Lung Cancer: Mechanisms and Markers—Carcinogens Other Than Asbestos

  • Sisko AnttilaEmail author


Many carcinogenic chemicals, including polycyclic aromatic hydrocarbons, present in combustion products and tobacco smoke, enter cells as procarcinogens and require metabolic activation by cytochrome P450 (CYP) enzymes to exert their deleterious effects, including binding to DNA and formation of DNA adducts which, if not repaired, may lead to mutations in critical genes and cancer initiation. The induction of oxygen radical damage is considered the main mechanism of particle and metal carcinogenesis. In workplace air many carcinogens exist as complex mixtures, in which chemical compounds are bound to metal and mineral particles of respirable size. In lung cells, the components of complex mixtures induce oxidative stress as well as activation of chemical procarcinogens via intermingled pathways that may potentiate the DNA damage caused by either particle or chemical carcinogen alone. Carcinogenic metals are thought to induce oxidative stress-mediated DNA damage. Recent studies have shown that carcinogenic metals may replace metal ions, such as iron and zinc, in critical enzymes involved in DNA repair, histone methylation, and hypoxic signaling, for example. Epigenetic carcinogenic mechanisms have recently been found to play a larger role than previously thought, in environmental carcinogenesis.


Occupational lung cancer Pulmonary carcinogenesis PAH Polycyclic aromatic hydrocarbons Oxygen radical damage Reactive oxygen species Chromosomal aberrations Epigenetic changes Carcinogenic metals Involuntary tobacco smoking Arsenic Beryllium Cadmium Chromium Nickel Ionizing radiation 


  1. 1.
    Anderson DS, Patchin ES, Silva RM, et al. Influence of particle size on persistence and clearance of aerosolized silver nanoparticles in the rat lung. Toxicol Sci. 2015;144(2):366–81.PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Hansen AM, Mathiesen L, Pedersen M, Knudsen LE. Urinary 1-hydroxypyrene (1-HP) in environmental and occupational studies—a review. Int J Hyg Environ Health. 2008;211(5–6):471–503.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Georgiadis P, Stoikidou M, Topinka J, et al. Personal exposures to PM(2.5) and polycyclic aromatic hydrocarbons and their relationship to environmental tobacco smoke at two locations in Greece. J Expo Anal Environ Epidemiol. 2001;11(3):169–83.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Knecht U, Elliehausen HJ, Woitowitz HJ. Gaseous and adsorbed PAH in an iron foundry. Br J Ind Med. 1986;43(12):834–8.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Liu HH, Yang HH, Chou CD, Lin MH, Chen HL. Risk assessment of gaseous/particulate phase PAH exposure in foundry industry. J Hazard Mater. 2010;181(1–3):105–11.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Luceri F, Pieraccini G, Moneti G, Dolara P. Primary aromatic amines from side-stream cigarette smoke are common contaminants of indoor air. Toxicol Ind Health. 1993;9(3):405–13.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Pleil JD, Vette AF, Rappaport SM. Assaying particle-bound polycyclic aromatic hydrocarbons from archived PM2.5 filters. J Chromatogr. 2004;1033(1):9–17.CrossRefGoogle Scholar
  8. 8.
    Penning TM. Human aldo-keto reductases and the metabolic activation of polycyclic aromatic hydrocarbons. Chem Res Toxicol. 2014;27(11):1901–17.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Grimmer G, Naujack KW, Dettbarn G. Gaschromatographic determination of polycyclic aromatic hydrocarbons, aza-arenes, aromatic amines in the particle and vapor phase of mainstream and sidestream smoke of cigarettes. Toxicol Lett. 1987;35(1):117–24.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Guerin M, Jenkins RA, Tomkins BA. Mainstream and sidestream cigarette smoke In: Eisenberg M, editor. The chemistry of environmental tobacco smoke: composition and measurement. Chelsea, MI: Lewis; 1992.Google Scholar
  11. 11.
    IARC. Tobacco smoke and involuntary smoking. IARC monographs on the evaluation of carcinogenic risks to human. IARC: Lyon; 2004.Google Scholar
  12. 12.
    Lodovici M, Akpan V, Evangelisti C, Dolara P. Sidestream tobacco smoke as the main predictor of exposure to polycyclic aromatic hydrocarbons. J Appl Toxicol. 2004;24(4):277–81.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Lee HL, Hsieh DP, Li LA. Polycyclic aromatic hydrocarbons in cigarette sidestream smoke particulates from a Taiwanese brand and their carcinogenic relevance. Chemosphere. 2011;82(3):477–82.PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Zainol Abidin N, Zainal Abidin E, Zulkifli A, Karuppiah K, Ismail SNS, Nordin ASA. Electronic cigarettes and indoor air quality: a review of studies using human volunteers. Rev Environ Health. 2017;32(3):235–44.Google Scholar
  15. 15.
