CHEMICALLY-INDUCED HISTONE MODIFICATION AS A PREDICTOR OF CARCINOGENICITY

The interaction between carcinogens and DNA is believed to initiate ne oplastic transformation, but evidence suggests that epigenetic mechani sms may also be of importance. Because the histone proteins have impor tant roles in chromatin structure and cellular function, they provide a reasonably well understood epigenetically-based system for the detec tion 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 re sult in acetylation of histones H3 and H4, and 12-O-tetradecanoylphorb ol-13-acetate (3 muM), known to result in phosphorylated histone H1, w ere tested initially. Electrophoresis of the histone fractions was cap able of resolving multiple forms of histones H1, H3, and H4. Propane s ultone (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 fractio n after 3 h. Experimental variability limited the statistically signif icant modifications to carbon tetrachloride and propane sultone, two k nown carcinogens, where new forms of modified histone were detected. T herefore, the histone modification assay, with further experimentation , may be an alternate method of detecting carcinogens, especially when conventional genotoxic tests prove unreliable.