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.

Transcriptional Suppression of Sertoli Cell Timp2 in Rodents Following Mono-(2-ethylhexyl) Phthalate Exposure Is Regulated by CEBPA and MYC1

“…Similarly, rats exposed to DBP showed an increase in MYC expression level in the liver, and increased MYC expression was associated with DNA repair and synthesis [37]. The molecular mechanism by which MYC interacts with its partner, Max, acting as a transcription activator is well understood [38], while their transcription repression by MYC is not yet fully resolved.…”

Multigenerational and transgenerational effects of endocrine disrupting chemicals: A role for altered epigenetic regulation?

“…Human epidemiological studies correlated higher urinary levels of phthalate metabolites with altered imprinted gene and LINE-1 methylation in placental tissue [75,76]. Rodent studies have reported altered global and locus-specific DNA methylation following di(2-ethylhexyl)phthalate (DEHP) exposure [77,78]. Additionally, DNMT and methyl-CpG binding proteins were affected in various tissue types upon DEHP exposure in rodents [73,79].…”

Maternal phthalate exposure during pregnancy is associated with DNA methylation of LINE-1 and Alu repetitive elements in Mexican-American children

“…Although animal studies have demonstrated consistent effects of phthalates on both global and site-specific methylation (Kang and Lee, 2005; Kostka et al, 2010; Martinez-Arguelles and Papadopoulos, 2015; Pogribny et al, 2008; Wu et al, 2010), data in human populations are more limited. Prenatal urinary phthalate metabolite concentrations have been associated with methylation of imprinted genes H19 and IGF2 (LaRocca et al, 2014) and LINE-1 repetitive elements (Zhao et al, 2015) in placental tissue.…”