    Bock KW, Köhle C. The mammalian aryl hydrocarbon (ah) receptor: from mediator of dioxin toxicity toward physiological functions in skin and liver. Biol Chem. 2009;390(12):1225–35.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Fujii-Kuriyama Y, Kawajiri K. Molecular mechanisms of the physiological functions of the aryl hydrocarbon (dioxin) receptor, a multifunctional regulator that senses and responds to environmental stimuli. Proc Jpn Acad Ser B Phys Biol Sci. 2010;86(1):40–53.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Shimada T. Xenobiotic-metabolizing enzymes involved in activation and detoxification of carcinogenic polycyclic aromatic hydrocarbons. Drug Metab Pharmacokinet. 2006;21(4):257–76.PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Anttila S, Raunio H, Hakkola J. Cytochrome p450-mediated pulmonary metabolism of carcinogens: regulation and cross-talk in lung carcinogenesis. Am J Respir Cell Mol Biol. 2011;44(5):583–90.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Jiang H, Shen YM, Quinn AM, Penning TM. Competing roles of cytochrome P450 1A1/1B1 and aldo-keto reductase 1A1 in the metabolic activation of (+/−)-7,8-dihydroxy-7,8-dihydro-benzo[a]pyrene in human bronchoalveolar cell extracts. Chem Res Toxicol. 2005;18(2):365–74.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Melendez-Colon VJ, Luch A, Seidel A, Baird WM. Comparison of cytochrome P450- and peroxidase-dependent metabolic activation of the potent carcinogen dibenzo[a,l]pyrene in human cell lines: formation of stable DNA adducts and absence of a detectable increase in apurinic sites. Cancer Res. 1999;59(7):1412–6.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Palackal NT, Burczynski ME, Harvey RG, Penning TM. The ubiquitous aldehyde reductase (AKR1A1) oxidizes proximate carcinogen trans-dihydrodiols to o-quinones: potential role in polycyclic aromatic hydrocarbon activation. Biochemistry. 2001;40(36):10901–10.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Denissenko MF, Pao A, Tang M, Pfeifer GP. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 1996;274(5286):430–2.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Hussain SP, Amstad P, Raja K, et al. Mutability of p53 hotspot codons to benzo(a)pyrene diol epoxide (BPDE) and the frequency of p53 mutations in nontumorous human lung. Cancer Res. 2001;61(17):6350–5.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Yoon JH, Smith LE, Feng Z, Tang M, Lee CS, Pfeifer GP. Methylated CpG dinucleotides are the preferential targets for G-to-T transversion mutations induced by benzo[a]pyrene diol epoxide in mammalian cells: similarities with the p53 mutation spectrum in smoking-associated lung cancers. Cancer Res. 2001;61(19):7110–7.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Köhle C, Bock KW. Coordinate regulation of phase I and II xenobiotic metabolisms by the ah receptor and Nrf2. Biochem Pharmacol. 2007;73(12):1853–62.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Yeager RL, Reisman SA, Aleksunes LM, Klaassen CD. Introducing the “TCDD-inducible AhR-Nrf2 gene battery”. Toxicol Sci. 2009;111(2):238–46.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Itoh K, Chiba T, Takahashi S, et al. An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochem Biophys Res Commun. 1997;236(2):313–22.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Jaiswal AK. Regulation of genes encoding NAD(P)H:quinone oxidoreductases. Free Radic Biol Med. 2000;29(3–4):254–62.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Menegon S, Columbano A, Giordano S. The dual roles of NRF2 in cancer. Trends Mol Med. 2016;22(7):578–93.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Shibata T, Ohta T, Tong KI, et al. Cancer related mutations in NRF2 impair its recognition by Keap1-Cul3 E3 ligase and promote malignancy. Proc Natl Acad Sci U S A. 2008;105(36):13568–73.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Singh A, Misra V, Thimmulappa RK, et al. Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer. PLoS Med. 2006;3(10):e420.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Ruosaari ST, Nymark PE, Aavikko MM, et al. Aberrations of chromosome 19 in asbestos-associated lung cancer and in asbestos-induced micronuclei of bronchial epithelial cells in vitro. Carcinogenesis. 2008;29(5):913–7.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Wang R, An J, Ji F, Jiao H, Sun H, Zhou D. Hypermethylation of the Keap1 gene in human lung cancer cell lines and lung cancer tissues. Biochem Biophys Res Commun. 2008;373(1):151–4.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Hayes JD, McMahon M. NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci. 2009;34(4):176–88.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Kotlo KU, Yehiely F, Efimova E, et al. Nrf2 is an inhibitor of the Fas pathway as identified by Achilles’ Heel method, a new function-based approach to gene identification in human cells. Oncogene. 2003;22(6):797–806.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    Morito N, Yoh K, Itoh K, et al. Nrf2 regulates the sensitivity of death receptor signals by affecting intracellular glutathione levels. Oncogene. 2003;22(58):9275–81.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Niture SK, Jaiswal AK. Nrf2 protein up-regulates antiapoptotic protein Bcl-2 and prevents cellular apoptosis. J Biol Chem. 2012;287(13):9873–86.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Niture SK, Jaiswal AK. Nrf2-induced antiapoptotic Bcl-xL protein enhances cell survival and drug resistance. Free Radic Biol Med. 2013;57:119–31.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Kim SY, Kim TJ, Lee KY. A novel function of peroxiredoxin 1 (Prx-1) in apoptosis signal-regulating kinase 1 (ASK1)-mediated signaling pathway. FEBS Lett. 2008;582(13):1913–8.PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Wikman H, Ruosaari S, Nymark P, et al. Gene expression and copy number profiling suggests the importance of allelic imbalance in 19p in asbestos-associated lung cancer. Oncogene. 2007;26(32):4730–7.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Valko M, Rhodes CJ, Moncol J, Izakovic M, Mazur M. Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem Biol Interact. 2006;160(1):1–40.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Kasai H, Iwamoto-Tanaka N, Miyamoto T, et al. Life style and urinary 8-hydroxydeoxyguanosine, a marker of oxidative DNA damage: effects of exercise, working conditions, meat intake, body mass index, and smoking. Jpn J Cancer Res. 2001;92(1):9–15.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Tamae K, Kawai K, Yamasaki S, et al. Effect of age, smoking and other lifestyle factors on urinary 7-methylguanine and 8-hydroxydeoxyguanosine. Cancer Sci. 2009;100(4):715–21.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Collins AR. The comet assay for DNA damage and repair: principles, applications, and limitations. Mol Biotechnol. 2004;26(3):249–61.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Tarantini A, Maitre A, Lefebvre E, et al. Relative contribution of DNA strand breaks and DNA adducts to the genotoxicity of benzo[a]pyrene as a pure compound and in complex mixtures. Mutat Res. 2009;671(1–2):67–75.PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    IARC. Arsenic, metals, fibres, and dusts. IARC monographs on the evaluation of carcinogenic risks to human. Lyon: IARC; 2012.Google Scholar
  47. 47.
    Huang C, Ke Q, Costa M, Shi X. Molecular mechanisms of arsenic carcinogenesis. Mol Cell Biochem. 2004;255(1–2):57–66.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Cohen SM, Arnold LL, Eldan M, Lewis AS, Beck BD. Methylated arsenicals: the implications of metabolism and carcinogenicity studies in rodents to human risk assessment. Crit Rev Toxicol. 2006;36(2):99–133.PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Kitchin KT. Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites. Toxicol Appl Pharmacol. 2001;172(3):249–61.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Styblo M, Del Razo LM, Vega L, et al. Comparative toxicity of trivalent and pentavalent inorganic and methylated arsenicals in rat and human cells. Arch Toxicol. 2000;74(6):289–99.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Shi H, Shi X, Liu KJ. Oxidative mechanism of arsenic toxicity and carcinogenesis. Mol Cell Biochem. 2004;255(1–2):67–78.PubMedCrossRefPubMedCentralGoogle Scholar
  52. 52.
