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. 2002 Oct;110(Suppl 5):739–743. doi: 10.1289/ehp.02110s5739

Chromate-induced epimutations in mammalian cells.

Catherine B Klein 1, Lin Su 1, Darlene Bowser 1, Joanna Leszczynska 1
PMCID: PMC1241236  PMID: 12426123

Abstract

Epigenetic gene silencing by aberrant DNA methylation of gene promoter regions is a nonmutagenic but heritable epigenetic mechanism that may mistakenly cause the silencing of important cancer-related tumor suppressor genes. Using a transgenic, V79-derived, mammalian cell line (G12) that contains a bacterial gpt reporter gene in its DNA, we can study carcinogen-induced gene inactivation by mutagenic as well as epigenetic DNA methylation mechanisms. Whereas numerous carcinogens have previously been shown to be mutagenic in these cells, a few carcinogens, including nickel, diethylstilbestrol, and X-rays, are also capable of silencing the G12 cell gpt transgene by aberrant DNA methylation. Here we report for the first time that carcinogenic potassium chromate salts can also induce aberrant DNA methylation in this system. In contrast insoluble barium chromate produced significant level of mutations in these cells but did not cause DNA methylation changes associated with transgene expression.

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Selected References

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  1. Bearzatto A., Szadkowski M., Macpherson P., Jiricny J., Karran P. Epigenetic regulation of the MGMT and hMSH6 DNA repair genes in cells resistant to methylating agents. Cancer Res. 2000 Jun 15;60(12):3262–3270. [PubMed] [Google Scholar]
  2. Bennicelli C., Camoirano A., Petruzzelli S., Zanacchi P., De Flora S. High sensitivity of Salmonella TA102 in detecting hexavalent chromium mutagenicity and its reversal by liver and lung preparations. Mutat Res. 1983 Oct;122(1):1–5. doi: 10.1016/0165-7992(83)90134-3. [DOI] [PubMed] [Google Scholar]
  3. Carlisle D. L., Pritchard D. E., Singh J., Patierno S. R. Chromium(VI) induces p53-dependent apoptosis in diploid human lung and mouse dermal fibroblasts. Mol Carcinog. 2000 Jun;28(2):111–118. doi: 10.1002/1098-2744(200006)28:2<111::aid-mc7>3.0.co;2-y. [DOI] [PubMed] [Google Scholar]
  4. Chen J. X., Zheng Y., West M., Tang M. S. Carcinogens preferentially bind at methylated CpG in the p53 mutational hot spots. Cancer Res. 1998 May 15;58(10):2070–2075. [PubMed] [Google Scholar]
  5. Chen J., Thilly W. G. Mutational spectrum of chromium(VI) in human cells. Mutat Res. 1994 Jan-Feb;323(1-2):21–27. doi: 10.1016/0165-7992(94)90040-x. [DOI] [PubMed] [Google Scholar]
  6. Cheng L., Liu S., Dixon K. Analysis of repair and mutagenesis of chromium-induced DNA damage in yeast, mammalian cells, and transgenic mice. Environ Health Perspect. 1998 Aug;106 (Suppl 4):1027–1032. doi: 10.1289/ehp.98106s41027. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cohen M. D., Zelikoff J. T., Chen L. C., Schlesinger R. B. Immunotoxicologic effects of inhaled chromium: role of particle solubility and co-exposure to ozone. Toxicol Appl Pharmacol. 1998 Sep;152(1):30–40. doi: 10.1006/taap.1998.8502. [DOI] [PubMed] [Google Scholar]
  8. Costa M., Klein C. B. Nickel carcinogenesis, mutation, epigenetics, or selection. Environ Health Perspect. 1999 Sep;107(9):A438–A439. doi: 10.1289/ehp.99107a438. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. De Flora S., Bagnasco M., Serra D., Zanacchi P. Genotoxicity of chromium compounds. A review. Mutat Res. 1990 Mar;238(2):99–172. doi: 10.1016/0165-1110(90)90007-x. [DOI] [PubMed] [Google Scholar]
  10. Denissenko M. F., Pao A., Tang M., Pfeifer G. P. Preferential formation of benzo[a]pyrene adducts at lung cancer mutational hotspots in P53. Science. 1996 Oct 18;274(5286):430–432. doi: 10.1126/science.274.5286.430. [DOI] [PubMed] [Google Scholar]
  11. Di Croce Luciano, Raker Veronica A., Corsaro Massimo, Fazi Francesco, Fanelli Mirco, Faretta Mario, Fuks Francois, Lo Coco Francesco, Kouzarides Tony, Nervi Clara. Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science. 2002 Feb 8;295(5557):1079–1082. doi: 10.1126/science.1065173. [DOI] [PubMed] [Google Scholar]
  12. Esteller M., Catasus L., Matias-Guiu X., Mutter G. L., Prat J., Baylin S. B., Herman J. G. hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis. Am J Pathol. 1999 Nov;155(5):1767–1772. doi: 10.1016/S0002-9440(10)65492-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hamilton J. W., Kaltreider R. C., Bajenova O. V., Ihnat M. A., McCaffrey J., Turpie B. W., Rowell E. E., Oh J., Nemeth M. J., Pesce C. A. Molecular basis for effects of carcinogenic heavy metals on inducible gene expression. Environ Health Perspect. 1998 Aug;106 (Suppl 4):1005–1015. doi: 10.1289/ehp.98106s41005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Herman J. G., Merlo A., Mao L., Lapidus R. G., Issa J. P., Davidson N. E., Sidransky D., Baylin S. B. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Cancer Res. 1995 Oct 15;55(20):4525–4530. [PubMed] [Google Scholar]
