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

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          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.

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          Author and article information

          Journal
          Toxicol Sci
          Toxicol. Sci
          toxsci
          toxsci
          Toxicological Sciences
          Oxford University Press
          1096-6080
          1096-0929
          November 2015
          06 August 2015
          : 148
          : 1
          : 183-191
          Affiliations
          Department of Pathology, Emory University, Atlanta, Georgia 30322
          Author notes
          1To whom correspondence should be addressed at Department of Pathology, Emory University, 101 Woodruff Circle, WMB 7205, Atlanta, GA 30322. Fax: 404-712-9007; E-mail: ckoczor@ 123456emory.edu .
          Article
          PMC4731408 PMC4731408 4731408 kfv170
          10.1093/toxsci/kfv170
          4731408
          26251327
          2aee01b9-b309-4ac6-a3be-27ec0d41c68a
          © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com
          History
          Page count
          Pages: 9
          Categories
          MDMA-Induced DNA Methylation and Gene Expression in the Heart

          DNA methylation,circadian rhythm heart,MDMA,ecstasy,microarray

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