    Yamanaka K, Takabayashi F, Mizoi M, An Y, Hasegawa A, Okada S. Oral exposure of dimethylarsinic acid, a main metabolite of inorganic arsenics, in mice leads to an increase in 8-Oxo-2′-deoxyguanosine level, specifically in the target organs for arsenic carcinogenesis. Biochem Biophys Res Commun. 2001;287(1):66–70.PubMedCrossRefPubMedCentralGoogle Scholar
  53. 53.
    Lau A, Whitman SA, Jaramillo MC, Zhang DD. Arsenic-mediated activation of the Nrf2-Keap1 antioxidant pathway. J Biochem Mol Toxicol. 2013;27(2):99–105.PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Matsui M, Nishigori C, Toyokuni S, et al. The role of oxidative DNA damage in human arsenic carcinogenesis: detection of 8-hydroxy-2′-deoxyguanosine in arsenic-related Bowen's disease. J Invest Dermatol. 1999;113(1):26–31.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Wanibuchi H, Hori T, Meenakshi V, et al. Promotion of rat hepatocarcinogenesis by dimethylarsinic acid: association with elevated ornithine decarboxylase activity and formation of 8-hydroxydeoxyguanosine in the liver. Jpn J Cancer Res. 1997;88(12):1149–54.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Barrett JC, Lamb PW, Wang TC, Lee TC. Mechanisms of arsenic-induced cell transformation. Biol Trace Elem Res. 1989;21:421–9.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Dong JT, Luo XM. Arsenic-induced DNA-strand breaks associated with DNA-protein crosslinks in human fetal lung fibroblasts. Mutat Res. 1993;302(2):97–102.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Hei TK, Liu SX, Waldren C. Mutagenicity of arsenic in mammalian cells: role of reactive oxygen species. Proc Natl Acad Sci U S A. 1998;95(14):8103–7.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Nakamuro K, Sayato Y. Comparative studies of chromosomal aberration induced by trivalent and pentavalent arsenic. Mutat Res. 1981;88(1):73–80.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Hartmann A, Speit G. Comparative investigations of the genotoxic effects of metals in the single cells gel (SCG) assay and the sister chromatid exchange (SCE) test. Environ Mol Mutagen. 1994;23(4):299–305.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Lee-Chen SF, Gurr JR, Lin IB, Jan KY. Arsenite enhances DNA double-strand breaks and cell killing of methyl methanesulfonate-treated cells by inhibiting the excision of alkali-labile sites. Mutat Res. 1993;294(1):21–8.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Mouron SA, Golijow CD, Dulout FN. DNA damage by cadmium and arsenic salts assessed by the single cell gel electrophoresis assay. Mutat Res. 2001;498(1–2):47–55.PubMedCrossRefPubMedCentralGoogle Scholar
  63. 63.
    Wang TS, Hsu TY, Chung CH, Wang AS, Bau DT, Jan KY. Arsenite induces oxidative DNA adducts and DNA-protein cross-links in mammalian cells. Free Radic Biol Med. 2001;31(3):321–30.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Hu Y, Su L, Snow ET. Arsenic toxicity is enzyme specific and its affects on ligation are not caused by the direct inhibition of DNA repair enzymes. Mutat Res. 1998;408(3):203–18.PubMedCrossRefPubMedCentralGoogle Scholar
  65. 65.
    Li JH, Rossman TG. Inhibition of DNA ligase activity by arsenite: a possible mechanism of its comutagenesis. Mol Toxicol. 1989a;2:1):1–9.PubMedPubMedCentralGoogle Scholar
  66. 66.
    Li JH, Rossman TG. Mechanism of comutagenesis of sodium arsenite with n-methyl-n-nitrosourea. Biol Trace Elem Res. 1989b;21:373–81.PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Lynn S, Lai HT, Gurr JR, Jan KY. Arsenite retards DNA break rejoining by inhibiting DNA ligation. Mutagenesis. 1997;12(5):353–8.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Morales ME, Derbes RS, Ade CM, Ortego JC, Stark J, Deininger PL, Roy-Engel AM. Heavy metal exposure influences double strand break DNA repair outcomes. PLoS One. 2016;11:e0151367. Scholar
  69. 69.
    Wu C-L, Huang L-Y, Chang CL. Linking arsenite- and cadmium-generated oxidative stress to microsatellite instability in vitro and in vivo. Free Radic Biol Med. 2017;112:12–23.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Guo HR, Wang NS, Hu H, Monson RR. Cell type specificity of lung cancer associated with arsenic ingestion. Cancer Epidemiol Biomarkers Prev. 2004;13(4):638–43.PubMedPubMedCentralGoogle Scholar
  71. 71.
    Taeger D, Johnen G, Wiethege T, et al. Major histopathological patterns of lung cancer related to arsenic exposure in German uranium miners. Int Arch Occup Environ Health. 2009;82(7):867–75.PubMedCrossRefPubMedCentralGoogle Scholar
  72. 72.
    Martinez VD, Buys TP, Adonis M, et al. Arsenic-related DNA copy-number alterations in lung squamous cell carcinomas. Br J Cancer. 2010;103(8):1277–83.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Martinez VD, Thu KL, Vucic EA, Hubaux R, Adonis M, Gil L, MacAulay C, Lam S, Lam WL. Whole-genome sequencing analysis identifies a distinctive mutational spectrum in an arsenic-related lung tumor. J Thorac Oncol. 2013;8(11):1451–5.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Arita A, Costa M. Epigenetics in metal carcinogenesis: nickel, arsenic, chromium and cadmium. Metallomics. 2009;1(3):222–8.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Zhao CQ, Young MR, Diwan BA, Coogan TP, Waalkes MP. Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. Proc Natl Acad Sci U S A. 1997;94(20):10907–12.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Zhou X, Sun H, Ellen TP, Chen H, Costa M. Arsenite alters global histone H3 methylation. Carcinogenesis. 2008;29(9):1831–6.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Marsit CJ, Karagas MR, Schned A, Kelsey KT. Carcinogen exposure and epigenetic silencing in bladder cancer. Ann N Y Acad Sci. 2006;1076:810–21.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Cui X, Wakai T, Shirai Y, Hatakeyama K, Hirano S. Chronic oral exposure to inorganic arsenate interferes with methylation status of p16INK4a and RASSF1A and induces lung cancer in A/J mice. Toxicol Sci. 2006;91(2):372–81.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Chai CY, Huang YC, Hung WC, Kang WY, Chen WT. Arsenic salt-induced DNA damage and expression of mutant p53 and COX-2 proteins in SV-40 immortalized human uroepithelial cells. Mutagenesis. 2007;22(6):403–8.PubMedCrossRefPubMedCentralGoogle Scholar
  80. 80.
