Ecstasy (MDMA) Alters Cardiac Gene Expression and DNA Methylation: Implications for Circadian Rhythm Dysfunction in the Heart

Toxicol Sci. 2015 Nov;148(1):183-91. doi: 10.1093/toxsci/kfv170. Epub 2015 Aug 6.

Abstract

MDMA (ecstasy) is an illicit drug that stimulates monoamine neurotransmitter release and inhibits reuptake. MDMA's acute cardiotoxicity includes tachycardia and arrhythmia which are associated with cardiomyopathy. MDMA acute cardiotoxicity has been explored, but neither long-term MDMA cardiac pathological changes nor epigenetic changes have been evaluated. Microarray analyses were employed to identify cardiac gene expression changes and epigenetic DNA methylation changes. To identify permanent MDMA-induced pathogenetic changes, mice received daily 10- or 35-day MDMA, or daily 10-day MDMA followed by 25-day saline washout (10 + 25 days). MDMA treatment caused differential gene expression (p < .05, fold change >1.5) in 752 genes following 10 days, 558 genes following 35 days, and 113 genes following 10-day MDMA + 25-day saline washout. Changes in MAPK and circadian rhythm gene expression were identified as early as 10 days. After 35 days, circadian rhythm genes (Per3, CLOCK, ARNTL, and NPAS2) persisted to be differentially expressed. MDMA caused DNA hypermethylation and hypomethylation that was independent of gene expression; hypermethylation of genes was found to be 71% at 10 days, 68% at 35 days, and 91% at 10 + 25 days washout. Differential gene expression paralleled DNA methylation in 22% of genes at 10-day treatment, 17% at 35 days, and 48% at 10 + 25 days washout. We show here that MDMA induced cardiac epigenetic changes in DNA methylation where hypermethylation predominated. Moreover, MDMA induced gene expression of key elements of circadian rhythm regulatory genes. This suggests a fundamental organism-level event to explain some of the etiologies of MDMA dysfunction in the heart.

Keywords: DNA methylation; MDMA; circadian rhythm heart; ecstasy; microarray.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / chemically induced*
  • Arrhythmias, Cardiac / metabolism
  • Arrhythmias, Cardiac / pathology
  • Arrhythmias, Cardiac / physiopathology
  • Cardiomyopathies / chemically induced*
  • Cardiomyopathies / metabolism
  • Cardiomyopathies / pathology
  • Cardiomyopathies / physiopathology
  • Cardiotoxins / toxicity
  • Circadian Rhythm Signaling Peptides and Proteins / agonists
  • Circadian Rhythm Signaling Peptides and Proteins / antagonists & inhibitors
  • Circadian Rhythm Signaling Peptides and Proteins / genetics
  • Circadian Rhythm Signaling Peptides and Proteins / metabolism
  • DNA Methylation / drug effects*
  • Dose-Response Relationship, Drug
  • Epigenesis, Genetic / drug effects
  • Female
  • Gene Expression Profiling
  • Gene Expression Regulation / drug effects*
  • Hallucinogens / toxicity*
  • Heart / drug effects*
  • Heart / physiopathology
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice, Inbred C57BL
  • Myocardium / metabolism
  • Myocardium / pathology
  • N-Methyl-3,4-methylenedioxyamphetamine / toxicity*
  • Survival Analysis
  • Tachycardia / etiology

Substances

  • Cardiotoxins
  • Circadian Rhythm Signaling Peptides and Proteins
  • Hallucinogens
  • N-Methyl-3,4-methylenedioxyamphetamine