Mol Carcinog 30:79–87
Chen H, Liu J, Zhao CQ, Diwan BA, Merrick BA, Waalkes MP (2001) Association of c- myc overexpression and hyperproliferation with arsenite-induced malignant transformation. Toxicol Appl Pharmacol 175:260–268
Takahashi M, Barrett JC, Tsutsui T (2002) Transformation by inorganic arsenic compounds of normal Syrian hamster embryo cells into a neoplastic state in which they become anchorage-independent and cause tumors in newborn hamsters †. Int J Cancer 99:629–634
Chai CY, Huang YC, Hung WC, Kang WY, Chen WT (2007) Arsenic salts induced autophagic cell death and hypermethylation of DAPK promoter in SV-40 immortalized human uroepithelial cells. Toxicol Lett 173:48–56
Cui X, Wakai T, Shirai Y, Yokoyama N, Hatakeyama K, Hirano S (2006) Arsenic trioxide inhibits DNA methyltransferase and restores methylation-silenced genes in human liver cancer cells. Hum Pathol 37:298–311
Thomas DJ, Styblo M, Lin S (2001) The cellular metabolism and systemic toxicity of arsenic. Toxicol Appl Pharmacol 176:127–144
Baylin SB, Esteller M, Rountree MR et al (2001) Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. Hum Mol Genet 10:687–692
Mass MJ, Wang L (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. Mutat Res 386:263–277
Bailey KA, Wu MC, Ward WO, Smeester L, Rager JE, García-Vargas G, del Razo LM, Drobná Z, Stýblo M, Fry RC (2013) Arsenic and the epigenome: interindividual differences in arsenic metabolism related to distinct patterns of DNA methylation. J Biochem Mol Toxicol 27:106–115
Feng J, Fan G (2009) Chapter 4—the role of DNA methylation in the central nervous system and neuropsychiatric disorders. Int Rev Neurobiol 89:67–84
Wan J, Oliver VF, Wang G, Zhu H, Zack DJ, Merbs SL, Qian J (2015) Characterization of tissue-specific differential DNA methylation suggests distinct modes of positive and negative gene expression regulation. BMC Genomics 16:49
Rothenburg S, Kochnolte F, Thiele HG et al (2001) DNA methylation contributes to tissue- and allele-specific expression of the T-cell differentiation marker RT6. Immunogenetics 52:231–241
Li E, Beard C, Jaenisch R (1993) Role for DNA methylation in genomic imprinting. Nature 366:362–365
Gopisetty G, Ramachandran K, Singal R (2006) DNA methylation and apoptosis. Mol Immunol 43:1729–1740
Ottaviano YL, Issa JP, Parl FF et al (1994) Methylation of the estrogen receptor gene CpG island marks loss of estrogen receptor expression in human breast cancer cells. Cancer Res 54:2552–2555
Fuke C, Shimabukuro M, Petronis A, Sugimoto J, Oda T, Miura K, Miyazaki T, Ogura C, Okazaki Y, Jinno Y (2004) Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study. Ann Hum Genet 68:196–204
Elmaarri O, Becker T, Junen J et al (2007) Gender specific differences in levels of DNA methylation at selected loci from human total blood: a tendency toward higher methylation levels in males. Hum Genet 122:505–514
Breitling LP, Yang R, Korn B, Burwinkel B, Brenner H (2011) Tobacco-smoking-related differential DNA methylation: 27K discovery and replication. Am J Hum Genet 88:450–457
Furniss CS, Marsit CJ, Houseman A et al (2008) Line region hypomethylation is associated with lifestyle and differs by human papillomavirus (HPV) status in head and neck squamous cell carcinomas. Cancer Epidemiol Biomarkers Prev 17:966–971
Bleich S, Lenz B, Ziegenbein M, Beutler S, Frieling H, Kornhuber J, Bonsch D (2006) Epigenetic DNA hypermethylation of the HERP gene promoter induces down-regulation of its mRNA expression in patients with alcohol dependence. Alcohol Clin Exp Res 30:587–591
Bönsch D, Lenz B, Kornhuber J et al (2005) DNA hypermethylation of the alpha synuclein promoter in patients with alcoholism. Neuroreport 16:167–170
Heijmans BT, Kremer D, Tobi EW, Boomsma DI, Slagboom PE (2007) Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus. Hum Mol Genet 16:547–554
Kaminsky ZA, Tang T, Wang SC, Ptak C, Oh GHT, Wong AHC, Feldcamp LA, Virtanen C, Halfvarson J, Tysk C, McRae AF, Visscher PM, Montgomery GW, Gottesman II, Martin NG, Petronis A (2009) DNA methylation profiles in monozygotic and dizygotic twins. Nat Genet 41:240–245
Esteller M (2002) CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene 21:5427–5440