    Chen WT, Hung WC, Kang WY, Huang YC, Chai CY. Urothelial carcinomas arising in arsenic-contaminated areas are associated with hypermethylation of the gene promoter of the death-associated protein kinase. Histopathology. 2007;51(6):785–92.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Mass MJ, Wang L. 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. 1997;386(3):263–77.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Chanda S, Dasgupta UB, Guhamazumder D, et al. DNA hypermethylation of promoter of gene p53 and p16 in arsenic-exposed people with and without malignancy. Toxicol Sci. 2006;89(2):431–7.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Zhou X, Li Q, Arita A, Sun H, Costa M. Effects of nickel, chromate, and arsenite on histone 3 lysine methylation. Toxicol Appl Pharmacol. 2009;236(1):78–84.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Chervona Y, et al. Associations between arsenic exposure and global posttranslational histone modifications among adults in Bangladesh. Cancer Epidemiol Biomarkers Prev. 2012;21(12):2252–60.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Sage AP, Minatel BC, Ng KW, Stewart GL, Dummer TJB, Lam WL, Martinez VD. Oncogenomic disruptions in arsenic-induced carcinogenesis. Oncotarget. 2017;8(15):25735–55.CrossRefGoogle Scholar
  86. 86.
    Salnikow K, Zhitkovich A. Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium. Chem Res Toxicol. 2008;21(1):28–44.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Humphries B, Wang Z, Yang C. The role of microRNAs in metal-induced cell malignant transformation and tumorigenesis. Food Chem Toxicol. 2016;98.(Pt A:58–65.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Pratheeshkumar P, Son Y-O, Divya SP, Wang L, Zhang Z, Shi X. Oncogenic transformation of human lung bronchial epithelial cells induced by arsenic involves ROS-dependent activation of STAT3-miR-21-PDCD4 mechanism. Sci Rep. 2016b;6:37227. Scholar
  89. 89.
    Chiang HC, Tsou TC. Arsenite enhances the benzo[a]pyrene diol epoxide (BPDE)-induced mutagenesis with no marked effect on repair of BPDE-DNA adducts in human lung cells. Toxicol In Vitro. 2009;23(5):897–905.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Lee TC, Huang RY, Jan KY. Sodium arsenite enhances the cytotoxicity, clastogenicity, and 6-thioguanine-resistant mutagenicity of ultraviolet light in Chinese hamster ovary cells. Mutat Res. 1985;148(1–2):83–9.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Li JH, Rossman TG. Comutagenesis of sodium arsenite with ultraviolet radiation in Chinese hamster V79 cells. Biol Met. 1991;4(4):197–200.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Rossman TG, Uddin AN, Burns FJ, Bosland MC. Arsenite cocarcinogenesis: an animal model derived from genetic toxicology studies. Environ Health Perspect. 2002;110(Suppl 5):749–52.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Rossman TG, Uddin AN, Burns FJ. Evidence that arsenite acts as a cocarcinogen in skin cancer. Toxicol Appl Pharmacol. 2004;198(3):394–404.PubMedCrossRefPubMedCentralGoogle Scholar
  94. 94.
    Tran HP, Prakash AS, Barnard R, Chiswell B, Ng JC. Arsenic inhibits the repair of DNA damage induced by benzo(a)pyrene. Toxicol Lett. 2002;133(1):59–67.PubMedCrossRefPubMedCentralGoogle Scholar
  95. 95.
    Wiencke JK, Yager JW. Specificity of arsenite in potentiating cytogenetic damage induced by the DNA crosslinking agent diepoxybutane. Environ Mol Mutagen. 1992;19(3):195–200.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Chen CL, Hsu LI, Chiou HY, et al. Ingested arsenic, cigarette smoking, and lung cancer risk: a follow-up study in arseniasis-endemic areas in Taiwan. JAMA. 2004;292(24):2984–90.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Ferreccio C, Gonzalez C, Milosavjlevic V, Marshall G, Sancha AM, Smith AH. Lung cancer and arsenic concentrations in drinking water in Chile. Epidimiology. 2000;11(6):673–9.CrossRefGoogle Scholar
  98. 98.
    Chen CL, Chiou HY, Hsu LI, Hsueh YM, Wu MM, Chen CJ. Ingested arsenic, characteristics of well water consumption and risk of different histological types of lung cancer in northeastern Taiwan. Environ Res. 2010a;110(5):455–62.PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Chen H, Giri NC, Zhang R, et al. Nickel ions inhibit histone demethylase JMJD1A and DNA repair enzyme ABH2 by replacing the ferrous iron in the catalytic centers. J Biol Chem. 2010b;285(10):7374–83.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Chen H, Kluz T, Zhang R, Costa M. Hypoxia and nickel inhibit histone demethylase JMJD1A and repress Spry2 expression in human bronchial epithelial BEAS-2B cells. Carcinogenesis. 2010c;31(12):2136–44.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Lee HL, Chang LW, Wu JP, et al. Enhancements of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) metabolism and carcinogenic risk via NNK/arsenic interaction. Toxicol Appl Pharmacol. 2008;227(1):108–14.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Wu JP, Chang LW, Yao HT, et al. Involvement of oxidative stress and activation of aryl hydrocarbon receptor in elevation of CYP1A1 expression and activity in lung cells and tissues by arsenic: an in vitro and in vivo study. Toxicol Sci. 2009;107(2):385–93.PubMedCrossRefPubMedCentralGoogle Scholar
  103. 103.
