COMPARISON OF EFFECTS OF DIRECT-ACTING DNA METHYLATING AND ETHYLATINGAGENTS ON INDUCIBLE GENE-EXPRESSION IN-VIVO

Our laboratory is interested in whether chemical carcinogen-induced DN A damage is non-randomly distributed in the genome, i.e., ''targeted,' ' at the level of individual genes. As one means of investigating this , we have examined whether carcinogen treatment differentially alters the expression of specific genes in vivo. In this study, we have compa red the effects of four direct-acting simple alkylating agents (methyl methanesulfonate, ethyl methanesulfonate, methylnitrosourea, and ethy lnitrosourea) on the steady-state mRNA expression of a model inducible gene, phosphoenolpyruvate corboxykinase (PEPCK), using the chick embr yo as a simple in vivo test system. We observed no effect of any of th ese four carcinogens on the steady-state mRNA expression of the consti tutively expressed beta-actin, transferrin, or albumin genes in chick embryo liver following a single dose of carcinogen. In contrast, these same treatments significantly altered both the basal and inducible ex pression of the glucocorticoid-inducible PEPCK gene. These results sup port the hypothesis that inducible gene expression is a target for the effects of chemical carcinogens in vivo. In addition, the direction, magnitude, and time course of these effects were agent-specific. Quali tative and quantitative differences in effects between the methylating and ethylating agents and between the methanesulfonates and nitrosour eas were correlated with differences in their specific patterns of DNA adduct formation, suggesting that different DNA lesions have differen t effects on inducible gene expression. (C) 1994 Wiley-Liss, Inc.