Chemically-induced histone modification as a predictor of carcinogenicity.
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 microM), 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.
Wagner
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Division of Genetic Toxicology, Microbiological Associates, Inc, Rockville, Maryland 20850.
Blevins
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D002251:Carbon Tetrachloride / Q000633:toxicity*; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000633:toxicity*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000737:chemistry* / Q000187:drug effects; D006657:Histones / Q000032:analysis / Q000187:drug effects*; D006801:Humans; D008297:Male; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D013876:Thiophenes / Q000633:toxicity*
D002273:Carcinogens; D006657:Histones; D013876:Thiophenes; D002251:Carbon Tetrachloride; C003218:1,3-propane sultone; D013755:Tetradecanoylphorbol Acetate