    Hollins DM, McKinley MA, Williams C, et al. Beryllium and lung cancer: a weight of evidence evaluation of the toxicological and epidemiological literature. Crit Rev Toxicol. 2009;39(Suppl 1):1–32.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Gordon T, Bowser D. Beryllium: genotoxicity and carcinogenicity. Mutat Res. 2003;533(1–2):99–105.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Belinsky SA, Snow SS, Nikula KJ, Finch GL, Tellez CS, Palmisano WA. Aberrant CpG island methylation of the p16(INK4a) and estrogen receptor genes in rat lung tumors induced by particulate carcinogens. Carcinogenesis. 2002;23(2):335–9.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Joseph P. Mechanisms of cadmium carcinogenesis. Toxicol Appl Pharmacol. 2009;238(3):272–9.PubMedCrossRefPubMedCentralGoogle Scholar
  107. 107.
    Kairdolf BA, Smith AM, Stokes TH, Wang AN, Young AN, Nie S. Semiconductor quantum dots for bioimaging and biodiagnostic applications. Annu Rev Anal Chem. 2013;6:143–62.CrossRefGoogle Scholar
  108. 108.
    Zheng W, Xu Y-M, Wu D-D, Yao Y, Liang Z-L, Tan HW, Lau ATY. Acute and chronic cadmium telluride quantum dots-exposed human bronchial epithelial cells: the effects of particle sizes on their cytotoxicity and carcinogenicity. Biochem Biophys Res Commun. 2018;495(1):899–903.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Pääkkö P, Anttila S, Kokkonen P, Kalliomäki PL. Cadmium in lung tissue as marker for smoking. Lancet. 1988;1(8583):477.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Liu J, Qu W, Kadiiska MB. Role of oxidative stress in cadmium toxicity and carcinogenesis. Toxicol Appl Pharmacol. 2009;238(3):209–14.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Misra RR, Page JE, Smith GT, Waalkes MP, Dipple A. Effect of cadmium exposure on background and anti-5 methylchrysene-1,2-dihydrodiol 3,4-epoxide-induced mutagenesis in the supF gene of pS189 in human Ad293 cells. Chem Res Toxicol. 1998a;11(3):211–6.PubMedCrossRefPubMedCentralGoogle Scholar
  112. 112.
    Misra RR, Smith GT, Waalkes MP. Evaluation of the direct genotoxic potential of cadmium in four different rodent cell lines. Toxicology. 1998b;126(2):103–14.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Ochi T, Ohsawa M. Participation of active oxygen species in the induction of chromosomal aberrations by cadmium chloride in cultured Chinese hamster cells. Mutat Res. 1985;143(3):137–42.PubMedCrossRefPubMedCentralGoogle Scholar
  114. 114.
    Price DJ, Joshi JG. Ferritin. Binding of beryllium and other divalent metal ions. J Biol Chem. 1983;258(18):10873–80.PubMedPubMedCentralGoogle Scholar
  115. 115.
    Schnekenburger M, Talaska G, Puga A. Chromium cross-links histone deacetylase 1-DNA methyltransferase 1 complexes to chromatin, inhibiting histone-remodeling marks critical for transcriptional activation. Mol Cell Biol. 2007;27(20):7089–101.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Nezis IP, Stenmark H. p62 at the interface of autophagy, oxidative stress signaling, and cancer. Antioxid Redox Signal. 2012;17(5):786–93.PubMedCrossRefPubMedCentralGoogle Scholar
  117. 117.
    Son YO, Pratheeshkumar P, Roy RV, Hitron JA, Wang L, Zhang Z, Shi X. Nrf2/p62 signaling in apoptosis resistance and its role in cadmium-induced carcinogenesis. J Biol Chem. 2014;289(41):28660–75.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Son YO, Wang L, Poyil P, Budhara A, Hitron JA, Zhang Z, Lee JC, Shi X. Cadmium induces carcinogenesis in BEAS-2B cells through ROS-dependent activation of P13K/AKT/GSK-3β/β-catenin signaling. Toxicol Appl Pharmacol. 2012;264(2):153–60.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Giaginis C, Gatzidou E, Theocharis S. DNA repair systems as targets of cadmium toxicity. Toxicol Appl Pharmacol. 2006;213(3):282–90.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Mikhailova MV, Littlefield NA, Hass BS, Poirier LA, Chou MW. Cadmium-induced 8-hydroxydeoxyguanosine formation, DNA strand breaks and antioxidant enzyme activities in lymphoblastoid cells. Cancer Lett. 1997;115(2):141–8.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    O’Connor TR, Graves RJ, de Murcia G, Castaing B, Laval J. Fpg protein of Escherichia coli is a zinc finger protein whose cysteine residues have a structural and/or functional role. J Biol Chem. 1993;268(12):9063–70.Google Scholar
  122. 122.
    Benbrahim-Tallaa L, Waterland RA, Dill AL, Webber MM, Waalkes MP. Tumor suppressor gene inactivation during cadmium-induced malignant transformation of human prostate cells correlates with overexpression of de novo DNA methyltransferase. Environ Health Perspect. 2007;115(10):1454–9.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Takiguchi M, Achanzar WE, Qu W, Li G, Waalkes MP. Effects of cadmium on DNA-(Cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp Cell Res. 2003;286(2):355–65.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Huang D, Zhang Y, Qi Y, Chen C, Ji W. Global DNA hypomethylation, rather than reactive oxygen species (ROS), a potential facilitator of cadmium-stimulated K562 cell proliferation. Toxicol Lett. 2008;179(1):43–7.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Ding M, Shi X, Castranova V, Vallyathan V. Predisposing factors in occupational lung cancer: inorganic minerals and chromium. J Environ Pathol Toxicol Oncol. 2000;19(1–2):129–38.PubMedPubMedCentralGoogle Scholar
  126. 126.
    Nickens KP, Patierno SR, Ceryak S. Chromium genotoxicity: a double-edged sword. Chem Biol Interact. 2010;188(2):276–88.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Liu K, Husler J, Ye J, et al. On the mechanism of Cr (VI)-induced carcinogenesis: dose dependence of uptake and cellular responses. Mol Cell Biochem. 2001;222(1–2):221–9.PubMedCrossRefPubMedCentralGoogle Scholar
  128. 128.
