Comparison of effects of direct-acting DNA methylating and ethylating agents on inducible gene expression in vivo.
Our laboratory is interested in whether chemical carcinogen-induced DNA 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 compared the effects of four direct-acting simple alkylating agents (methyl methanesulfonate, ethyl methanesulfonate, methylnitrosourea, and ethylnitrosourea) on the steady-state mRNA expression of a model inducible gene, phosphoenolpyruvate carboxykinase (PEPCK), using the chick embryo as a simple in vivo test system. We observed no effect of any of these four carcinogens on the steady-state mRNA expression of the constitutively 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 expression of the glucocorticoid-inducible PEPCK gene. These results support 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. Qualitative and quantitative differences in effects between the methylating and ethylating agents and between the methanesulfonates and nitrosoureas were correlated with differences in their specific patterns of DNA adduct formation, suggesting that different DNA lesions have different effects on inducible gene expression.
McCaffrey
J
J
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire 05755-3835.
Hamilton
J W
JW
D000477:Alkylating Agents / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000378:metabolism / Q000633:toxicity*; D002642:Chick Embryo; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004790:Enzyme Induction / Q000187:drug effects*; D005020:Ethyl Methanesulfonate / Q000378:metabolism / Q000633:toxicity; D005038:Ethylnitrosourea / Q000378:metabolism / Q000633:toxicity; D005796:Genes / Q000187:drug effects; D008741:Methyl Methanesulfonate / Q000378:metabolism / Q000633:toxicity; D008745:Methylation; D008770:Methylnitrosourea / Q000378:metabolism / Q000633:toxicity; D016297:Mutagenesis, Site-Directed; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*
D000477:Alkylating Agents; D002273:Carcinogens; D008770:Methylnitrosourea; D004247:DNA; D005020:Ethyl Methanesulfonate; D008741:Methyl Methanesulfonate; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005038:Ethylnitrosourea