ECSTASY (MDMA) ALTERS CARDIAC GENE EXPRESSION AND DNA METHYLATION: IMPLICATIONS FOR CIRCADIAN RHYTHM DYSFUNCTION IN THE HEART
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE68216 | GEO | 2015/12/11
SECONDARY ACCESSION(S): PRJNA282037
REPOSITORIES: GEO
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Project description: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.
| S-EPMC4731408 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2015-12-11 | E-GEOD-68216 | biostudies-arrayexpress
Project description:MDMA (ecstasy) is an illicit drug that stimulates monoamine neurotransmitter release and inhibits reuptake. MDMAâs acute cardiotoxicity includes tachycardia and arrhythmia which are associated with cardiomyopathy (CM). 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 10d or 35d MDMA , or daily 10d MDMA followed by 25d saline washout (10+25d). MDMA treatment (10d) caused differentially gene expression (p<0.05, fold change >1.5), with 752 genes 558 genes following 35d MDMA, and 113 genes following 10d treatment +25d washout. Changes in MAPK and circadian rhythm gene expression were identified following 10d administration. After 35d, circadian rhythm genes (Per3, CLOCK, ARNTL, and NPAS2) remained differentially expressed. MDMA caused DNA hypermethylation and hypomethylation that was independent of gene expression; hypermethylation of genes was 71% at 10d, 68% at 35d, and 91% at 10+25d. Differential gene expression that corresponded directly with DNA methylation changes occurred in 22% of genes at 10d, 17% at 35d, and 48% at 10d+25d washout. MDMA treatment resulted in epigenetic changes in cardiac DNA methylation. Hypermethylation was the predominant effect. MDMA induced gene expression of key elements of circadian rhythm regulatory genes and suggest a fundamental mechanism for MDMA dysfunction in the heart. This study addresses how MDMA (ecstasy) affects cardiac (left ventricle) gene expression and epigenetic nuclear DNA methylation. Each sample was fluorescently labeled and hybridized to Roche Nimblegen 2.1M Deluxe Promoter Arrays.
2015-12-11 | E-GEOD-68199 | biostudies-arrayexpress
Project description:MDMA (ecstasy) is an illicit drug that stimulates monoamine neurotransmitter release and inhibits reuptake. MDMAâs acute cardiotoxicity includes tachycardia and arrhythmia which are associated with cardiomyopathy (CM). 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 10d or 35d MDMA , or daily 10d MDMA followed by 25d saline washout (10+25d). MDMA treatment (10d) caused differentially gene expression (p<0.05, fold change >1.5), with 752 genes 558 genes following 35d MDMA, and 113 genes following 10d treatment +25d washout. Changes in MAPK and circadian rhythm gene expression were identified following 10d administration. After 35d, circadian rhythm genes (Per3, CLOCK, ARNTL, and NPAS2) remained differentially expressed. MDMA caused DNA hypermethylation and hypomethylation that was independent of gene expression; hypermethylation of genes was 71% at 10d, 68% at 35d, and 91% at 10+25d. Differential gene expression that corresponded directly with DNA methylation changes occurred in 22% of genes at 10d, 17% at 35d, and 48% at 10d+25d washout. MDMA treatment resulted in epigenetic changes in cardiac DNA methylation. Hypermethylation was the predominant effect. MDMA induced gene expression of key elements of circadian rhythm regulatory genes and suggest a fundamental mechanism for MDMA dysfunction in the heart. This study addresses how MDMA (ecstasy) affects cardiac (left ventricle) gene expression and epigenetic nuclear DNA methylation. Each sample was fluorescently labeled and hybridized to Roche Nimblegen 12X135kb MM9 Gene Expression Arrays.
2015-12-11 | E-GEOD-68175 | biostudies-arrayexpress
Project description: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 (CM). 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 10d or 35d MDMA , or daily 10d MDMA followed by 25d saline washout (10+25d). MDMA treatment (10d) caused differentially gene expression (p<0.05, fold change >1.5), with 752 genes 558 genes following 35d MDMA, and 113 genes following 10d treatment +25d washout. Changes in MAPK and circadian rhythm gene expression were identified following 10d administration. After 35d, circadian rhythm genes (Per3, CLOCK, ARNTL, and NPAS2) remained differentially expressed. MDMA caused DNA hypermethylation and hypomethylation that was independent of gene expression; hypermethylation of genes was 71% at 10d, 68% at 35d, and 91% at 10+25d. Differential gene expression that corresponded directly with DNA methylation changes occurred in 22% of genes at 10d, 17% at 35d, and 48% at 10d+25d washout. MDMA treatment resulted in epigenetic changes in cardiac DNA methylation. Hypermethylation was the predominant effect. MDMA induced gene expression of key elements of circadian rhythm regulatory genes and suggest a fundamental mechanism for MDMA dysfunction in the heart. This study addresses how MDMA (ecstasy) affects cardiac (left ventricle) gene expression and epigenetic nuclear DNA methylation.
2015-12-11 | GSE68199 | GEO
Project description: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 (CM). 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 10d or 35d MDMA , or daily 10d MDMA followed by 25d saline washout (10+25d). MDMA treatment (10d) caused differentially gene expression (p<0.05, fold change >1.5), with 752 genes 558 genes following 35d MDMA, and 113 genes following 10d treatment +25d washout. Changes in MAPK and circadian rhythm gene expression were identified following 10d administration. After 35d, circadian rhythm genes (Per3, CLOCK, ARNTL, and NPAS2) remained differentially expressed. MDMA caused DNA hypermethylation and hypomethylation that was independent of gene expression; hypermethylation of genes was 71% at 10d, 68% at 35d, and 91% at 10+25d. Differential gene expression that corresponded directly with DNA methylation changes occurred in 22% of genes at 10d, 17% at 35d, and 48% at 10d+25d washout. MDMA treatment resulted in epigenetic changes in cardiac DNA methylation. Hypermethylation was the predominant effect. MDMA induced gene expression of key elements of circadian rhythm regulatory genes and suggest a fundamental mechanism for MDMA dysfunction in the heart. This study addresses how MDMA (ecstasy) affects cardiac (left ventricle) gene expression and epigenetic nuclear DNA methylation.
