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Epigenetic side-effects of common pharmaceuticals: A potential new field in medicine and pharmacology

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Abstract

The term "Epigenetics" refers to DNA and chromatin modifications that persist from one cell division to the next, despite a lack of change in the underlying DNA sequence. The "epigenome" refers to the overall epigenetic state of a cell, and serves as an interface between the environment and the genome. The epigenome is dynamic and responsive to environmental signals not only during development, but also throughout life; and it is becoming increasingly apparent that chemicals can cause changes in gene expression that persist long after exposure has ceased. Here we present the hypothesis that commonly-used pharmaceutical drugs can cause such persistent epigenetic changes. Drugs may alter epigenetic homeostasis by direct or indirect mechanisms. Direct effects may be caused by drugs which affect chromatin architecture or DNA methylation. For example the antihypertensive hydralazine inhibits DNA methylation. An example of an indirectly acting drug is isotretinoin, which has transcription factor activity. A two-tier mechanism is postulated for indirect effects in which acute exposure to a drug influences signaling pathways that may lead to an alteration of transcription factor activity at gene promoters. This stimulation results in the altered expression of receptors, signaling molecules, and other proteins necessary to alter genetic regulatory circuits. With more chronic exposure, cells adapt by an unknown hypothetical process that results in more permanent modifications to DNA methylation and chromatin structure, leading to enduring alteration of a given epigenetic network. Therefore, any epigenetic side-effect caused by a drug may persist after the drug is discontinued. It is further proposed that some iatrogenic diseases such as tardive dyskinesia and drug-induced SLE are epigenetic in nature. If this hypothesis is correct the consequences for modern medicine are profound, since it would imply that our current understanding of pharmacology is an oversimplification. We propose that epigenetic side-effects of pharmaceuticals may be involved in the etiology of heart disease, cancer, neurological and cognitive disorders, obesity, diabetes, infertility, and sexual dysfunction. It is suggested that a systems biology approach employing microarray analyses of gene expression and methylation patterns can lead to a better understanding of long-term side-effects of drugs, and that in the future, epigenetic assays should be incorporated into the safety assessment of all pharmaceutical drugs. This new approach to pharmacology has been termed "phamacoepigenomics", the impact of which may be equal to or greater than that of pharmacogenetics. We provide here an overview of this potentially major new field in pharmacology and medicine.

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... PSSD has been increasingly recognized [16,23,24,39,48]. SSRIs can trigger epigenetic changes that cause a persistent downregulation of 5-HT1A receptors which has been linked to the regulation of sexual motivation. ...
... SSRIs can trigger epigenetic changes that cause a persistent downregulation of 5-HT1A receptors which has been linked to the regulation of sexual motivation. Csoka and Szyf [48] indicate that the persistent desensitization of the receptor, even after withdrawal could be a result of gene expression alterations, specifically DNA methylation due to increase expression of methyl-binding proteins. These epigenetic changes have been observed in three areas of the brain: the frontal cortex, the dentate gyrus of the hippocampus, and the caudate putamen [39,48]. ...
... Csoka and Szyf [48] indicate that the persistent desensitization of the receptor, even after withdrawal could be a result of gene expression alterations, specifically DNA methylation due to increase expression of methyl-binding proteins. These epigenetic changes have been observed in three areas of the brain: the frontal cortex, the dentate gyrus of the hippocampus, and the caudate putamen [39,48]. ...
Article
Background : Sexual dysfunction is highly prevalent worldwide. A specific form is persistent sexual dysfunction after SSRI withdrawal. We conducted a systematic literature review in order to characterize factors related to post SSRI sexual dysfunction (PSSD) and analyzed spontaneous reports of persistent sexual dysfunction reported to the Netherlands Pharmacovigilance Centre Lareb. Research Design and Methods A systematic literature review was conducted following the PRISMA-ScR guidelines. In addition, reports of PSSD submitted to the Netherlands Pharmacovigilance Centre Lareb between 1992 and 2021 were analyzed. Results : A total of 237 articles were retrieved through the search and 33 articles were selected for inclusion in this review, in accordance with the inclusion criteria. Information regarding the characteristics of the condition, it’s clinical management, patient characteristics and impact of PSSD is presented. A total of 86 reports of persistent sexual dysfunction, were analyzed. The longest case being a patient with PSSD for 23 years. The main symptoms were: loss or decreased libido (n= 53), erectile dysfunction (n= 23) and anorgasmia (n= 5). Conclusions PSSD impact includes sexual, psychological and social consequences. Little is known about the mechanisms underlying PSSD and no effective treatment exists. It is necessary to increase recognition of PSSD among prescribers and improve its management at the clinical level.
