Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters DNA methyltransferase (dnmt) expression in zebrafish (Danio rerio)

Toxicol Appl Pharmacol. 2015 Apr 15;284(2):142-51. doi: 10.1016/j.taap.2015.02.016. Epub 2015 Feb 27.


DNA methylation is one of the most important epigenetic modifications involved in the regulation of gene expression. The DNA methylation reaction is catalyzed by DNA methyltransferases (DNMTs). Recent studies have demonstrated that toxicants can affect normal development by altering DNA methylation patterns, but the mechanisms of action are poorly understood. Hence, we tested the hypothesis that developmental exposure to TCDD affects dnmt gene expression patterns. Zebrafish embryos were exposed to 5nM TCDD for 1h from 4 to 5h post-fertilization (hpf) and sampled at 12, 24, 48, 72, and 96 hpf to determine dnmt gene expression and DNA methylation patterns. We performed a detailed analysis of zebrafish dnmt gene expression during development and in adult tissues. Our results demonstrate that dnmt3b genes are highly expressed in early stages of development, and dnmt3a genes are more abundant in later stages. TCDD exposure upregulated dnmt1 and dnmt3b2 expression, whereas dnmt3a1, 3b1, and 3b4 are downregulated following exposure. We did not observe any TCDD-induced differences in global methylation or hydroxymethylation levels, but the promoter methylation of aryl hydrocarbon receptor (AHR) target genes was altered. In TCDD-exposed embryos, AHR repressor a (ahrra) and c-fos promoters were differentially methylated. To characterize the TCDD effects on DNMTs, we cloned the dnmt promoters with xenobiotic response elements and conducted AHR transactivation assays using a luciferase reporter system. Our results suggest that ahr2 can regulate dnmt3a1, dnmt3a2, and dnmt3b2 expression. Overall, we demonstrate that developmental exposure to TCDD alters dnmt expression and DNA methylation patterns.

Keywords: Aryl hydrocarbon receptor; DNA methylation; Dioxin; TCDD; Zebrafish development; dnmt.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • DNA / genetics
  • DNA Methylation / drug effects*
  • Down-Regulation / drug effects
  • Embryo, Nonmammalian / drug effects
  • Gene Expression Regulation, Developmental / drug effects*
  • Methyltransferases / genetics
  • Polychlorinated Dibenzodioxins / toxicity*
  • Promoter Regions, Genetic
  • Receptors, Aryl Hydrocarbon / genetics
  • Response Elements
  • Up-Regulation / drug effects
  • Zebrafish
  • Zebrafish Proteins / genetics


  • Polychlorinated Dibenzodioxins
  • Receptors, Aryl Hydrocarbon
  • Zebrafish Proteins
  • DNA
  • Methyltransferases