Yun J, Song SH, Park J et al (2012) Gene silencing of EREG mediated by DNA methylation and histone modification in human gastric cancers. Lab Invest 92:1033
Paul S, Banerjee N, Chatterjee A, Sau TJ, Das JK, Mishra PK, Chakrabarti P, Bandyopadhyay A, Giri AK (2014) Arsenic-induced promoter hypomethylation and over-expression of ERCC2 reduces DNA repair capacity in humans by non-disjunction of the ERCC2-Cdk7 complex. Metallomics 6:864–873
Ml G, Cp P, Sm L et al (2003) Prostate cancer detection by GSTP1 methylation analysis of postbiopsy urine specimens. Clin Cancer Res 9:2673–2677
Ogino S, Hazra A, Tranah GJ, Kirkner GJ, Kawasaki T, Nosho K, Ohnishi M, Suemoto Y, Meyerhardt JA, Hunter DJ, Fuchs CS (2007) MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer. Carcinogenesis 28:1985–1990
Duncan BK, Miller JH (1980) Mutagenic deamination of cytosine residues in DNA. Nature 287:560–561
Britten RJ, Baron WF, Stout DB, Davidson EH (1988) Sources and evolution of human Alu repeated sequences. Proc Natl Acad Sci U S A 85:4770–4774
Sved J, Bird A (1990) The expected equilibrium of the CpG dinucleotide in vertebrate genomes under a mutation model. Proc Natl Acad Sci U S A 87:4692–4696
Lindahl T (1974) An N-glycosidase from Escherichia coli that releases free uracil from DNA containing deaminated cytosine residues. Proc Natl Acad Sci U S A 71:3649–3653
Lindahl T, Karran P, Wood RD (1997) DNA excision repair pathways. Curr Opin Genet Dev 7:158–169
Aguilera O, Fernández AF, Muñoz A et al (2010) Epigenetics and environment: a complex relationship. J Appl Physiol 109:243–251
Beard C, Li E, Jaenisch R (1995) Loss of methylation activates Xist in somatic but not in embryonic cells. Genes Dev 9:2325–2334
Bestor TH (2000) The DNA methyltransferases of mammals. Hum Mol Genet 9:2395–2402
Morgan HD, Santos F, Green K et al (2005) Epigenetic reprogramming in mammals. Hum Mol Genet 14:47–58
Wang FY, Zhou SY, Wang YL, Wang LN, Zhou JP, Wang HL, Li CM, Chang MX (2015) Association of DNMT1 gene polymorphisms with congenital heart disease in child patients. Pediatr Cardiol 36:906–911
Zhang F, Su X, Wu Q et al (2010) A functional polymorphism in the DNA methyltransferase-3A promoter modifies the susceptibility in gastric cancer but not in esophageal carcinoma. BMC Med 8:12
Shen H, Wang L, Spitz MR et al (2002) A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer. Cancer Res 62:4992–4995
Singal R, Das PM, Manoharan M et al (2005) Polymorphisms in the DNA methyltransferase 3b gene and prostate cancer risk. Oncol Rep 14:569–573
Arakawa Y, Watanabe M, Inoue N, Sarumaru M, Hidaka Y, Iwatani Y (2012) Association of polymorphisms in DNMT1, DNMT3A, DNMT3B, MTHFR and MTRR genes with global DNA methylation levels and prognosis of autoimmune thyroid disease. Clin Exp Immunol 170:194–201
Tajuddin SM, Amaral AFS, Fernández AF et al (2013) Genetic and non-genetic predictors of LINE-1 methylation in leukocyte DNA. Environ Health Perspect 121:650–656
Chen X, Li S, Yang Y et al (2012) Genome-wide association study validation identifies novel loci for atherosclerotic cardiovascular disease. J Thromb Haemost 10:1508–1514
Xuan Y, Wang LN, Wei PM et al (2015) B-cell lymphoma 2 rs17757541 C>G polymorphism was associated with an increased risk of coronary artery disease in a Chinese population. Int J Clin Exp Pathol 8(11):15147–15154
Tseng CH (2007) Arsenic methylation, urinary arsenic metabolites and human diseases: current perspective. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev 25:1–22
Li X, Li B, Xu Y, Wang Y, Jin Y, Itoh T, Yoshida T, Sun G (2011) Arsenic methylation capacity and its correlation with skin lesions induced by contaminated drinking water consumption in residents of chronic arsenicosis area. Environ Toxicol 26:118–123
Huang YK, Huang YL, Hsueh YM, Yang MH, Wu MM, Chen SY, Hsu LI, Chen CJ (2008) Arsenic exposure, urinary arsenic speciation, and the incidence of urothelial carcinoma: a twelve-year follow-up study. Cancer Causes Control 19:829–839
Yoshida T, Yamauchi H, Fan SG (2004) Chronic health effects in people exposed to arsenic via the drinking water: dose-response relationships in review. Toxicol Appl Pharmacol 198:243–252
Hsieh YC, Lien LM, Chung WT, Hsieh FI, Hsieh PF, Wu MM, Tseng HP, Chiou HY, Chen CJ (2011) Significantly increased risk of carotid atherosclerosis with arsenic exposure and polymorphisms in arsenic metabolism genes. Environ Res 111:804–810