... Studies show that epigenetic mechanisms can lead to modifications that can be transmitted to daughter cells 11 . Chemicals such as in pharmaceuticals, supplements, environmental contaminants etc. can have transgenerational effects on organisms [1][2][3][4][5][6]10 . A wide range of transgenerational effects of chemicals have been documented in animals. ...
... A wide range of transgenerational effects of chemicals have been documented in animals. Recent works suggest that transgenerational effects of pharmaceuticals may include heart disease, cancer, neurological and cognitive disorders, obesity, diabetes, infertility, and sexual dysfunction in humans 5 . ...
... Thus, VPA is commonly prescribed in the treatment of migraines, epilepsy etc 7 . VPA is known as a teratogen 5,7 . Beetles were exposed to VPA at different concentrations (0.01%, 0.1%, 1%) 2 . ...
... It has been hypothesized that pharmaceutical drugs can cause long-term epigenetic changes in the human genome [1,2]. There is also evidence from animal models that antipsychotics can cause epigenetic changes [3] and that some drugs including antidepressants can interfere with the action of epigenetic enzymes, such as DNA methyltransferase 1 [4]. ...
... A plausible cause of these persistent side effects is changes to the epigenome [1][2][3]. The epigenome of a cell is a unique, dynamic entity consisting of distinct DNA methylation patterns across gene enhancers, promoters, and bodies along with histone modifications that do not involve any changes to the actual DNA sequence. ...
... Epigenetic changes resulting from environmental effects such as traumatic life events can rewire neural circuits and alter neurotransmitter and endocrine systems resulting in stressrelated psychiatric disorders such as major depression or posttraumatic stress disorder [15]. Based on this evidence, it can be posited that potential unknown mechanisms of action of SSRIs, as well as side effects, could be through epigenetic modification of genes [1,2,15]. ...
Article
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Commonly used pharmaceutical drugs might alter the epigenetic state of cells, leading to varying degrees of long-term repercussions to human health. To test this hypothesis, we cultured HEK-293 cells in the presence of 50 μ M citalopram, a common antidepressant, for 30 days and performed whole-genome DNA methylation analysis using the NimbleGen Human DNA Methylation 3x720K Promoter Plus CpG Island Array. A total of 626 gene promoters, out of a total of 25,437 queried genes on the array (2.46%), showed significant differential methylation ( p<0.01 ); among these, 272 were hypomethylated and 354 were hypermethylated in treated versus control. Using Ingenuity Pathway Analysis, we found that the chief gene networks and signaling pathways that are differentially regulated include those involved in nervous system development and function and cellular growth and proliferation. Genes implicated in depression, as well as genetic networks involving nucleic acid metabolism, small molecule biochemistry, and cell cycle regulation were significantly modified. Involvement of upstream regulators such as BDNF, FSH, and NF κ B was predicted based on differential methylation of their downstream targets. The study validates our hypothesis that pharmaceutical drugs can have off-target epigenetic effects and reveals affected networks and pathways. We view this study as a first step towards understanding the long-term epigenetic consequences of prescription drugs on human health.
... Thus, statins represent the first-line drugs in primary and secondary prevention of cardiovascular diseases [48,49]. Moreover, statins can also epigenetically control cholesterol levels by acting as an inhibitor of HDACs [47,50,51]. In this way, statins can affect the cellular acetylation systems by increasing the acetylated protein levels which guide cells and tissues toward an active transcriptional activity [50,51]. ...
... Moreover, statins can also epigenetically control cholesterol levels by acting as an inhibitor of HDACs [47,50,51]. In this way, statins can affect the cellular acetylation systems by increasing the acetylated protein levels which guide cells and tissues toward an active transcriptional activity [50,51]. ...
