MDMA's Effect on Myocardial DNA Methylation and its Association with Dilated Cardiomyopathy Public

Abstract

MDMA ("Ecstasy") is an illicit psychoactive drug that has increased in popularity in the past two decades. However, the cardiovascular toxicological mechanism of MDMA has not been fully characterized. The present study utilized microarray analysis to determine gene expression and DNA methylation modifications after MDMA exposure in the murine heart. Alterations in gene expression and epigenetics may serve a critical function in the development of dilated cardiomyopathy (DCM) and heart failure. Three different drug administration timeframes were used to determine the permanence of MDMA-associated DNA methylation and gene expression changes. MDMA decreased the transcription of genes found in the circadian rhythm pathway, which was verified via quantitative RT-PCR. This pathway has been shown to have an important role in regulating mitochondrial metabolism and maintaining cardiac function. Differential expression of the myosin heavy chain (Myh7) gene was identified across all treatment groups, which has been associated with cardiac dysfunction and cardiomyopathy. Furthermore, MDMA treated mice displayed genome-wide hypermethylation compared to controls. Similar genome-wide DNA methylation changes have been reported in DCM patients. Collectively, these results suggest that MDMA may be toxic to the heart through its ability to change DNA methylation patterns and alter gene transcription leading to disease onset.

Table of Contents

Introduction (pg.1)

MDMA's Short Term Effects (pg.1)

MDMA's Long Term Effects (pg.1)

Gene Expression Association with Cardiac Function (pg.2)

DNA Methylation Association with Cardiac Function (pg.3)

MDMA's Effect on DNA Methylation and Gene Expression (pg.4)

Methods (pg.6)

Reagents (pg.6)

Mouse Protocols (pg.6)

Gene Expression Analysis (pg.6)

Quantitative RT-PCR (pg.7)

DNA Methylation Analysis (pg.7)

Statistical Analysis (pg.8)

Results (pg.10)

Cardiac Physiology (pg.10)

Gene Expression (pg.10)

Quantitative RT-PCR (pg.11)

DNA Methylation (pg.12)

Discussion (pg.14)

Conclusion (pg.20)

References (pg.21)

Tables and Figures (pg.1)

Figure 1 (pg.1)

Figure 2 (pg.2)

Figure 3 (pg.3)

Figure 4 (pg.4)

Figure 5 (pg.5)

Figure 6 (pg.6)

Figure 7 (pg.8)

Appendices (pg.1)

Supplemental Table 1 (pg.1)

Supplemental Table 2 (pg.2)

Supplemental Table 3 (pg.42)

Supplemental Table 4 (pg.84)

About this Master's Thesis

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School	Rollins School of Public Health
Department	Environmental Health
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Toxicology
Mot-clé	MDMA Gene Expression DNA Methylation Cardiovascular Toxicology Dilated Cardiomyopathy Ecstasy
Committee Chair / Thesis Advisor	Caudle, William Michael, Emory University
Committee Members	Tolbert, Paige, Emory University Lewis, William, Emory University
Partnering Agencies	Emory University schools, faculty or affiliated programs

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