    Liu KJ, Shi X. In vivo reduction of chromium (VI) and its related free radical generation. Mol Cell Biochem. 2001;222(1–2):41–7.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Holmes AL, Wise SS, Sandwick SJ, Wise JP Sr. The clastogenic effects of chronic exposure to particulate and soluble Cr(VI) in human lung cells. Mutat Res. 2006;610(1–2):8–13.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Wise JP Sr, Wise SS, Little JE. The cytotoxicity and genotoxicity of particulate and soluble hexavalent chromium in human lung cells. Mutat Res. 2002;517(1–2):221–9.PubMedCrossRefPubMedCentralGoogle Scholar
  131. 131.
    Zhitkovich A. Importance of chromium-DNA adducts in mutagenicity and toxicity of chromium(VI). Chem Res Toxicol. 2005;18(1):3–11.PubMedCrossRefPubMedCentralGoogle Scholar
  132. 132.
    O’Brien TJ, Ceryak S, Patierno SR. Complexities of chromium carcinogenesis: role of cellular response, repair and recovery mechanisms. Mutat Res. 2003;533(1–2):3–36.PubMedCrossRefPubMedCentralGoogle Scholar
  133. 133.
    Wakeman TP, Kim WJ, Callens S, Chiu A, Brown KD, Xu B. The ATM-SMC1 pathway is essential for activation of the chromium[VI]-induced S-phase checkpoint. Mutat Res. 2004;554(1–2):241–51.PubMedCrossRefPubMedCentralGoogle Scholar
  134. 134.
    Wakeman TP, Yang A, Dalal NS, Boohaker RJ, Zeng Q, Ding Q, Xu B. DNA mismatch repair protein Mlh1 is required for tetravalent chromium intermediate-induced DNA damage. Oncotarget. 2017;8(48):83975–85.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Hirose T, Kondo K, Takahashi Y, et al. Frequent microsatellite instability in lung cancer from chromate-exposed workers. Mol Carcinog. 2002;33(3):172–80.PubMedCrossRefPubMedCentralGoogle Scholar
  136. 136.
    Takahashi Y, Kondo K, Hirose T, et al. Microsatellite instability and protein expression of the DNA mismatch repair gene, hMLH1, of lung cancer in chromate-exposed workers. Mol Carcinog. 2005;42(3):150–8.PubMedCrossRefPubMedCentralGoogle Scholar
  137. 137.
    Rodrigues CF, Urbano AM, Matoso E, et al. Human bronchial epithelial cells malignantly transformed by hexavalent chromium exhibit an aneuploid phenotype but no microsatellite instability. Mutat Res. 2009;670(1–2):42–52.PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Ewis AA, Kondo K, Lee J, et al. Occupational cancer genetics: infrequent ras oncogenes point mutations in lung cancer samples from chromate workers. Am J Ind Med. 2001;40(1):92–7.PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Kondo K, Hino N, Sasa M, et al. Mutations of the p53 gene in human lung cancer from chromate-exposed workers. Biochem Biophys Res Commun. 1997;239(1):95–100.PubMedCrossRefPubMedCentralGoogle Scholar
  140. 140.
    Wei YD, Tepperman K, Huang MY, Sartor MA, Puga A. Chromium inhibits transcription from polycyclic aromatic hydrocarbon-inducible promoters by blocking the release of histone deacetylase and preventing the binding of p300 to chromatin. J Biol Chem. 2004;279(6):4110–9.PubMedCrossRefPubMedCentralGoogle Scholar
  141. 141.
    Sun H, Zhou X, Chen H, Li Q, Costa M. Modulation of histone methylation and MLH1 gene silencing by hexavalent chromium. Toxicol Appl Pharmacol. 2009;237(3):258–66.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Ali AH, Kondo K, Namura T, et al. Aberrant DNA methylation of some tumor suppressor genes in lung cancers from workers with chromate exposure. Mol Carcinog. 2011;50(2):89–99.CrossRefGoogle Scholar
  143. 143.
    Kondo K, Takahashi Y, Hirose Y, et al. The reduced expression and aberrant methylation of p16(INK4a) in chromate workers with lung cancer. Lung Cancer. 2006;53(3):295–302.CrossRefGoogle Scholar
  144. 144.
    Cano CE, Hamidi T, Sandi MJ, Iovanna JL. Nupr1: the Swiss-knife of cancer. J Cell Physiol. 2011;226(6):1439–43.PubMedCrossRefPubMedCentralGoogle Scholar
  145. 145.
    Chen D, Kluz T, Fang L, Zhang X, Sun H, Jin C, Costa M. Hexavalent chromium (Cr(VI)) down-regulates acetylation of histone H4 at lysine 16 through induction of stressor protein Nupr1. PLoS One. 2016;11(6):e0157317. Scholar
  146. 146.
    He J, Qian X, Carpenter R, Xu Q, Wang L, Qi Y, Wang ZX, Liu LZ, Jiang BH. Repression of miR-143 mediates cr(VI)-induced tumor angiogenesis via IGF-IR/IRS1/ERK/IL-8 pathway. Toxicol Sci. 2013;134(1):26–38.PubMedPubMedCentralCrossRefGoogle Scholar
  147. 147.
    Pratheeshkumar P, Son Y-O, Divya SP, Turcios L, Roy RV, Hitron JA, Wang L, Kim D, Dai J, Asha P, Zhang Z, Shi X. Hexavalent chromium induces malignant transformation of human lung bronchial epithelial cells via ROS-dependent activation of miR-21-PDCD4 signaling. Oncotarget. 2016a;7(32):51193–210.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Vincent JH, Werner MA. Critical evaluation of historical occupational aerosol exposure records: applications to nickel and lead. Ann Occup Hyg. 2003;47(1):49–59.PubMedPubMedCentralGoogle Scholar
  149. 149.
    Lu H, Shi X, Costa M, Huang C. Carcinogenic effect of nickel compounds. Mol Cell Biochem. 2005;279(1–2):45–67.PubMedCrossRefPubMedCentralGoogle Scholar
  150. 150.
    Barceloux DG. Nickel. J Toxicol. 1999;37(2):239–58.Google Scholar
  151. 151.
    Biggart NW, Costa M. Assessment of the uptake and mutagenicity of nickel chloride in salmonella tester strains. Mutat Res. 1986;175(4):209–15.PubMedCrossRefPubMedCentralGoogle Scholar
  152. 152.