Article
Heart failure and liver dysfunction can coexist owing to complex cardiohepatic interactions including the development of hypoxic hepatitis and congestive hepatopathy in patients with heart failure as well as 'cirrhotic cardiomyopathy' in advanced liver disease and following liver transplantation. The involvement of liver dysfunction in patients with heart failure reflects crucial systemic hemodynamic modifications occurring during the evolution of this syndrome. The arterial hypoperfusion and downstream hypoxia can lead to hypoxic hepatitis in acute heart failure patients whereas passive congestion is correlated with congestive hepatopathy occurring in patients with chronic heart failure. Nowadays, liquid biopsy strategies measuring liver function are well established in evaluating the prognosis of patients with heart failure. Large randomized clinical trials confirmed that gamma-glutamyltransferase, bilirubin, lactate deihydrogenase, and transaminases are useful prognostic biomarkers in patients with heart failure after transplantation. Deeper knowledge about the pathogenic mechanisms underlying cardiohepatic interactions would be useful to improve diagnosis, prognosis, and treatments of these comorbid patients. Epigenetic-sensitive modifications are heritable changes to gene expression without involving DNA sequence, comprising DNA methylation, histone modifications, and noncoding RNAs which seem to be relevant in the pathogenesis of heart failure and liver diseases when considered in a separate way. The goal of our review is to highlight the pertinence of detecting epigenetic modifications during the complex cardiohepatic interactions in clinical setting. Moreover, we propose a clinical research program which may be useful to identify epigenetic-sensitive biomarkers of cardiohepatic interactions and advance personalized therapy in these comorbid patients.
... Isotretinoin is often used to treat severe acne and is considered a strong teratogen and trypanocide [28]. Isotretinoin has been studied for its epigenetic effects and has been shown to be a strong DNA demethylation agent [29,30]. On the other hand, thalidomide is a sedative-hypnotic and multiple myeloma medication [30], and is also considered a strong teratogenic drug [31]. ...
... Isotretinoin has been studied for its epigenetic effects and has been shown to be a strong DNA demethylation agent [29,30]. On the other hand, thalidomide is a sedative-hypnotic and multiple myeloma medication [30], and is also considered a strong teratogenic drug [31]. The mechanisms of action of both isotretinoin and thalidomide remain poorly understood; however, the observed levels of c-MYC mRNA in this study indicate that the drugs may act as antagonists of each other. ...
Article
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Hepatocellular carcinoma (HCC) is the most common form of liver cancer. The number of cases is increasing and the trend for the next few years is not encouraging. HCC is usually detected in the advanced stages of the disease, and pharmacological therapies are not entirely effective. For this reason, it is necessary to search for new therapeutic options. The objective of this work was to evaluate the effect of the drugs isotretinoin and thalidomide on c-MYC expression and cancer-related proteins in an HCC cellular model. The expression of c-MYC was measured using RT-qPCR and western blot assays. In addition, luciferase activity assays were performed for the c-MYC promoters P1 and P2 using recombinant plasmids. Dose-response-time analyses were performed for isotretinoin or thalidomide in cells transfected with the c-MYC promoters. Finally, a proteome profile analysis of cells exposed to these two drugs was performed and the results were validated by western blot. We demonstrated that in HepG2 cells, isotretinoin and thalidomide reduced c-MYC mRNA expression levels, but this decrease in expression was linked to the regulation of P1 and P1-P2 c-MYC promoter activity in isotretinoin only. Thalidomide did not exert any effect on c-MYC promoters. Also, isotretinoin and thalidomide were capable of inducing and repressing proteins associated with cancer. In conclusion, isotretinoin and thalidomide down-regulate c-MYC mRNA expression and this is partially due to P1 or P2 promoter activity, suggesting that these drugs could be promising options for modulating the expression of oncogenes and tumor suppressor genes in HCC.
... For instance, Valproic acid (VPA) can directly bind to a transcription factor of the gene promoter, among other possibilities of action [26]. Quite relevant to the present study, the pre-natal exposure to xenobiotics with affinity for endogenous transcription factors is likely to induce persistent regulations of genes involved in the enzymatic activity [27]. With respect to interactions between maternal and fetal neuromodulators, exposure to maternal inflammation or MDD imply atypical concentrations of placental 5-HT. ...
