Epigenetics and the Environment

Abstract: DNA methylation and histone modification promote changes in chromatin structure that may affect gene expression in a heritable manner without directly altering the genome. As such, these phenomena are considered to be epigenetic in nature and are believed to contribute to the normal processes of human development but also to aberrant disease states such as cancer. Epigenetic processes probably contribute mechanistically to toxicant‐induced changes in gene expression and cancer. Nickel is a potent human carcinogen that has been shown to alter DNA methylation patterns and affect histone acetylation status. Both of these changes are associated with the proximity of the affected regions to heterochromatin. The two processes probably occur in concert in mammalian cells. However, in yeast cells, DNA methylation is absent, and nickel is capable of regulating gene expression through changes in acetylation of the lysine residues in the N terminal tail of histone H4. Arsenic is another important environmental carcinogen, and it is methylated during its metabolism. Hence, it has been proposed that arsenic metabolism may deplete intracellular methyl group stores and thereby lead to changes in DNA methylation that may be involved in carcinogenesis. However, the data concerning DNA methylation changes following arsenic exposure are equivocal, leading researchers to propose that DNA hypo‐ and hypermethylation are both important in the development of arsenic‐induced cancers. Heightened awareness by toxicologists of the importance of epigenetics in normal human development and in carcinogenesis should lead to the identification of other toxicants that manifest their effects, at least in part, via epigenetic mechanisms.

[1]  C. Davis,et al.  Dietary selenium and arsenic affect DNA methylation in vitro in Caco-2 cells and in vivo in rat liver and colon. , 2000, The Journal of nutrition.

[2]  T. Skopek,et al.  Transgenic chinese hamster V79 cell lines which exhibit variable levels of gpt mutagenesis , 1990, Environmental and molecular mutagenesis.

[3]  H. Mollenhauer,et al.  Carcinogenic activity of particulate nickel compounds is proportional to their cellular uptake. , 1980, Science.

[4]  M. Mass,et al.  Both hypomethylation and hypermethylation of DNA associated with arsenite exposure in cultures of human cells identified by methylation-sensitive arbitrarily-primed PCR. , 2001, Toxicology letters.

[5]  R. Watson,et al.  Epigenetics and DNA methylation come of age in toxicology. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[6]  Paul Tempst,et al.  MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex , 1999, Nature Genetics.

[7]  P. Marks,et al.  Histone deacetylases and cancer: causes and therapies , 2001, Nature Reviews Cancer.

[8]  J. Barrett,et al.  Senescence of nickel-transformed cells by an X chromosome: possible epigenetic control. , 1991, Science.

[9]  A. Bird,et al.  MeCP2 Is a Transcriptional Repressor with Abundant Binding Sites in Genomic Chromatin , 1997, Cell.

[10]  Lung-Chi Chen,et al.  Inhibition and reversal of nickel-induced transformation by the histone deacetylase inhibitor trichostatin A. , 2003, Toxicology and applied pharmacology.

[11]  Rudolf Jaenisch,et al.  DNA hypomethylation leads to elevated mutation rates , 1998, Nature.

[12]  B. Tycko Genomic imprinting and cancer. , 1999, Results and problems in cell differentiation.

[13]  K. Kitchin Recent advances in arsenic carcinogenesis: modes of action, animal model systems, and methylated arsenic metabolites. , 2001, Toxicology and applied pharmacology.

[14]  J. Basilion,et al.  Preferential DNA-protein cross-linking by NiCl2 in magnesium-insoluble regions of fractionated Chinese hamster ovary cell chromatin. , 1985, Cancer research.

[15]  J. Arbiser,et al.  Reactive Oxygen-induced Carcinogenesis Causes Hypermethylation of p16Ink4a and Activation of MAP Kinase , 2002, Molecular medicine.

[16]  Luke Hughes-Davies,et al.  DNA methyltransferase Dnmt1 associates with histone deacetylase activity , 2000, Nature Genetics.

[17]  G. Pfeifer p53 mutational spectra and the role of methylated CpG sequences. , 2000, Mutation research.

[18]  B. Diwan,et al.  Association of arsenic-induced malignant transformation with DNA hypomethylation and aberrant gene expression. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[19]  A. Feinberg,et al.  Reduced genomic 5-methylcytosine content in human colonic neoplasia. , 1988, Cancer research.

[20]  T. Bestor,et al.  Cytosine methylation and human cancer. , 2000, Current opinion in oncology.

[21]  Colin A. Johnson,et al.  Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex , 1998, Nature.

[22]  R. Caprioli,et al.  Phagocytosis, cellular distribution, and carcinogenic activity of particulate nickel compounds in tissue culture. , 1981, Cancer research.

[23]  C. Klein,et al.  Nickel carcinogenesis, mutation, epigenetics, or selection. , 1999, Environmental health perspectives.

[24]  S. Cross,et al.  Gene silencing by methyl-CpG-binding proteins. , 1998, Novartis Foundation symposium.

