Heavy metals in the cell nucleus - role in pathogenesis

• Authors: Hanna Sas-Nowosielska , Natalia Pawlas
• Languages of publication: EN

Abstracts

EN

People are exposed to heavy metals both in an occupational and natural environment. The most pronounced effects of heavy metals result from their interaction with cellular genetic material packed in form of chromatin. Heavy metals influence chromatin, mimicking and substituting natural microelements in various processes taking place in the cell, or interacting chemically with nuclear components: nucleic acids, proteins and lipids. This paper is a review of current knowledge on the effects of heavy metals on chromatin, exerted at the level of various nuclear components.

Keywords

EN

heavy metal; nucleus; chromatin; DNA; RNA; telomere

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2015
• Volume: 62
• Issue: 1
• Pages: 7-13

Dates

published

2015

received

2014-06-11

revised

2014-11-29

accepted

2015-01-09

online

2015-02-04

Contributors

author

Hanna Sas-Nowosielska

• Nencki Institute of Experimental Biology PAS, Warszawa, Poland

author

Natalia Pawlas

• Institute of Occupational Medicine and Environmental Health, Sosnowiec, Poland

References

• Ahmed K, Dehghani H, Rugg-Gunn P, Fussner E, Rossant J, Bazett-Jones DP (2010) Global chromatin architecture reflects pluripotency and lineage commitment in the early mouse embryo. PLoS ONE 5: e10531.
• Altman SA, Zastawny TH, Randers-Eichhorn L, Cacciuttolo MA, Akman SA, Dizdaroglu M, Rao G (1995) Formation of DNA-protein cross-links in cultured mammalian cells upon treatment with iron ions. Free Radic Biol Med 19: 897-902.
• Arakawa H, Weng MW, Chen WC, Tang MS (2012) Chromium (VI) induces both bulky DNA adducts and oxidative DNA damage at adenines and guanines in the p53 gene of human lung cells. Carcinogenesis 33: 1993-2000.
• Arakawa H, Wu F, Costa M, Rom W, Tang MS (2006) Sequence specificity of cr(III)-DNA adduct formation in the p53 gene: NGG sequences are preferential adduct-forming sites. Carcinogenesis 27: 639-645.
• Arita A, Shamy MY, Chervona Y, Clancy HA, Sun H, Hall MN, Qu Q, Gamble MV, Costa M (2012) The effect of exposure to carcinogenic metals on histone tail modifications and gene expression in human subjects. J Trace Elem Med Biol 26: 174-178.
• Badisa VL, Latinwo LM, Odewumi CO, Ikediobi CO, Badisa RB, Brooks-Walter A, Lambert AT, Nwoga J (2008) Cytotoxicity and stress gene microarray analysis in cadmium-exposed crl-1439 normal rat liver cells. Int J Mol Med 22: 213-219.
• Bal W, Liang R, Lukszo J, Lee SH, Dizdaroglu M, Kasprzak KS (2000) Ni(II) specifically cleaves the C-terminal tail of the major variant of histone H2A and forms an oxidative damage-mediating complex with the cleaved-off octapeptide. Chem Res Toxicol 13: 616-624.
• Banfalvi G, Gacsi M, Nagy G, Kiss ZB, Basnakian AG (2005) Cadmium induced apoptotic changes in chromatin structure and subphases of nuclear growth during the cell cycle in CHO cells. Apoptosis 10: 631-642.
• Banfalvi G, Sarvari A, Nagy G (2012) Chromatin changes induced by Pb and Cd in human cells. Toxicol In Vitro 26: 1064-1071.
• Bihaqi SW, Huang H, Wu J, Zawia NH (2011) Infant exposure to lead (Pb) and epigenetic modifications in the aging primate brain: Implications for Alzheimer's disease. J Alzheimers Dis 27: 819-833.
• Blankert SA, Coryell VH, Picard BT, Wolf KK, Lomas RE, Stearns DM (2003) Characterization of nonmutagenic Cr(III)-DNA interactions. Chem Res Toxicol 16: 847-854.
• Bridgewater LC, Manning FC, Woo ES, Patierno SR (1994) DNA polymerase arrest by adducted trivalent chromium. Mol Carcinog 9: 122-133.