... These epigenetic mechanisms are likely to maintain homeostasis (e.g.: 5HT-NE coupling, accessible through cellular feedback) by counteracting the effect of a xenobiotic. Whereas the initial pool of neurons and glia cells may benefit from this epigenetic balancing, the following cells generations would only undergo the long-term relevant regulation after the end of the 'excess MAOA' episode [27] (Fig. 1). Before the 2-year delay for MAOB to significantly impact DA and presumably uncovers the 5HT-NE uncoupling, the latter would arise with the exhaustion of the first pools of neural stem cells for which the persistent regulation was initiated. ...
Article
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Background Environmental factors can modify the expression of genes, including those involved in the metabolism of neurotransmitters. Accounting for a control role of monoamine neurotransmitters, the guided propagation (GP) memory model may contribute to investigate the consequences of neuromodulation impairments on development disorders such as autism. A prenatal transient excess of ‘monoamine oxidase A’ enzyme is assumed here to trigger persistent epigenetic regulations that would induce imbalanced metabolisms of synaptic monoamines. When imported into the ‘offline’ encoding cycles of a GP model, the consequent ‘serotoninergic noise’ leads to aberrant memory structures that can be linked with autism symptoms. Results In computer experiments, different levels of uncoupling between representations of monoamines correlate with the amount of impaired GP modules, the severity of irrelevant connections, as well as network overgrowth. Two types of faulty connections are respectively assumed to underlie autism traits, namely repetitive behavior and perceptual oversensitivity. Besides computational modelling, a genetic family-tree shows how the autism sex-ratio can result from combinations of pharmacological and epigenetic features. Conclusions These results suggest that the current rise of autism is favored by three possible sources of biological masking: (1) during sleep, when cyclic variations of monoamines may undergo disrupted enzymatic activities; (2) across generations of ‘healthy carriers’ protected by the X-chromosome silencing and a specific genetic variant; (3) early in life, as long as the brain development draws on pools of neurons born when the transient enzymatic excess and its persistent epigenetic regulation overlapped, and as long as the B type of monoamine oxidase does not significantly impact dopamine. A disease-modifying therapy can be derived from this study, which involves relevant biomarkers to be first monitored over several months of clinical trial. Electronic supplementary material The online version of this article (10.1186/s12868-018-0477-1) contains supplementary material, which is available to authorized users.
... Therefore, to implement the correct usage of this epigenetic mark, that is, methylation of SREBF1 and LDLR genes, as biomarker for the development of metabolic syndrome, serum B12 level measurement needs to be made mandatory. Likewise, therapeutic drugs can influence the epigenetic modifications [15,79,80]. For instance, the antihypertensive drug-hydralazine-inhibits DNA methylation [80]. ...
... Likewise, therapeutic drugs can influence the epigenetic modifications [15,79,80]. For instance, the antihypertensive drug-hydralazine-inhibits DNA methylation [80]. Most chemotherapeutic drugs induce DNA damage and affect DNA repair mechanisms and hence might induce changes in DNA methylation and other epigenetic modifications [81,82]. ...
... Thus, statins represent the first-line drugs in primary and secondary prevention of cardiovascular diseases [48,49]. Moreover, statins can also epigenetically control cholesterol levels by acting as an inhibitor of HDACs [47,50,51]. In this way, statins can affect the cellular acetylation systems by increasing the acetylated protein levels which guide cells and tissues toward an active transcriptional activity [50,51]. ...
... Moreover, statins can also epigenetically control cholesterol levels by acting as an inhibitor of HDACs [47,50,51]. In this way, statins can affect the cellular acetylation systems by increasing the acetylated protein levels which guide cells and tissues toward an active transcriptional activity [50,51]. ...
Article
The emergence of highly pathogenic strains of influenza virus and coronavirus (CoV) has been responsible for large epidemic and pandemic outbreaks characterised by severe pulmonary illness associated with high morbidity and mortality. One major challenge for critical care is to stratify and minimise the risk of multi-organ failure during the stay in the intensive care unit (ICU). Epigenetic-sensitive mechanisms, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) methylation, histone modifications, and non-coding RNAs may lead to perturbations of the host immune-related transcriptional programmes by regulating chromatin structure and gene expression patterns. Viruses causing severe pulmonary illness can use epigenetic-regulated mechanisms during host–pathogen interaction to interfere with innate and adaptive immunity, adequacy of inflammatory response, and overall outcome of viral infections. For example, Middle East respiratory syndrome-CoV and H5N1 can affect host antigen presentation through DNA methylation and histone modifications. The same mechanisms would presumably occur in patients with coronavirus disease 2019, in which tocilizumab may epigenetically reduce microvascular damage. Targeting epigenetic pathways by immune modulators (e.g. tocilizumab) or repurposed drugs (e.g. statins) may provide novel therapeutic opportunities to control viral–host interaction during critical illness. In this article, we provide an update on epigenetic-sensitive mechanisms and repurposed drugs interfering with epigenetic pathways which may be clinically suitable for risk stratification and beneficial for treatment of patients affected by severe viral respiratory infections.