2015-12-11 | GSE68175 | GEO
Project description:Artificial light has been increasingly in use for the past 70 years. The aberrant light exposure and round-the-clock nature of work lead to the disruption of biological clock. Circadian rhythm disruption (CRD) contributes to multiple metabolic and neurodegenerative diseases. However, its effect on vision is not understood. Moreover, the mammalian retina possesses an autonomous clock that could be reset with light exposure. We evaluated the impact of CRD on retinal morphology, physiology, and vision after housing mice in a disruption inducing shorter light/dark cycle (L10:D10). Interestingly, the mice under L10:D10 exhibited three different entrainment behaviors; "entrained," "free-running," and "zigzagging." These behavior groups under CRD exhibited reduced visual acuity, retinal thinning, and a decrease in the number of photoreceptors. Intriguingly, the electroretinogram response was decreased only in the mice exhibiting "entrained" behavior. The retinal proteome showed distinct changes with each entrainment behavior, and there was a dysfunctional oxidative stress-antioxidant mechanism. These results demonstrate that CRD alters entrainment behavior and leads to visual dysfunction in mice. Our studies uniquely show the effect of entrainment behavior on retinal physiology. Our data have broader implications in understanding and mitigating the impact of CRD on vision and its potential role in the etiology of retinal diseases.
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Project description:Mammalian physiology and behavior are regulated by an internal time-keeping system, referred to as circadian rhythm. The circadian timing system has a hierarchical organization composed of the master clock in the suprachiasmatic nucleus (SCN) and local clocks in extra-SCN brain regions and peripheral organs. The circadian clock molecular mechanism involves a network of transcription-translation feedback loops. In addition to the clinical association between circadian rhythm disruption and mood disorders, recent studies have suggested a molecular link between mood regulation and circadian rhythm. Specifically, genetic deletion of the circadian nuclear receptor Rev-erbα induces mania-like behavior caused by increased midbrain dopaminergic (DAergic) tone at dusk. The association between circadian rhythm and emotion-related behaviors can be applied to pathological conditions, including neurodegenerative diseases. In Parkinson's disease (PD), DAergic neurons in the substantia nigra pars compacta progressively degenerate leading to motor dysfunction. Patients with PD also exhibit non-motor symptoms, including sleep disorder and neuropsychiatric disorders. Thus, it is important to understand the mechanisms that link the molecular circadian clock and brain machinery in the regulation of emotional behaviors and related midbrain DAergic neuronal circuits in healthy and pathological states. This review summarizes the current literature regarding the association between circadian rhythm and mood regulation from a chronobiological perspective, and may provide insight into therapeutic approaches to target psychiatric symptoms in neurodegenerative diseases involving circadian rhythm dysfunction.
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Project description:Cardiac arrhythmias are a leading cause of cardiovascular death. It has long been accepted that life-threatening cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, and sudden cardiac death) are more likely to occur in the morning after waking. It is perhaps less well recognized that there is a circadian rhythm in cardiac pacemaking and other electrophysiological properties of the heart. In addition, there is a circadian rhythm in other arrhythmias, for example, bradyarrhythmias and supraventricular arrhythmias. Two mechanisms may underlie this finding: (1) a central circadian clock in the suprachiasmatic nucleus in the hypothalamus may directly affect the electrophysiology of the heart and arrhythmogenesis via various neurohumoral factors, particularly the autonomic nervous system; or (2) a local circadian clock in the heart itself (albeit under the control of the central clock) may drive a circadian rhythm in the expression of ion channels in the heart, which in turn varies arrhythmic substrate. This review summarizes the current understanding of the circadian rhythm in cardiac electrophysiology, arrhythmogenesis, and the underlying molecular mechanisms.
| S-EPMC6520649 | biostudies-literature
Project description:The endogenous circadian pacemaker influences key physiologic functions, such as body temperature and heart rate, and is normally synchronized with the sleep/wake cycle. Epidemiological studies demonstrate a 24-h pattern in adverse cardiovascular events with a peak at approximately 10 a.m. It is unknown whether this pattern in cardiac risk is caused by a day/night pattern of behaviors, including activity level and/or influences from the internal circadian pacemaker. We recently found that a scaling index of cardiac vulnerability has an endogenous circadian peak at the circadian phase corresponding to approximately 10 a.m., which conceivably could contribute to the morning peak in cardiac risk. Here, we test whether this endogenous circadian influence on cardiac dynamics is caused by circadian-mediated changes in motor activity or whether activity and heart rate dynamics are decoupled across the circadian cycle. We analyze high-frequency recordings of motion from young healthy subjects during two complementary protocols that decouple the sleep/wake cycle from the circadian cycle while controlling scheduled behaviors. We find that static activity properties (mean and standard deviation) exhibit significant circadian rhythms with a peak at the circadian phase corresponding to 5-9 p.m. ( approximately 9 h later than the peak in the scale-invariant index of heartbeat fluctuations). In contrast, dynamic characteristics of the temporal scale-invariant organization of activity fluctuations (long-range correlations) do not exhibit a circadian rhythm. These findings suggest that endogenous circadian-mediated activity variations are not responsible for the endogenous circadian rhythm in the scale-invariant structure of heartbeat fluctuations and likely do not contribute to the increase in cardiac risk at approximately 10 a.m.
| S-EPMC2410066 | biostudies-literature