• Broday L, Peng W, Kuo MH, Salnikow K, Zoroddu M, Costa M (2000) Nickel compounds are novel inhibitors of histone H4 acetylation. Cancer Res 60: 238-241.
• CDC (2009) Centers for Disease Control and Prevention. Fourth Report on Human Exposure to Environmental Chemicals. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention..
• CDC (2013) Centers for Disease Control and Prevention. Fourth Report on Human Exposure to Environmental Chemicals, Updated Tables, (September, 2013). Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention.
• Chen H, Ke Q, Kluz T, Yan Y, Costa M (2006) Nickel ions increase histone H3 lysine 9 dimethylation and induce transgene silencing. Mol Cell Biol 26: 3728-3737.
• Chen H, Li S, Liu J, Diwan BA, Barrett JC, Waalkes MP (2004) Chronic inorganic arsenic exposure induces hepatic global and individual gene hypomethylation: Implications for arsenic hepatocarcinogenesis. Carcinogenesis 25: 1779-1786.
• Chen H, Liu J, Merrick BA, Waalkes MP (2001) Genetic events associated with arsenic-induced malignant transformation: Applications of cDNA microarray technology. Mol Carcinog 30: 79-87.
• Cheng TF, Choudhuri S, Muldoon-Jacobs K (2012) Epigenetic targets of some toxicologically relevant metals: A review of the literature. J Appl Toxicol 32: 643-653.
• Chuang CH, Carpenter AE, Fuchsova B, Johnson T, De Lanerolle P, Belmont AS (2006) Long-range directional movement of an interphase chromosome site. Curr Biol 16: 825-831.
• Cui Y, Han Z, Hu Y, Song G, Hao C, Xia H, Ma X (2012) MicroRNA-181b and microRNA-9 mediate arsenic-induced angiogenesis via NRP1. J Cell Physiol 227: 772-783.
• Dalledonne I, Milzani A, Colombo R (1997) Actin assembly by cadmium ions. Biochim Biophys Acta 1357: 5-17.
• Darbre PD (2006) Metalloestrogens: An emerging class of inorganic xenoestrogens with potential to add to the oestrogenic burden of the human breast. J Appl Toxicol 26: 191-197.
• Davidson T, Ke Q, Costa M (2011) Selected molecular mechanisms of metal toxicity and carcinogenicity. In Handbook on the Toxicology of Metals, Nordberg GF, Fowler BA, Nordberg M, Friberg LT, eds, pp 79-100. Elsevier Science, New York.
• Dieppois G, Stutz F (2010) Connecting the transcription site to the nuclear pore: A multi-tether process that regulates gene expression. J Cell Sci 123: 1989-1999.
• Djupedal I, Ekwall K (2009) Epigenetics: Heterochromatin meets RNAi. Cell Res 19: 282-295.
• Draper DE (2004) A guide to ions and RNA structure. RNA 10: 335-343.
• Duguid J, Bloomfield VA, Benevides J, Thomas GJ Jr (1993) Raman spectroscopy of DNA-metal complexes. I. Interactions and conformational effects of the divalent cations: Mg, Ca, Sr, Ba, Mn, Co, Ni, Cu, Pd, and Cd. Biophys J 65: 1916-1928.
• Dulout FN, Grillo CA, Seoane AI, Maderna CR, Nilsson R, Vahter M, Darroudi F, Natarajan AT (1996) Chromosomal aberrations in peripheral blood lymphocytes from native Andean women and children from northwestern argentina exposed to arsenic in drinking water. Mutat Res 370: 151-158.
• Dundr M (2013) Nucleation of nuclear bodies. Methods Mol Biol 1042: 351-364.
• Edelmann P, Bornfleth H, Zink D, Cremer T, Cremer C (2001) Morphology and dynamics of chromosome territories in living cells. Biochim Biophys Acta 1551: M29-M40.
• EEA (No 5/2013) Report Eur 25933 en environment and human health joint EEA-JRC report.
• Eichhorn GL, Butzow JJ, Shin YA (1985) Some effects of metal ions on DNA structure and genetic information transfer. J Biosci 8: 527-535.