... Epigenetics is defined as heritable modifications of the DNA that do not affect the sequence of nucleotides. DNA methylation, a vastly studied epigenetic mark in somatic cells [12], is known to change with age, lifestyle, disease and medications [13][14][15], suggesting that epigenetic factors could act as mechanisms through which environmental and genetic factors in MS interact. A major role of DNA methylation is the regulation of Mapping the DNA methylation profiles at the genome-wide level of immune cells from MS patients longitudinally, could aid to increase the understanding of biological mechanisms involved in MS, and thereby support MS diagnosis, provide better guidance for therapeutic strategy and identify leads for the development of new therapeutic targets. ...
Article
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Multiple sclerosis (MS) is an autoimmune, neurological disease. We investigated genome-wide DNA methylation profiles of CD4⁺ and CD8⁺ T cells from MS patients and healthy controls at baseline and a follow-up visit. Patients were all treatment-naïve at baseline, and either on treatment or remained untreated at the follow-up visit. MS patients show more changes in their T cell DNA methylation profiles as compared to healthy controls over time, with the most pronounced differences observed in the untreated MS patients. These findings underline the potential of DNA methylation as biomarkers in MS.
... Beyond the molecular phenomenon of DNA damage, SVAGs also induce epigenetic and chromatin modifications that alter neural gene expression [39,[79][80][81][82][83][84][85][86][87][88][89]. In the studies, faulty gene expression was seen to lead to a variety of defects of neural development and function, including errors of protein synthesis, cytoskeleton formation, signal transduction, synaptic plasticity, dendritic spine density and levels of the brain-derived neurotrophic factor (BDNF), among other defects. ...
Article
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Agents of general anesthesia (GA) are commonly employed in surgical, dental and diagnostic procedures to effectuate global suppression of the nervous system, but in addition to somatic targets, the subject’s germ cells—from the embryonic primordial stage to the mature gametes—may likewise be exposed. Although GA is generally considered safe for most patients, evidence has accumulated that various compounds, in particular the synthetic volatile anesthetic gases (SVAGs) such as sevoflurane, can exert neurotoxic, genotoxic and epigenotoxic effects, with adverse consequences for cellular and genomic function in both somatic and germline cells. The purpose of this paper is to review the evidence demonstrating that GA, and in particular, SVAGs, may in some circumstances adversely impact the molecular program of germ cells, resulting in brain and behavioral pathology in the progeny born of the exposed cells. Further, we exhort the medical and scientific communities to undertake comprehensive experimental and epidemiological research programs to address this critical gap in risk assessment.
... Epigenetic targets have been of high importance in drug ability for drug able targets to emerge in 10 years. Such purposes have been turreted for the oncology researches, also have certain effect on the cardiovascular, neurological, metabolic, and inflammatory disorders (18,19). Effective epigenetic drug studies requiring tools of high-quality, involving epigenetic assays, validated antibodies, genetic recombinant with regard to proteins and enzymes modification ( fig.3). ...
Article
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The strategies of biological manipulation bio-catalysis for synthesis of pharmaceuticals has raised in previous years. This review covers the following methods to candidate catalysis genes coding to enzymes in high expression to modified the microorganisms genetically. The operation will tend to create a new bio-therapy used as catalysts for synthesis a new pharmaceutical assessable product, on both a laboratory and a commercial scale. © 2020, Hampstead Psychological Associates. All rights reserved.
... The contribution of genetic pre-disposition must be reconsidered under these aspects as well as possible modifications by epigenetic mechanisms. This means that also at the level of the genes, effects of certain attitudes and of individual behaviors can be traced and can be influenced in their early stages (Csoka, Szyf 2009;Karberg 2009;Martin 2009). As exercise and training must be considered to be important contributors in this framework of stimuli, there is much reason to carry out more research in this field. ...