    Fletcher GG, Rossetto FE, Turnbull JD, Nieboer E. Toxicity, uptake, and mutagenicity of particulate and soluble nickel compounds. Environ Health Perspect. 1994;102(Suppl 3):69–79.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Kargacin B, Klein CB, Costa M. Mutagenic responses of nickel oxides and nickel sulfides in Chinese hamster V79 cell lines at the xanthine-guanine phosphoribosyl transferase locus. Mutat Res. 1993;300(1):63–72.PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Patierno SR, Dirscherl LA, Xu J. Transformation of rat tracheal epithelial cells to immortal growth variants by particulate and soluble nickel compounds. Mutat Res. 1993;300(3–4):179–93.PubMedCrossRefPubMedCentralGoogle Scholar
  155. 155.
    Tveito G, Hansteen IL, Dalen H, Haugen A. Immortalization of normal human kidney epithelial cells by nickel(II). Cancer Res. 1989;49(7):1829–35.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Costa M. Molecular mechanisms of nickel carcinogenesis. Annu Rev Pharmacol Toxicol. 1991;31:321–37.PubMedCrossRefPubMedCentralGoogle Scholar
  157. 157.
    Das KK, Buchner V. Effect of nickel exposure on peripheral tissues: role of oxidative stress in toxicity and possible protection by ascorbic acid. Rev Environ Health. 2007;22(2):157–73.PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Das KK, Das SN, Dhundasi SA. Nickel, its adverse health effects & oxidative stress. Indian J Med Res. 2008;128(4):412–25.PubMedPubMedCentralGoogle Scholar
  159. 159.
    Higinbotham KG, Rice JM, Diwan BA, Kasprzak KS, Reed CD, Perantoni AO. GGT to GTT transversions in codon 12 of the K-ras oncogene in rat renal sarcomas induced with nickel subsulfide or nickel subsulfide/iron are consistent with oxidative damage to DNA. Cancer Res. 1992;52(17):4747–51.PubMedPubMedCentralGoogle Scholar
  160. 160.
    Kawanishi S, Oikawa S, Inoue S, Nishino K. Distinct mechanisms of oxidative DNA damage induced by carcinogenic nickel subsulfide and nickel oxides. Environ Health Perspect. 2002;110(Suppl 5):789–91.PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Wu S, Bai YN, Pu HQ, He J, Zheng TZ, Li HY, Dai M, Cheng N. Dynamic changes in DNA damage and repair biomarkers with employment length among nickel smelting workers. Biomed Environ Sci. 2015;28(9):679–82.PubMedPubMedCentralGoogle Scholar
  162. 162.
    Son Y-O, Pratheeshkumar P, Divya SP, Zhang Z, Shi X. Nuclear factor erythroid 2-related factor 2 enhances carcinogenesis by suppressing apoptosis and promoting autophagy in nickel-transformed cells. J Biol Chem. 2017;292(20):8315–30.PubMedPubMedCentralCrossRefGoogle Scholar
  163. 163.
    Lee YW, Klein CB, Kargacin B, et al. Carcinogenic nickel silences gene expression by chromatin condensation and DNA methylation: a new model for epigenetic carcinogens. Mol Cell Biol. 1995;15(5):2547–57.PubMedPubMedCentralCrossRefGoogle Scholar
  164. 164.
    Sutherland JE, Costa M. Epigenetics and the environment. Ann N Y Acad Sci. 2003;983:151–60.PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Ellen TP, Kluz T, Harder ME, Xiong J, Costa M. Heterochromatinization as a potential mechanism of nickel-induced carcinogenesis. Biochemistry. 2009;48(21):4626–32.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Cameron KS, Buchner V, Tchounwou PB. Exploring the molecular mechanisms of nickel-induced genotoxicity and carcinogenicity: a literature review. Rev Environ Health. 2011;26(2):81–92.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Kang J, Zhang Y, Chen J, et al. Nickel-induced histone hypoacetylation: the role of reactive oxygen species. Toxicol Sci. 2003;74(2):279–86.PubMedCrossRefPubMedCentralGoogle Scholar
  168. 168.
    Yan Y, Kluz T, Zhang P, Chen HB, Costa M. Analysis of specific lysine histone H3 and H4 acetylation and methylation status in clones of cells with a gene silenced by nickel exposure. Toxicol Appl Pharmacol. 2003;190(3):272–7.PubMedCrossRefPubMedCentralGoogle Scholar
  169. 169.
    Chen H, Ke Q, Kluz T, Yan Y, Costa M. Nickel ions increase histone H3 lysine 9 dimethylation and induce transgene silencing. Mol Cell Biol. 2006;26(10):3728–37.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Jose CC, Xu B, Jagannathan L, Trac C, Mallela RK, Hattori T, Lai D, Koide S, Schones DE, Cuddapah S. Epigenetic dysregulation by nickel through repressive chromatin disruption. PNAS. 2014;111(40):14631–6.PubMedCrossRefPubMedCentralGoogle Scholar
  171. 171.
    Govindarajan B, Klafter R, Miller MS, et al. Reactive oxygen-induced carcinogenesis causes hypermethylation of p16(Ink4a) and activation of MAP kinase. Mol Med. 2002;8:1):1–8.PubMedPubMedCentralCrossRefGoogle Scholar
  172. 172.
    Zhang J, Zhang J, Li M, et al. Methylation of RAR-beta2, RASSF1A, and CDKN2A genes induced by nickel subsulfide and nickel-carcinogenesis in rats. Biomed Environ Sci. 2011;24(2):163–71.PubMedPubMedCentralGoogle Scholar
  173. 173.
    Arita A, Niu J, Qu Q, Zhao N, Ruan Y, Nadas A, Chervona Y, Wu F, Sun H, Hayes RB, Costa M. Global levels of histone modifications in peripheral blood mononuclear cells of subjects with exposure to nickel. Environ Health Perspect. 2012;120(2):198–203.PubMedCrossRefPubMedCentralGoogle Scholar
  174. 174.
    Brocato J, Costa M. 10th NTES conference: nickel and arsenic compounds alter the epigenome of peripheral blood mononuclear cells. J Trace Elem Med Biol. 2015;31:209–13.PubMedCrossRefPubMedCentralGoogle Scholar
  175. 175.
