Abstract
Epigenetic modifications on histones and DNA exercise precise regulation of gene expression, and thus have a profound influence on cellular function. Through unclear mechanisms, xenobiotics are known to cause perturbations in the epigenome, resulting in altered biological states and aberrant outcomes.
In this study, 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) administered orally at 3μg/kg bodyweight caused Cyp1a1 promoter demethylation within 24 h in the mouse liver, indicating possible active DNA demethylation. This change in DNA methylation occurred with changes in 5-hydroxymethylcytosine, an active DNA demethylation intermediate, and persisted up to 40 days post treatment. As anticipated, there was a concurrent increase in the transcriptionally permissive H3K4me3 mark. These findings were replicated in vitro in isolated mouse hepatocytes. The epigenetic changes induced by TCDD were Ahr dependent, as Ahr KO mice and derived hepatocytes had intact Cyp1a1 promoter methylation levels. Additionally, TCDD did not change mRNA expression levels of known mediators of active DNA demethylation including Tet1, Tet2, Tet3, Tdg, Apex1, Gadd45a and Apobec1.
We show that TCDD, through Ahr, induces epigenetic switching at the Cyp1a1 promoter which results in memorization of the xenobiotic exposure event.