Article
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... Some drugs may be teratogenic or pathogenic [177,178] thereby illustrating that genetic changes caused by drugs can be deployed with positive and negative effects, and that such effects may be shortlasting but can also persist long after exposure to the drug has ceased. Many drugs influence the genome and/or epigenome by altering the underlying genetic sequence or by creating epigenetic [179] or chromatin modifications [180] which influence the ability of the gene to express a protein. ...
Article
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The first precise mathematical model of the relationship between sense perception, brain structure and/or function, the autonomic nervous system and/or physiological systems, and cellular and molecular biology was developed by Dr. Igor Gennadyevich Grakov in the period 1981-1997. The aim of this article is to illustrate how such knowledge can be applied to better comprehend how the whole body functions and, in particular, how this can be applied to understand the process (es) responsible for aging and to understand why we ultimately expire. It supports the conclusion that the aging process is associated with the many and various factors which materially influence the stable function of the autonomic nervous system and physiological systems and that our ultimate demise is associated with the inability of the brain to sustain such functional relationships. The author presents this knowledge in the 'Autonomic Hypothesis' outlined in this report, discusses the significance of the many and various factors which influence the stable and coherent function of the autonomic nervous system, which sustains the body's function and thereby influences the aging process. It incorporates case reports to justify such hypothesis, in particular how this knowledge can be used to screen patient health and optimize longevity.
... Paroxetine has also been found to alter DNMT1 phosphorylation, which affects the enzyme's activity, in A C C E P T E D M A N U S C R I P T 12 peripheral blood cells obtained from depressed patients (Gassen et al., 2015). Evidence suggests that the SSRI fluoxetine indirectly alters the epigenetic landscape through chronic elevation of serotonin, which in turn increases expression of methyl-CpG-binding protein, a transcription factor involved in DNA methylation, and a specific histone deacetylase (HDAC), an enzyme that removes acetyl groups from histones (Csoka and Szyf, 2009). Furthermore, the serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine (Qiao et al., 2019) and ...
Article
Background: Major depressive disorder (MDD) is a leading cause of disability worldwide, and over half of patients do not achieve symptom remission following an initial antidepressant course. Despite evidence implicating a strong genetic basis for the pathophysiology of MDD, there are no adequately validated biomarkers of treatment response routinely used in clinical practice. Pharmacoepigenetics is an emerging field that has the potential to combine both genetic and environmental information into treatment selection and further the goal of precision psychiatry. However, this field is in its infancy compared to the more established pharmacogenetics approaches. Methods: We prepared a narrative review using literature searches of studies in English pertaining to pharmacoepigenetics and treatment of depressive disorders conducted in PubMed, Google Scholar, PsychINFO, and Ovid Medicine from inception through January 2019. We reviewed studies of DNA methylation and histone modifications in both humans and animal models of depression. Results: Emerging evidence from human and animal work suggests a key role for epigenetic marks, including DNA methylation and histone modifications, in the prediction of antidepressant response. The challenges of heterogeneity of patient characteristics and loci studied as well as lack of replication that have impacted the field of pharmacogenetics also pose challenges to the development of pharmacoepigenetic tools. Additionally, given the tissue specific nature of epigenetic marks as well as their susceptibility to change in response to environmental factors and aging, pharmacoepigenetic tools face additional challenges to their development. Limitations: This is a narrative and not systematic review of the literature on the pharmacoepigenetics of antidepressant response. We highlight key studies pertaining to pharmacoepigenetics and treatment of depressive disorders in humans and depressive-like behaviors in animal models, regardless of sample size or methodology. While we discuss DNA methylation and histone modifications, we do not cover microRNAs, which have been reviewed elsewhere recently. Conclusions: Utilization of genome-wide approaches and reproducible epigenetic assays, careful selection of the tissue assessed, and integration of genetic and clinical information into pharmacoepigenetic tools will improve the likelihood of developing clinically useful tests.