• Ellen TP, Kluz T, Harder ME, Xiong J, Costa M (2009) Heterochromatinization as a potential mechanism of nickel-induced carcinogenesis. Biochemistry 48: 4626-4632.
• Engreitz JM, Pandya-Jones A, Mcdonel P, Shishkin A, Sirokman K, Surka C, Kadri S, Xing J, Goren A, Lander ES, Plath K, Guttman M (2013) The XIST lncRNA exploits three-dimensional genome architecture to spread across the X chromosome. Science 341: 1237973.
• Eskiw CH, Dellaire G, Bazett-Jones DP (2004) Chromatin contributes to structural integrity of promyelocytic leukemia bodies through a SUMO-1-independent mechanism. J Biol Chem 279: 9577-9585.
• Eskiw CH, Dellaire G, Mymryk JS, Bazett-Jones DP (2003) Size, position and dynamic behavior of PML nuclear bodies following cell stress as a paradigm for supramolecular trafficking and assembly. J Cell Sci 116: 4455-4466.
• Fabbri M, Urani C, Sacco MG, Procaccianti C, Gribaldo L (2012) Whole genome analysis and microRNAs regulation in HepG2 cells exposed to cadmium. ALTEX 29: 173-182.
• Farkas E, Ujvarosi K, Nagy G, Posta J, Banfalvi G (2010) Apoptogenic and necrogenic effects of mercuric acetate on the chromatin structure of K562 human erythroleukemia cells. Toxicol In Vitro 24: 267-275.
• Feig AL, Uhlenbeck OC (1999) The role of metal ions in RNA biochemistry. In The RNA World, 2nd edn, Gesteland RF, Cech TR, Atkins JF, eds, pp 287-319. Cold Spring Harbor Laboratory Press.
• Ferrario D, Collotta A, Carfi M, Bowe G, Vahter M, Hartung T, Gribaldo L (2009) Arsenic induces telomerase expression and maintains telomere length in human cord blood cells. Toxicology 260: 132-141.
• Fowler BA, Nordberg GF, Nordberg M, Friberg L (2011) Handbook on the Toxicology of Metals: Elsevier Science, New York.
• Fragou D, Fragou A, Kouidou S, Njau S, Kovatsi L (2011) Epigenetic mechanisms in metal toxicity. Toxicol Mech Methods 21: 343-352.
• Garcia JJ, Martinez-Ballarin E, Millan-Plano S, Allue JL, Albendea C, Fuentes L, Escanero JF (2005) Effects of trace elements on membrane fluidity. J Trace Elem Med Biol 19: 19-22.
• Ghildiyal M, Zamore PD (2009) Small silencing RNAs: An expanding universe. Nat Rev Genet 10: 94-108.
• Hartwig A (2013) Metal interaction with redox regulation: An integrating concept in metal carcinogenesis? Free Radic Biol Med 55: 63-72.
• Hartwig A, Mullenders LF, Asmuß M, Benters M, Krüger I (1999) Effect of metal compounds on the function of zinc finger proteins involved in DNA repair. In Metals and Genetics, Sarkar B, ed, pp 159-169. Springer US.
• Hayes JJ, Hansen JC (2001) Nucleosomes and the chromatin fiber. Curr Opin Genet Dev 11: 124-129.
• Hendrix DK, Brenner SE, Holbrook SR (2005) RNA structural motifs: Building blocks of a modular biomolecule. Q Rev Biophys 38: 221-243.
• Holaska JM, Wilson KL, Mansharamani M (2002) The nuclear envelope, lamins and nuclear assembly. Curr Opin Cell Biol 14: 357-364.
• Hou C, Corces VG (2012) Throwing transcription for a loop: Expression of the genome in the 3D nucleus. Chromosoma 121: 107-116.
• Hou L, Wang D, Baccarelli A (2011) Environmental chemicals and microRNAs. Mutat Res 714: 105-112.
• Kapka L, Baumgartner A, Siwinska E, Knudsen LE, Anderson D, Mielzynska D (2007) Environmental lead exposure increases micronuclei in children. Mutagenesis 22: 201-207.
• Karaczyn AA, Cheng RY, Buzard GS, Hartley J, Esposito D, Kasprzak KS (2009) Truncation of histone H2A's c-terminal tail, as is typical for Ni(II)-assisted specific peptide bond hydrolysis, has gene expression altering effects. Ann Clin Lab Sci 39: 251-262.
• Karaczyn AA, Golebiowski F, Kasprzak KS (2005) Truncation, deamidation, and oxidation of histone H2B in cells cultured with nickel(II). Chem Res Toxicol 18: 1934-1942.