[25]  J. Strouboulis,et al.  Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription , 1998, Nature Genetics.

[26]  S. Patierno,et al.  Morphological and neoplastic transformation of C3H/10T1/2 Cl 8 mouse embryo cells by insoluble carcinogenic nickel compounds , 1989, Environmental and molecular mutagenesis.

[27]  H. Molinari,et al.  Interaction of Ni(II) and Cu(II) with a metal binding sequence of histone H4: AKRHRK, a model of the H4 tail. , 2000, Biochimica et biophysica acta.

[28]  B. Tycko,et al.  Epigenetic gene silencing in cancer. , 2000, The Journal of clinical investigation.

[29]  V. Karantza,et al.  Interaction of Nickel(II) with histones: in vitro binding of nickel(II) to the core histone tetramer. , 1999, Archives of biochemistry and biophysics.

[30]  M. Nishiyama,et al.  Histone deacetylase as a new target for cancer chemotherapy , 2001, Cancer Chemotherapy and Pharmacology.

[31]  S. Patierno,et al.  DNA-protein cross-links induced by nickel compounds in intact cultured mammalian cells. , 1985, Chemico-biological interactions.

[32]  C. Allis,et al.  The language of covalent histone modifications , 2000, Nature.

[33]  Y. W. Lee,et al.  Mutagenicity of soluble and insoluble nickel compounds at the gpt locus in G12 chinese hamster cells , 1993, Environmental and molecular mutagenesis.

[34]  E. Nieboer,et al.  Toxicity, uptake, and mutagenicity of particulate and soluble nickel compounds. , 1994, Environmental health perspectives.

[35]  Peter A. Jones,et al.  DNA Methylation as a Target for Drug Design , 1998, Pharmaceutical Research.

[36]  A. Feinberg DNA methylation, genomic imprinting and cancer. , 2000, Current topics in microbiology and immunology.

[37]  Hsu Tc A possible function of constitutive heterochromatin: the bodyguard hypothesis. , 1975 .

[38]  M. Costa,et al.  Antagonistic effect of magnesium chloride on the nickel chloride-induced inhibition of DNA replication in Chinese hamster ovary cells. , 1986, Journal of biochemical toxicology.

[39]  A. Bird,et al.  Analysis of the NuRD subunits reveals a histone deacetylase core complex and a connection with DNA methylation. , 1999, Genes & development.

[40]  M. Costa,et al.  Pathway of nickel uptake influences its interaction with heterochromatic DNA. , 1986, Toxicology and applied pharmacology.

[41]  Jie Liu,et al.  Association of c-myc overexpression and hyperproliferation with arsenite-induced malignant transformation. , 2001, Toxicology and applied pharmacology.

[42]  E. Ballestar,et al.  Mi-2 complex couples DNA methylation to chromatin remodelling and histone deacetylation , 1999, Nature Genetics.

[43]  M. Costa,et al.  Metal mutagenesis in transgenic Chinese hamster cell lines. , 1994, Environmental health perspectives.

[44]  W. Wilson,et al.  Inhibitor of histone deacetylation, depsipeptide (FR901228), in the treatment of peripheral and cutaneous T-cell lymphoma: a case report. , 2001, Blood.

[45]  M. Tang,et al.  Mutation hotspots and DNA methylation. , 2000, Current topics in microbiology and immunology.

[46]  R. S. Yang,et al.  Pharmacokinetics, metabolism, and carcinogenicity of arsenic. , 2001, Reviews of environmental contamination and toxicology.

[47]  J. Herman,et al.  DNA hypermethylation in tumorigenesis: epigenetics joins genetics. , 2000, Trends in genetics : TIG.

[48]  N. Rushton,et al.  Neoplastic transformation of cells by soluble but not particulate forms of metals used in orthopaedic implants. , 1998, Biomaterials.

[49]  M. Costa,et al.  Nickel enhances telomeric silencing in Saccharomyces cerevisiae. , 1999, Mutation research.

[50]  M. Kuo,et al.  Nickel compounds are novel inhibitors of histone H4 acetylation. , 2000, Cancer research.

[51]  V. Richon,et al.  Histone deacetylase inhibitors as new cancer drugs , 2001, Current opinion in oncology.

[52]  Peter A. Jones,et al.  The Role of DNA Methylation in Mammalian Epigenetics , 2001, Science.

[53]  J. Herman,et al.  Synergy of demethylation and histone deacetylase inhibition in the re-expression of genes silenced in cancer , 1999, Nature Genetics.

[54]  W. Bal,et al.  Interactions of Nickel(II) with histones: interactions of Nickel(II) with CH3CO-Thr-Glu-Ser-His-His-Lys-NH2, a peptide modeling the potential metal binding site in the "C-Tail" region of histone H2A. , 1998, Chemical research in toxicology.