... Thus, the correlational nature of the findings implies that either DNA methylation precedes psychopathology or appears afterwards as a downstream consequence of the symptoms; this phenomenon is also known as reverse causation (Tobi et al., 2018). Similarly, pharmacological treatment for depression might also influence the DNA methylation landscape (Csoka and Szyf, 2009); thus, studies focusing on current sub-threshold symptomatology rather than categorical diagnoses can help find the genuine biomarkers of disease. All the studies analyzed DNA methylation in peripheral tissues, mainly peripheral blood; although brain tissue appears as the most relevant source to explore psychiatric disorders, it remains inaccessible in human studies; however, neuroendocrine and immune components of the depressive phenotype are likely to be biologically programmed in peripheral tissues (Raison and Miller, 2017). ...
Article
Monozygotic (MZ) twin studies constitute a key resource for the dissection of environmental and biological risk factors for human complex disorders. Given that epigenetic differences accumulate throughout the lifespan, the assessment of MZ twin pairs discordant for depression offers a genetically informative design to explore DNA methylation while accounting for the typical confounders of the field, shared by co-twins of a pair. In this review, we systematically evaluate all twin studies published to date assessing DNA methylation in association with depressive phenotypes. However, difficulty to recruit large numbers of MZ twin pairs fails to provide enough sample size to develop genome-wide approaches. Alternatively, region and pathway analysis revealed an enrichment for nervous system related functions; likewise, evidence supports an accumulation of methylation variability in affected subjects when compared to their co-twins. Nevertheless, longitudinal studies incorporating known risk factors for depression such as childhood trauma are required for understanding the role that DNA methylation plays in the etiology of depression.
... Epigenetic processes have been now studied for a few years in the context of neurodegenerative diseases and are now starting to be used as targets for therapeutic intervention [98]. However, this field is still young, and requires additional research [99,100]. Early epigenetic research focused on discovering modifications in genes identified by genome-wide association studies (GWAS) for the different neurodegenerative diseases [101]. ...
Article
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Purpose of Review In the quest for understanding the pathophysiological processes underlying degeneration of nervous systems, synapses are emerging as sites of great interest as synaptic dysfunction is thought to play a role in the initiation and progression of neuronal loss. In particular, the synapse is an interesting target for the effects of epigenetic mechanisms in neurodegeneration. Here, we review the recent advances on epigenetic mechanisms driving synaptic compromise in major neurodegenerative disorders. Recent Findings Major developments in sequencing technologies enabled the mapping of transcriptomic patterns in human postmortem brain tissues in various neurodegenerative diseases, and also in cell and animal models. These studies helped identify changes in classical neurodegeneration pathways and discover novel targets related to synaptic degeneration. Summary Identifying epigenetic patterns indicative of synaptic defects prior to neuronal degeneration may provide the basis for future breakthroughs in the field of neurodegeneration.
... While these results look promising, future studies are required, including larger sample sizes and genetic variants covering the whole region of the NET gene. Furthermore, although not detected in this study, future research should also include patients currently undergoing pharmacotherapy as it may affect the DNA methylation [47,48]. ...
Article
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Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a robust genetic influence. The norepinephrine transporter (NET) is of particular interest as it is one of the main targets in treatment of the disorder. As ADHD is a complex and polygenetic condition, the possible regulation by epigenetic processes has received increased attention. We sought to determine possible differences in NET promoter DNA methylation between patients with ADHD and healthy controls. DNA methylation levels in the promoter region of the NET were determined in 23 adult patients with ADHD and 23 healthy controls. A subgroup of 18 patients with ADHD and 18 healthy controls underwent positron emission tomography (PET) with the radioligand (S,S)-[18F]FMeNER-D2 to quantify the NET in several brain areas in vivo. Analyses revealed significant differences in NET methylation levels at several cytosine–phosphate–guanine (CpG) sites between groups. A defined segment of the NET promoter (“region 1”) was hypermethylated in patients in comparison with controls. In ADHD patients, a negative correlation between methylation of a CpG site in this region and NET distribution in the thalamus, locus coeruleus, and the raphe nuclei was detected. Furthermore, methylation of several sites in region 1 was negatively associated with the severity of hyperactivity–impulsivity symptoms. Our results point to an epigenetic dysregulation in ADHD, possibly due to a compensatory mechanisms or additional factors involved in transcriptional processing.