• Karaczyn AA, Golebiowski F, Kasprzak KS (2006) Ni(II) affects ubiquitination of core histones H2B and H2A. Exp Cell Res 312: 3252-3259.
• Kashyap B, Reddy PS (2012) Micronuclei assay of exfoliated oral buccal cells: Means to assess the nuclear abnormalities in different diseases. J Cancer Res Thers 8: 184-191.
• Ke Q, Li Q, Ellen TP, Sun H, Costa M (2008) Nickel compounds induce phosphorylation of histone H3 at serine 10 by activating jnk-MAPK pathway. Carcinogenesis 29: 1276-1281.
• Kohen R, Nyska A (2002) Oxidation of biological systems: Oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol 30: 620-650.
• Kopera E, Schwerdtle T, Hartwig A, Bal W (2004) Co(II) and cd(II) substitute for zn(II) in the zinc finger derived from the DNA repair protein XPA, demonstrating a variety of potential mechanisms of toxicity. Chem Res Toxicol 17: 1452-1458.
• Krebs JE, Goldstein ES, Kilpatrick ST (2013) Lewin's Genes XI: Jones & Bartlett Publ, Sudbury.
• Lee YW, Klein CB, Kargacin B, Salnikow K, Kitahara J, Dowjat K, Zhitkovich A, Christie NT, Costa M (1995) Carcinogenic nickel silences gene expression by chromatin condensation and DNA methylation: A new model for epigenetic carcinogens. Mol Cell Biol 15: 2547-2557.
• Li H, Engstrom K, Vahter M, Broberg K (2012) Arsenic exposure through drinking water is associated with longer telomeres in peripheral blood. Chem Res Toxicol 25: 2333-2339.
• Li Q, Ke Q, Costa M (2009) Alterations of histone modifications by cobalt compounds. Carcinogenesis 30: 1243-1251.
• Liu H, Duan X, Yu S, Sun X (2011) Analysis of nucleosome positioning determined by DNA helix curvature in the human genome. BMC Genomics 12: 72.
• Liu J, She C, Hu Z, Xiong Z, Liu L, Song Y (2004) A new chromosome fluorescence banding technique combining DAPI staining with image analysis in plants. Chromosoma 113: 16-21.
• Lloyd DR, Phillips DH (1999) Oxidative DNA damage mediated by copper(II), iron(II) and nickel(II) Fenton reactions: Evidence for site-specific mechanisms in the formation of double-strand breaks, 8-hydroxydeoxyguanosine and putative intrastrand cross-links. Mutat Res 424: 23-36.
• Lu W, Zhang Y, Liu D, Songyang Z, Wan M (2013) Telomeres - structure, function, and regulation. Exp Cell Res 319: 133-141.
• Luger K (2006) Dynamic nucleosomes. Chromosome Res 14: 5-16.
• Luzhna L, Kathiria P, Kovalchuk O (2013) Micronuclei in genotoxicity assessment: From genetics to epigenetics and beyond. Front Genet 4: 131.
• Macfie A, Hagan E, Zhitkovich A (2009) Mechanism of DNA-protein cross-linking by chromium. Chem Res Toxicol 23: 341-347.
• Mao YS, Zhang B, Spector DL (2011) Biogenesis and function of nuclear bodies. Trends Genet 27: 295-306.
• Marshall WF, Straight A, Marko JF, Swedlow J, Dernburg A, Belmont A, Murray AW, Agard DA, Sedat JW (1997) Interphase chromosomes undergo constrained diffusional motion in living cells. Curr Biol 7: 930-939.
• Martinez P, Blasco MA (2011) Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat Rev Cancer 11: 161-176.
• Meldi L, Brickner JH (2011) Compartmentalization of the nucleus. Trends Cell Biol 21: 701-708.
• Mewborn SK, Puckelwartz MJ, Abuisneineh F, Fahrenbach JP, Zhang Y, Macleod H, Dellefave L, Pytel P, Selig S, Labno CM, Reddy K, Singh H, Mcnally E (2010) Altered chromosomal positioning, compaction, and gene expression with a lamin A/C gene mutation. PLoS ONE 5: e14342.
• Mishra S, Dwivedi SP, Singh R (2010) A review on epigenetic effect of heavy metal carcinogens on human health. Open Nutraceuticals J 3: 188-193.