    Ma L, Bai Y, Pu H, Gou F, Dai M, Wang H, He J, Zheng T, Cheng N. Histone methylation in nickel-smelting industrial workers. PLoS One. 2015;10(10):e0140339. Scholar
  176. 176.
    Salnikow K, Davidson T, Zhang Q, Chen LC, Su W, Costa M. The involvement of hypoxia-inducible transcription factor-1-dependent pathway in nickel carcinogenesis. Cancer Res. 2003;63(13):3524–30.PubMedPubMedCentralGoogle Scholar
  177. 177.
    Chen H, Costa M. Iron- and 2-oxoglutarate-dependent dioxygenases: an emerging group of molecular targets for nickel toxicity and carcinogenicity. Biometals. 2009;22(1):191–6.PubMedCrossRefPubMedCentralGoogle Scholar
  178. 178.
    Kang GS, Li Q, Chen H, Costa M. Effect of metal ions on HIF-1alpha and Fe homeostasis in human A549 cells. Mutat Res. 2006;610(1–2):48–55.PubMedCrossRefPubMedCentralGoogle Scholar
  179. 179.
    Witkiewicz-Kucharczyk A, Bal W. Damage of zinc fingers in DNA repair proteins, a novel molecular mechanism in carcinogenesis. Toxicol Lett. 2006;162(1):29–42.PubMedPubMedCentralCrossRefGoogle Scholar
  180. 180.
    Scanlon SE, Scanlon CD, Hegan DC, Sulkowski PL, Glazer PM. Nickel induces transcriptional down-regulation of DNA repair pathways in tumorigenic and non-tumorigenic lung cells. Carcinogenesis. 2017;38(6):627–37.PubMedPubMedCentralCrossRefGoogle Scholar
  181. 181.
    Brugge D, de Lemos JL, Oldmixon B. Exposure pathways and health effects associated with chemical and radiological toxicity of natural uranium: a review. Rev Environ Health. 2005;20(3):177–93.PubMedCrossRefPubMedCentralGoogle Scholar
  182. 182.
    Jostes RF. Genetic, cytogenetic, and carcinogenic effects of radon: a review. Mutat Res. 1996;340(2–3):125–39.PubMedCrossRefPubMedCentralGoogle Scholar
  183. 183.
    Kusiak RA, Ritchie AC, Muller J, Springer J. Mortality from lung cancer in Ontario uranium miners. Br J Ind Med. 1993;50(10):920–8.PubMedPubMedCentralGoogle Scholar
  184. 184.
    Bao CY, Ma AH, Evans HH, et al. Molecular analysis of hypoxanthine phosphoribosyltransferase gene deletions induced by alpha- and X-radiation in human lymphoblastoid cells. Mutat Res. 1995;326(1):1–15.PubMedCrossRefPubMedCentralGoogle Scholar
  185. 185.
    Richardson D, Sugiyama H, Nishi N, et al. Ionizing radiation and leukemia mortality among Japanese Atomic Bomb Survivors, 1950-2000. Radiat Res. 2009a;172(3):368–82.PubMedCrossRefPubMedCentralGoogle Scholar
  186. 186.
    Richardson DB, Sugiyama H, Wing S, et al. Positive associations between ionizing radiation and lymphoma mortality among men. Am J Epidemiol. 2009b;169(8):969–76.PubMedPubMedCentralCrossRefGoogle Scholar
  187. 187.
    Richardson DB. Exposure to ionizing radiation in adulthood and thyroid cancer incidence. Epidimiology. 2009a;20(2):181–7.CrossRefGoogle Scholar
  188. 188.
    Richardson RB. Ionizing radiation and aging: rejuvenating an old idea. Aging. 2009b;1(11):887–902.PubMedPubMedCentralCrossRefGoogle Scholar
  189. 189.
    Ward JF. DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog Nucleic Acid Res Mol Biol. 1988;35:95–125.PubMedCrossRefPubMedCentralGoogle Scholar
  190. 190.
    Kadhim MA, Macdonald DA, Goodhead DT, Lorimore SA, Marsden SJ, Wright EG. Transmission of chromosomal instability after plutonium alpha-particle irradiation. Nature. 1992;355(6362):738–40.PubMedCrossRefPubMedCentralGoogle Scholar
  191. 191.
    Liu D, Momoi H, Li L, Ishikawa Y, Fukumoto M. Microsatellite instability in thorotrast-induced human intrahepatic cholangiocarcinoma. Int J Cancer. 2002;102(4):366–71.PubMedCrossRefPubMedCentralGoogle Scholar
  192. 192.
    Chaudhry MA. Base excision repair of ionizing radiation-induced DNA damage in G1 and G2 cell cycle phases. Cancer Cell Int. 2007;7:15.PubMedPubMedCentralCrossRefGoogle Scholar
  193. 193.
    Hussain SP, Kennedy CH, Amstad P, Lui H, Lechner JF, Harris CC. Radon and lung carcinogenesis: mutability of p53 codons 249 and 250 to 238Pu alpha-particles in human bronchial epithelial cells. Carcinogenesis. 1997;18(1):121–5.PubMedCrossRefPubMedCentralGoogle Scholar
  194. 194.
    Taylor JA, Watson MA, Devereux TR, Michels RY, Saccomanno G, Anderson M. p53 mutation hotspot in radon-associated lung cancer. Lancet. 1994;343(8889):86–7.PubMedCrossRefPubMedCentralGoogle Scholar
  195. 195.
    Su S, Jin Y, Zhang W, et al. Aberrant promoter methylation of p16(INK4a) and O(6)-methylguanine-DNA methyltransferase genes in workers at a Chinese uranium mine. J Occup Health. 2006;48(4):261–6.PubMedCrossRefPubMedCentralGoogle Scholar
  196. 196.
    Gilliland FD, Harms HJ, Crowell RE, Li YF, Willink R, Belinsky SA. 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. 2002;62(8):2248–52.PubMedPubMedCentralGoogle Scholar
  197. 197.
    Belinsky SA, Klinge DM, Liechty KC, et al. Plutonium targets the p16 gene for inactivation by promoter hypermethylation in human lung adenocarcinoma. Carcinogenesis. 2004;25(6):1063–7.PubMedCrossRefPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of PathologyUniversity of Helsinki and Helsinki University HospitalHelsinkiFinland

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