[55]  H. Wesch,et al.  Nickel subsulfide is genotoxic in vitro but shows no mutagenic potential in respiratory tract tissues of BigBlue rats and Muta Mouse mice in vivo after inhalation. , 1998, Mutation research.

[56]  H. Mollenhauer,et al.  Phagocytosis of nickel subsulfide particles during the early stages of neoplastic transformation in tissue culture. , 1980, Cancer research.

[57]  A. Bird,et al.  Effects of DNA methylation on DNA-binding proteins and gene expression. , 1993, Current opinion in genetics & development.

[58]  M. Tang,et al.  Cytosine methylation determines hot spots of DNA damage in the human P53 gene. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[59]  T. Richmond,et al.  Crystal structure of the nucleosome core particle at 2.8 Å resolution , 1997, Nature.

[60]  R Doll,et al.  Cancers of the lung and nasal sinuses in nickel workers: a reassessment of the period of risk. , 1977, British journal of industrial medicine.

[61]  M. Ehrlich,et al.  The 5-methylcytosine content of DNA from human tumors. , 1983, Nucleic acids research.

[62]  A. Wolffe,et al.  Relationships between chromatin organization and DNA methylation in determining gene expression. , 1999, Seminars in cancer biology.

[63]  S. Patierno,et al.  Effects of nickel(II) on nuclear protein binding to DNA in intact mammalian cells. , 1987, Cancer biochemistry biophysics.

[64]  A. Bird,et al.  Repression of genes by DNA methylation depends on CpG density and promoter strength: evidence for involvement of a methyl‐CpG binding protein. , 1992, The EMBO journal.

[65]  M. Costa,et al.  Mutagenic responses of nickel oxides and nickel sulfides in Chinese hamster V79 cell lines at the xanthine-guanine phosphoribosyl transferase locus. , 1993, Mutation research.

[66]  M. Costa,et al.  Nonrandom chromosomal alterations in nickel-transformed Chinese hamster embryo cells. , 1989, Cancer research.

[67]  E. Pennisi Behind the Scenes of Gene Expression , 2001, Science.

[68]  R. Watson,et al.  Altered DNA methylation: a secondary mechanism involved in carcinogenesis. , 2002, Annual review of pharmacology and toxicology.

[69]  S. Robison,et al.  Selective phagocytosis of crystalline metal sulfide particles and DNA strand breaks as a mechanism for the induction of cellular transformation. , 1982, Cancer research.

[70]  B. D. Beck,et al.  The enigma of arsenic carcinogenesis: role of metabolism. , 1999, Toxicological sciences : an official journal of the Society of Toxicology.

[71]  M. Costa,et al.  Factors influencing the phagocytosis, neoplastic transformation, and cytotoxicity of particulate nickel compounds in tissue culture systems. , 1981, Toxicology and applied pharmacology.

[72]  M. Lübbert,et al.  DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. , 2000, Current topics in microbiology and immunology.

[73]  M. Costa,et al.  Video time-lapse microscopy of phagocytosis and intracellular fate of crystalline nickel sulfide particles in cultured mammalian cells. , 1982, Cancer research.

[74]  A. Bird,et al.  Mammalian methyltransferases and methyl-CpG-binding domains: proteins involved in DNA methylation. , 2000, Current topics in microbiology and immunology.

[75]  C. Allis,et al.  Translating the Histone Code , 2001, Science.

[76]  M. Dizdaroglu,et al.  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. , 2000, Chemical research in toxicology.

[77]  Liang Wang,et al.  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. , 1997, Mutation research.

[78]  A. Haugen,et al.  Immortalization of normal human kidney epithelial cells by nickel(II). , 1989, Cancer research.

[79]  R. Jirtle,et al.  Genomic imprinting and cancer. , 1999, Experimental cell research.

[80]  P. Laird Oncogenic mechanisms mediated by DNA methylation. , 1997, Molecular medicine today.

[81]  S. Murphy,et al.  Imprinted genes as potential genetic and epigenetic toxicologic targets. , 2000, Environmental health perspectives.

[82]  M. Costa,et al.  The histone deacetylase inhibitor trichostatin A reduces nickel-induced gene silencing in yeast and mammalian cells. , 2001, Mutation research.

[83]  A. Wolffe Packaging principle: how DNA methylation and histone acetylation control the transcriptional activity of chromatin. , 1998, The Journal of experimental zoology.

[84]  Y. W. Lee,et al.  Carcinogenic nickel silences gene expression by chromatin condensation and DNA methylation: a new model for epigenetic carcinogens , 1995, Molecular and cellular biology.

[85]  S. Baylin,et al.  Abnormal patterns of DNA methylation in human neoplasia: potential consequences for tumor progression. , 1991, Cancer cells.

[86]  A. Wolffe,et al.  Epigenetics: regulation through repression. , 1999, Science.

[87]  B. Fowler,et al.  Arsenic: health effects, mechanisms of actions, and research issues. , 1999, Environmental health perspectives.