• Mohideen K, Muhammad R, Davey CA (2010) Perturbations in nucleosome structure from heavy metal association. Nucleic Acids Res 38: 6301-6311.
• Nackerdien Z, Rao G, Cacciuttolo MA, Gajewski E, Dizdaroglu M (1991) Chemical nature of DNA-protein cross-links produced in mammalian chromatin by hydrogen peroxide in the presence of iron or copper ions. Biochemistry 30: 4873-4879.
• Nickens KP, Patierno SR, Ceryak S (2010) Chromium genotoxicity: A double-edged sword. Chem Biol Interact 188: 276-288.
• Nordberg GF, Fowler BA, Nordberg M., Friberg, LT eds (2007) Handbook on the Toxicology of Metals. Amsterdam, Boston, Heidelberg, London, New York, Oxford, Paris, San Diego, San Francisco, Singapore, Sydney, Tokyo: Elsevier Science.
• Olewińska E, Kasperczyk A, Kapka L, Kozłowska A, Pawlas N, Dobrakowski M, Birkner E, Kasperczyk S (2010) Level of DNA damage in lead-exposed workers. Ann Agric Environ Med 17: 231-236.
• Parada LA, Misteli T (2002) Chromosome positioning in the interphase nucleus. Trends Cell Biol 12: 425-432.
• Patra RC, Rautray AK, Swarup D (2011) Oxidative stress in lead and cadmium toxicity and its amelioration. Vet Med Int 2011: 457327.
• Pawlak S, Deckert J (2007) Histone modifications under environmental stress. Biol Lett 44: 65-73.
• Penedo JC, Wilson TJ, Jayasena SD, Khvorova A, Lilley DM (2004) Folding of the natural hammerhead ribozyme is enhanced by interaction of auxiliary elements. RNA 10: 880-888.
• Peyser YM, Ben-Hur M, Werber MM, Muhlrad A (1996) Effect of divalent cations on the formation and stability of myosin subfragment 1-ADP-phosphate analog complexes. Biochemistry 35: 4409-4416.
• Podlevsky JD, Chen JJ (2012) It all comes together at the ends: telomerase structure, function, and biogenesis. Mutat Res 730: 3-11.
• Pottier G, Viau M, Ricoul M, Shim G, Bellamy M, Cuceu C, Hempel WM, Sabatier L (2013) Lead exposure induces telomere instability in human cells. PLoS ONE 8: e67501.
• Qin Q, Qin S, Wang L, Lei W (2012) Immune responses and ultrastructural changes of hemocytes in freshwater crab Sinopotamon henanense exposed to elevated cadmium. Aquat Toxicol 106-107: 140-146.
• Rabbani-Chadegani A, Abdosamadi S, Fani N, Mohammadian S (2009) A comparison of the effect of lead nitrate on rat liver chromatin, DNA and histone proteins in solution. Arch Toxicol 83: 565-570.
• Raja NS, Nair BU (2008) Chromium(III) complexes inhibit transcription factors binding to DNA and associated gene expression. Toxicology 251: 61-65.
• Reichard JF, Puga A (2010) Effects of arsenic exposure on DNA methylation and epigenetic gene regulation. Epigenomics 2: 87-104.
• Ren X, Mchale CM, Skibola CF, Smith AH, Smith MT, Zhang L (2011) An emerging role for epigenetic dysregulation in arsenic toxicity and carcinogenesis. Environ Health Perspect 119: 11-19.
• Rohlf T, Steiner L, Przybilla J, Prohaska S, Binder H, Galle J (2012) Modeling the dynamic epigenome: from histone modifications towards self-organizing chromatin. Epigenomics 4: 205-219.
• Salnikow K, Zhitkovich A (2008) Genetic and epigenetic mechanisms in metal carcinogenesis and cocarcinogenesis: nickel, arsenic, and chromium. Chem Res Toxicol 21: 28-44.
• Schnekenburger M, Talaska G, Puga A (2007) Chromium cross-links histone deacetylase 1-DNA methyltransferase 1 complexes to chromatin, inhibiting histone-remodeling marks critical for transcriptional activation. Mol Cell Biol 27: 7089-7101.
• Sen P, Conway K, Costa M (1987) Comparison of the localization of chromosome damage induced by calcium chromate and nickel compounds. Cancer Res 47: 2142-2147.
• Silva N, Peiris-John R, Wickremasinghe R, Senanayake H, Sathiakumar N (2012) Cadmium a metalloestrogen: are we convinced? J Appl Toxicol 32: 318-332.
