Abstract
The interaction between carcinogens and DNA is believed to initiate neoplastic transformation, but evidence suggests that epigenetic mechanisms may also be of importance. Because the histone proteins have important roles in chromatin structure and cellular function, they provide a reasonably well understood epigenetically-based system for the detection of carcinogens. In this study, human foreskin fibroblastic cells were exposed to one of several mutagens and/or carcinogens for 3, 12, or 24 h to determine if induced histone modification may be a means of predicting chemical carcinogenicity.
Butyric acid (5 mM), known to result in acetylation of histones H3 and H4, and 12-O-tetradecanoylphorbol-13-acetate (3 μM), known to result in phosphorylated histone H1, were tested initially. Electrophoresis of the histone fractions was capable of resolving multiple forms of histones H1, H3, and H4.
Propane sultone (0.1 mM) induced a broadening of the H2A and H2B bands after a 24 h exposure and carbon tetrachloride (1 mM) induced the formation of new histone forms in the H1 fraction after 24 h and in the H3 fraction after 3 h. Experimental variability limited the statistically significant modifications to carbon tetrachloride and propane sultone, two known carcinogens, where new forms of modified histone were detected. Therefore, the histone modification assay, with further experimentation, may be an alternate method of detecting carcinogens, especially when conventional genotoxic tests prove unreliable.
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References
Allfrey VG, Boffa LC (1979) Modifications of nuclear protein structure and function during carcinogenesis. In: Busch H (ed), The cell nucleus. Academic Press, NY, Vol 7, pp 521–562
Balhorn R, Balhorn M, Morris HP, Chalkley R (1972) Comparative high-resolution electrophoresis of tumor histones: Variation in phosphorylation as a function of cell replication rate. Cancer Res 32:1775–1784
Boffa LC, Gruss RJ, Allfrey VG (1982) Aberrant and nonrandom methylation of chromosomal DNA-binding proteins of colonic epithelial cells by 1,2-dimethylhydrazine. Cancer Res 42:382–388
Bradbury EM, Maclean N, Matthews HR (1981) DNA, chromatin and chromosomes. John Wiley and Sons, NY
Cox R, Tuck MT (1981) Alteration of methylation patterns in rat liver histones following administration of ethionine, a liver carcinogen. Cancer Res 41:1253–1256
Eagle H (1959) Amino acid metabolism in mammalian cell cultures. Science 130:432–437
Farber E (1981) Chemical carcinogenesis. N Engl J Med 305:1379–1389
Hardison R, Chalkley R (1978) Polyacrylamide gel electrophoretic fractionation of histones. In: Stein G, Stein J, Kleinsmith LJ, (eds) Methods in cell biology, Academic Press, NY, Vol 17, pp 235–251
Link R, Marks F (1981) Histone phosphorylation in phorbol ester stimulated and 2-adrenergically stimulated mouse epidermis in vivo and characterization of an epidermal protein phorphorylation system. Biochim Biophys Acta 675:265–275
Mon MJ, Haas AE, Stein JL, Stein GS (1981) Influence of psychoactive and nonpsychoactive cannabinoids on chromatin structure and function in human cells. Biochem Pharmacol 30:45–58
Munir KM, Custer RP, Sorof S (1989) Normal hepatocytes exhibiting histone H3 with antibody accessible sites that are cryptic in carcinogen altered hepatocytes. Cancer Res 49:424–432
Perotti D, Cimino L, Ferrari S, Sacchi A (1991) Differential expression of transforming growth factor-beta 1 gene in 3LL metastatic variants. Cancer Res 51:5491–5494
Reeves R, Cserjesi P (1979) Sodium butyrate induces new gene expression in friend erythroleukemic cells. J Biol Chem 254:4283–4290
Ruiz-Carrillo A, Wangh LJ, Allfrey VG (1976) Selective synthesis and modification of nuclear proteins during maturation of avian erythroid cells. Arch Biochem Biophys 174:273–290
Schmatchenko VV, Varshavsky AJ (1978) A technique of low-pH gel electrophoresis of chromosomal proteins which does not require preliminary removal of DNA. Anal Biochem 85:42–46
Sokal RR, Rohlf FJ (1981) Biometry, 2nd ed. WH Freeman, San Francisco
Stein GS, Stein JL, Thomason JA (1978) Chromosomal proteins in transformed and neoplastic cells: A review. Cancer Res 38:1181–1201
Vidali G, Boffa LC, Bradbury EM, Allfrey VG (1978) Butyrate suppression of histone deacetylation leads to accumulation of multi-acetylated forms of histones H3 and H4 and increased DNase I sensitivity of the associated DNA sequences. Proc Natl Acad Sci USA 75:2239–2243
Zytkovicz TH, Moses HL, Spelsberg TC (1979) Nuclear interaction of polycyclic aromatic hydrocarbons. In: Busch H (ed) The cell nucleus. Academic Press, NY, Vol 7, pp 479–517
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Wagner, V.O., Blevins, R.D. Chemically-induced histone modification as a predictor of carcinogenicity. Arch. Environ. Contam. Toxicol. 25, 260–266 (1993). https://doi.org/10.1007/BF00212139
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DOI: https://doi.org/10.1007/BF00212139