  15. Horikawa I., Cable P. L., Afshari C., Barrett J. C. Cloning and characterization of the promoter region of human telomerase reverse transcriptase gene. Cancer Res. 1999 Feb 15;59(4):826–830. [PubMed] [Google Scholar]
  16. Kaltreider R. C., Pesce C. A., Ihnat M. A., Lariviere J. P., Hamilton J. W. Differential effects of arsenic(III) and chromium(VI) on nuclear transcription factor binding. Mol Carcinog. 1999 Jul;25(3):219–229. [PubMed] [Google Scholar]
  17. Kargacin B., Klein C. B., 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 Jun;300(1):63–72. doi: 10.1016/0165-1218(93)90141-y. [DOI] [PubMed] [Google Scholar]
  18. Kim G., Yurkow E. J. Chromium induces a persistent activation of mitogen-activated protein kinases by a redox-sensitive mechanism in H4 rat hepatoma cells. Cancer Res. 1996 May 1;56(9):2045–2051. [PubMed] [Google Scholar]
  19. Klein C. B., Kargacin B., Su L., Cosentino S., Snow E. T., Costa M. Metal mutagenesis in transgenic Chinese hamster cell lines. Environ Health Perspect. 1994 Sep;102 (Suppl 3):63–67. doi: 10.1289/ehp.94102s363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Klein C. B., Rossman T. G. Transgenic Chinese hamster V79 cell lines which exhibit variable levels of gpt mutagenesis. Environ Mol Mutagen. 1990;16(1):1–12. doi: 10.1002/em.2850160102. [DOI] [PubMed] [Google Scholar]
  21. Klein C. B., Su L., Rossman T. G., Snow E. T. Transgenic gpt+ V79 cell lines differ in their mutagenic response to clastogens. Mutat Res. 1994 Jan 16;304(2):217–228. doi: 10.1016/0027-5107(94)90214-3. [DOI] [PubMed] [Google Scholar]
  22. Klein C. B., Su L., Singh J., Snow E. T. Characterization of gpt deletion mutations in transgenic Chinese hamster cell lines. Environ Mol Mutagen. 1997;30(4):418–428. [PubMed] [Google Scholar]
  23. Lee Y. W., Klein C. B., Kargacin B., Salnikow K., Kitahara J., Dowjat K., Zhitkovich A., Christie N. T., Costa M. Carcinogenic nickel silences gene expression by chromatin condensation and DNA methylation: a new model for epigenetic carcinogens. Mol Cell Biol. 1995 May;15(5):2547–2557. doi: 10.1128/mcb.15.5.2547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Lefebvre Y., Pezerat H. Reactive oxygen species produced from chromate pigments and ascorbate. Environ Health Perspect. 1994 Sep;102 (Suppl 3):243–245. doi: 10.1289/ehp.94102s3243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Liu S., Dixon K. Induction of mutagenic DNA damage by chromium (VI) and glutathione. Environ Mol Mutagen. 1996;28(2):71–79. doi: 10.1002/(SICI)1098-2280(1996)28:2<71::AID-EM2>3.0.CO;2-H. [DOI] [PubMed] [Google Scholar]
  26. Liu S., Medvedovic M., Dixon K. Mutational specificity in a shuttle vector replicating in chromium(VI)-treated mammalian cells. Environ Mol Mutagen. 1999;33(4):313–319. doi: 10.1002/(sici)1098-2280(1999)33:4<313::aid-em8>3.0.co;2-v. [DOI] [PubMed] [Google Scholar]
  27. McCaffrey J., Wolf C. M., Hamilton J. W. Effects of the genotoxic carcinogen chromium(VI) on basal and hormone-inducible phosphoenolpyruvate carboxykinase gene expression in vivo: correlation with glucocorticoid- and developmentally regulated expression. Mol Carcinog. 1994 Aug;10(4):189–198. doi: 10.1002/mc.2940100403. [DOI] [PubMed] [Google Scholar]
  28. Pfeifer G. P. p53 mutational spectra and the role of methylated CpG sequences. Mutat Res. 2000 May 30;450(1-2):155–166. doi: 10.1016/s0027-5107(00)00022-1. [DOI] [PubMed] [Google Scholar]
  29. Pritchard D. E., Ceryak S., Ha L., Fornsaglio J. L., Hartman S. K., O'Brien T. J., Patierno S. R. Mechanism of apoptosis and determination of cellular fate in chromium(VI)-exposed populations of telomerase-immortalized human fibroblasts. Cell Growth Differ. 2001 Oct;12(10):487–496. [PubMed] [Google Scholar]
  30. Robertson K. D., Jones P. A. DNA methylation: past, present and future directions. Carcinogenesis. 2000 Mar;21(3):461–467. doi: 10.1093/carcin/21.3.461. [DOI] [PubMed] [Google Scholar]
  31. Snow E. T. Metal carcinogenesis: mechanistic implications. Pharmacol Ther. 1992;53(1):31–65. doi: 10.1016/0163-7258(92)90043-y. [DOI] [PubMed] [Google Scholar]
  32. Sutherland J. E., Peng W., Zhang Q., Costa M. The histone deacetylase inhibitor trichostatin A reduces nickel-induced gene silencing in yeast and mammalian cells. Mutat Res. 2001 Aug 8;479(1-2):225–233. doi: 10.1016/s0027-5107(01)00163-4. [DOI] [PubMed] [Google Scholar]
  33. Yang J. L., Hsieh Y. C., Wu C. W., Lee T. C. Mutational specificity of chromium(VI) compounds in the hprt locus of Chinese hamster ovary-K1 cells. Carcinogenesis. 1992 Nov;13(11):2053–2057. doi: 10.1093/carcin/13.11.2053. [DOI] [PubMed] [Google Scholar]

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