• Siomi H, Siomi MC (2009) On the road to reading the RNA-interference code. Nature 457: 396-404.
• Starr DA (2009) A nuclear-envelope bridge positions nuclei and moves chromosomes. J Cell Sci 122: 577-586.
• Sun H, Zhou X, Chen H, Li Q, Costa M (2009) Modulation of histone methylation and MLH1 gene silencing by hexavalent chromium. Toxicol Appl Pharmacol 237: 258-266.
• Tabrez S, Priyadarshini M, Priyamvada S, Khan MS, Na A, Zaidi SK (2014) Gene-environment interactions in heavy metal and pesticide carcinogenesis. Mutat Res Genet Toxicol Environ Mutagen 760: 1-9.
• Takiguchi M, Achanzar WE, Qu W, Li G, Waalkes MP (2003) Effects of cadmium on DNA-(cytosine-5) methyltransferase activity and DNA methylation status during cadmium-induced cellular transformation. Exp Cell Res 286: 355-365.
• Tan ZJ, Chen SJ (2012) Ion-mediated RNA structural collapse: effect of spatial confinement. Biophys J 103: 827-836.
• Tapisso JT, Marques CC, Mathias Mda L, Ramalhinho Mda G (2009) Induction of micronuclei and sister chromatid exchange in bone-marrow cells and abnormalities in sperm of Algerian mice (Mus spretus) exposed to cadmium, lead and zinc. Mutat Res 678: 59-64.
• Van Wolfswinkel JC, Ketting RF (2010) The role of small non-coding RNAs in genome stability and chromatin organization. J Cell Sci 123: 1825-1839.
• Verma R, Xu X, Jaiswal MK, Olsen C, Mears D, Caretti G, Galdzicki Z (2011) In vitro profiling of epigenetic modifications underlying heavy metal toxicity of tungsten-alloy and its components. Toxicol Appl Pharmacol 253: 178-187.
• Vogler C, Huber C, Waldmann T, Ettig R, Braun L, Izzo A, Daujat S, Chassignet I, Lopez-Contreras AJ, Fernandez-Capetillo O, Dundr M, Rippe K, Längst G, Schneider R (2010) Histone H2A C-terminus regulates chromatin dynamics, remodeling, and histone H1 binding. PLoS Genetics 6: e1001234.
• Wang Z, Chin TA, Templeton DM (1996) Calcium-independent effects of cadmium on actin assembly in mesangial and vascular smooth muscle cells. Cell Motil Cytoskeleton 33: 208-222.
• Wang Z, Templeton DM (1996) Cellular factors mediate cadmium-dependent actin depolymerization. Toxicol Appl Pharmacol 139: 115-121.
• Witkiewicz-Kucharczyk A, Bal W (2006) Damage of zinc fingers in DNA repair proteins, a novel molecular mechanism in carcinogenesis. Toxicol Lett 162: 29-42.
• Woodson SA (2005) Metal ions and RNA folding: A highly charged topic with a dynamic future. Curr Opin Chem Biol 9: 104-109.
• Wu M, Tinoco I (1998) RNA folding causes secondary structure rearrangement. Proc Nat Acad Scis 95: 11555-11560.
• Wu Y, Liu Y, Ni N, Bao B, Zhang C, Lu L (2012) High lead exposure is associated with telomere length shortening in chinese battery manufacturing plant workers. Occup Environ Med 69: 557-563.
• Yan Y, Kluz T, Zhang P, Chen HB, Costa M (2003) 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 190: 272-277.
• 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 Nat Acad Scis 94: 10907-10912.
• Zheng XH, Watts GS, Vaught S, Gandolfi AJ (2003) Low-level arsenite induced gene expression in HEK293 cells. Toxicology 187: 39-48.
• Zhou X, Li Q, Arita A, Sun H, Costa M (2009) Effects of nickel, chromate, and arsenite on histone 3 lysine methylation. Toxicol Appl Pharmacol 236: 78-84.
• Zhou X, Sun H, Ellen TP, Chen H, Costa M (2008) Arsenite alters global histone H3 methylation. Carcinogenesis 29: 1831-1836.
• Zimber A, Nguyen QD, Gespach C (2004) Nuclear bodies and compartments: Functional roles and cellular signalling in health and disease. Cell Signal 16: 1085-1104.