Babenko O, Kovalchuk I, Metz GA (2012) Epigenetic programming of neurodegenerative diseases by an adverse environment. Brain Res 1444:96–111
Bollati V, Schwartz J, Wright R, Litonjua A, Tarantini L, Suh H, Sparrow D, Vokonas P, Baccarelli A (2009) Decline in genomic DNA methylation through aging in a cohort of elderly subjects. Mech Ageing Dev 130:234–239
Feil R (2006) Environmental and nutritional effects on the epigenetic regulation of genes. Mutat Res Fundam Mol Mech Mutagen 600:46–57
Feil R, Fraga MF (2012) Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet 13:97–109
Fd G, Hj H, Re C et al (2002) Glutathione S-transferase P1 and NADPH quinone oxidoreductase polymorphisms are associated with aberrant promoter methylation of P16(INK4a) and O(6)-methylguanine-DNA methyltransferase in sputum. Cancer Res 62:2248–2252
Boks MP, Derks EM, Weisenberger DJ, Strengman E, Janson E, Sommer IE, Kahn RS, Ophoff RA (2009) The relationship of DNA methylation with age, gender and genotype in twins and healthy controls. PLoS One 4:e6767
Garagnani P, Bacalini MG, Pirazzini C et al (2012) Methylation of ELOVL 2 gene as a new epigenetic marker of age. Aging Cell 11(6):1132–1134
Heyn H, Li N, Ferreira HJ, Moran S, Pisano DG, Gomez A, Diez J, Sanchez-Mut JV, Setien F, Carmona FJ, Puca AA, Sayols S, Pujana MA, Serra-Musach J, Iglesias-Platas I, Formiga F, Fernandez AF, Fraga MF, Heath SC, Valencia A, Gut IG, Wang J, Esteller M (2012) Distinct DNA methylomes of newborns and centenarians. Proc Natl Acad Sci U S A 109:10522–10527
Hernandez DG, Nalls MA, Gibbs JR, Arepalli S, van der Brug M, Chong S, Moore M, Longo DL, Cookson MR, Traynor BJ, Singleton AB (2011) Distinct DNA methylation changes highly correlated with chronological age in the human brain. Hum Mol Genet 20:1164–1172
Bork S, Pfister S, Witt H et al (2009) DNA methylation pattern changes upon long-term culture and aging of human mesenchymal stromal cells. Aging Cell 9:54–63
Liu Y, Lan Q, Siegfried JM, Luketich JD, Keohavong P (2006) Aberrant promoter methylation of p16 and MGMT genes in lung tumors from smoking and never-smoking lung cancer patients. Neoplasia 8:46–51
Engeland MV, Weijenberg MP, Roemen GMJM et al (2003) Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer. Cancer Res 63:3133–3137
Mostowska A, Sajdak S, Pawlik P, Lianeri M, Jagodzinski PP (2013) DNMT1, DNMT3A and DNMT3B gene variants in relation to ovarian cancer risk in the Polish population. Mol Biol Rep 40:4893–4899
Xiang G, Zhenkun F, Shuang C, Jie Z, Hua Z, Wei J, da P, Dianjun L (2010) Association of DNMT1 gene polymorphisms in exons with sporadic infiltrating ductal breast carcinoma among Chinese Han women in the Heilongjiang Province. Clin Breast Cancer 10:373–377
Hossain MB, Vahter M, Concha G, Broberg K (2012) Low-level environmental cadmium exposure is associated with DNA hypomethylation in Argentinean women. Environ Health Perspect 120:879–884
Engström K, Vahter M, Mlakar SJ et al (2011) Polymorphisms in arsenic(+III oxidation state) methyltransferase (AS3MT) predict gene expression of AS3MT as well as arsenic metabolism. Environ Health Perspect 119:182–188
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The authors thank the sample donors for making this work possible.
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The National Natural Science Foundation of China (grant no. 81372936) funded this study.
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Yanting Zhang, Lanrong Luo, and Qian He extracted and selected samples and sent them for testing. Yanhui Gao, Yuanyuan Li, Hongqi Feng, Lijun Zhao, and Wei Wei collected all samples. Songbo Fu and Dianjun Sun guided and edited the article. Yanting Zhang performed the statistical analysis and wrote the manuscript. The manuscript was critically reviewed and approved by all authors.
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Zhang, Y., Li, Y., Luo, L. et al. Factors Affecting Differential Methylation of DNA Promoters in Arsenic-Exposed Populations. Biol Trace Elem Res 189, 437–446 (2019). https://doi.org/10.1007/s12011-018-1504-x
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DOI: https://doi.org/10.1007/s12011-018-1504-x