Di-butyl phthalate—induced hypomethylation of the c-myc gene in rat liver

Abstract

Peroxisome proliferators (PPs)-induced DNA hypomethylation has been proposed as a mechanism of their toxicity, including carcinogenic action. The effect of di-butyl phthalate (DBP), a known peroxisome proliferators, on the methylation level of the c-myc promoter region in rat liver was studied. Changes in the methylation status of the c-myc gene were correlated with changes in DNA synthesis, DNA methyltransferase (DNMTs) activity and liver weight. Male Wistar rats received DBP in one, three or fourteen daily oral doses of 1800 mg/kg body weight (b.w.) x day(-1) (this dose is close to the dose that increases the numbers of peroxisomes in male Wistar rats). We have demonstrated that DBP decreased the methylation of the c-myc gene. Cytosine hypomethylation in the analyzed CpG sites of the c-myc gene promoter occurred during the whole period of study, although after 14 doses of DBP the difference from control was only on the borderline of significance (p = 0.066). An increase in DNA synthesis was only observed after 24 hours of treatment with DBP, and it preceded liver growth. We hypothesize that DBP-induced demethylation of the c-myc gene was an active mechanism, not associated with DNMTs activity and DNA replication.