Abstract
The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that plays an important role in the manifestation of toxicity induced by polycyclic aromatic hydrocarbons. As a xenobiotic sensor, Ahr is involved in chemical biotransformation through activation of drug metabolizing enzymes. The activated Ahr cooperates with coactivator complexes to induce epigenetic modifications at target genes. Thus, it is conceivable that 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent Ahr ligand, may elicit robust epigenetic changes in vivo at the Ahr target gene cytochrome P450 1a1 (Cyp1a1). A single dose of TCDD administered to adult mice induced Ahr-dependent CpG hypomethylation, changes in histone modifications, and thymine DNA glycosylase (Tdg) recruitment at the Cyp1a1 promoter in the liver within 24 hrs. These epigenetic changes persisted until 40 days post-TCDD treatment and there was Cyp1a1 mRNA hyperinduction upon repeat administration of TCDD at this time-point. Our demethylation assay using siRNA knockdown and an in vitro methylated plasmid showed that Ahr, Tdg, and the ten-eleven translocation methyldioxygenases Tet2 and Tet3 are required for the TCDD-induced DNA demethylation. These results provide novel evidence of Ahr-driven active DNA demethylation and epigenetic memory. The epigenetic alterations influence response to subsequent chemical exposure and imply an adaptive mechanism to xenobiotic stress.
Highlights
The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that mediates toxic response to environmentally persistent organic pollutants (POPs) including polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)[1]
A single dose of TCDD induced cytochrome P450 1a1 (Cyp1a1) mRNA expression within 6 hrs which peaked at 12 hrs, and was followed by a gradual decrease after 24 hrs (Fig. 1a)
The present study provides novel evidence that Ahr drives robust epigenetic modulation at the Cyp1a1 promoter
Summary
The aryl hydrocarbon receptor (Ahr) is a highly conserved nuclear receptor that mediates toxic response to environmentally persistent organic pollutants (POPs) including polycyclic aromatic hydrocarbons (PAHs) and halogenated aromatic hydrocarbons (HAHs), such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)[1]. Ahr plays a role in chemical biotransformation through activation of drug metabolizing enzymes[2]. The ligand-activated Ahr dimerizes with its partner factor, Ahr nuclear translocator (Arnt), and binds xenobiotic responsive elements (XREs) found on target gene promoters, including phase I and phase II drug metabolizing enzymes[2]. As a regulator of multiple gene transcription networks, epigenetic modifications are anticipated to play a significant role in Ahr signalling. The initial events involve Ahr-directed DNA demethylation and changes in histone modifications, followed by a long-term maintenance of this epigenetic configuration and Cyp1a1 transcriptional memory. These epigenetic alterations influence response to subsequent chemical exposure and imply an adaptive mechanism to xenobiotic stress
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