... It is constantly prone to perpetual fluctuations throughout the lifespan and is profoundly altered in ageing organisms. The resulting gene expression profile, however, can be relatively easily modified by pharmaceuticals [64], physical exercise [65], diet [66] and even gut microbiota [67]. ...
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The human population is getting ageing. Both ageing and age-related diseases are correlated with an increased number of senescent cells in the organism. Senescent cells do not divide but are metabolically active and influence their environment by secreting many proteins due to a phenomenon known as senescence associated secretory phenotype (SASP). Senescent cells differ from young cells by several features. They possess more damaged DNA, more impaired mitochondria and an increased level of free radicals that cause the oxidation of macromolecules. However, not only biochemical and structural changes are related to senescence. Senescent cells have an altered chromatin structure, and in consequence, altered gene expression. With age, the level of heterochromatin decreases, and less condensed chromatin is more prone to DNA damage. On the one hand, some gene promoters are easily available for the transcriptional machinery; on the other hand, some genes are more protected (locally increased level of heterochromatin). The structure of chromatin is precisely regulated by the epigenetic modification of DNA and posttranslational modification of histones. The methylation of DNA inhibits transcription, histone methylation mostly leads to a more condensed chromatin structure (with some exceptions) and acetylation plays an opposing role. The modification of both DNA and histones is regulated by factors present in the diet. This means that compounds contained in daily food can alter gene expression and protect cells from senescence, and therefore protect the organism from ageing. An opinion prevailed for some time that compounds from the diet do not act through direct regulation of the processes in the organism but through modification of the physiology of the microbiome. In this review we try to explain the role of some food compounds, which by acting on the epigenetic level might protect the organism from age-related diseases and slow down ageing. We also try to shed some light on the role of microbiome in this process.
... It has been suggested and observed that long-term use of 5-HT1A receptors along with increased expression of methyl-binding proteins such as MeCP2 and MDB1 which leads to increased production of HDAC2 mRNA and decreased production of histone H3 deacetylase. 18 Hormonal factors have also been implicated in SSRI-induced sexual dysfunction such as increase in prolactin and decrease in testosterone, oxytocin, and nitric oxide. 19 Through 5-HT2A and 5-HT2C actions, serotonin also regulates the action of proopiomelanocortin and melanocortin, which play a major role in skin coloration as well as in sexual behavior. ...
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Sexual dysfunction is one of the more common features of depressive disorders, presenting with dysfunction across sexual response cycle. Variety of factors play a role in causing sexual dysfunction in these patients, such as psychological, biological, social and interpersonal factors. Another cause of sexual dysfunction in these patients can be the side effect of antidepressants making it difficult to conclude if the dysfunction is the result of the depression or the treatment of depression. Clinicians need to be aware about the sexual dysfunction as it can have big impact on the overall quality of life of an individual.
... TD may demonstrate a comorbidity of 20-30% with SCZ (3,4). Recent studies have reported that complex interactions of genetic, environmental and epigenetic factors play important roles in SCZ and TD (4)(5)(6)(7). DNA methylation is an epigenetic mechanism that influences CG dinucleotides by adding a methyl group (CH 3 ) to them. ...
Article
Tardive dyskinesia (TD) is a serious side effect of certain antipsychotic medications that are used to treat schizophrenia (SCZ) and other mental illnesses. The methylation status of the insulin receptor substrate 1 (IRS1) gene is reportedly associated with SCZ; however, no study, to the best of the authors' knowledge, has focused on the quantitative DNA methylation levels of the IRS1 gene using pyrosequencing in SCZ with or without TD. The present study aimed to quantify DNA methylation levels of 4 CpG sites in the IRS1 gene using a Chinese sample including SCZ patients with TD and without TD (NTD) and healthy controls (HCs). The general linear model (GLM) was used to detect DNA methylation levels among the 3 proposed groups (TD vs. NTD vs. HC). Mean DNA methylation levels of 4 CpG sites demonstrated normal distribution. Pearson's correlation analysis did not reveal any significant correlations between the DNA methylation levels of the 4 CpG sites and the severity of SCZ. GLM revealed significant differences between the 3 groups for CpG site 1 and the average of the 4 CpG sites (P=0.0001 and P=0.0126, respectively). Furthermore, the TD, NTD and TD + NTD groups demonstrated lower methylation levels in CpG site 1 (P=0.0003, P<0.0001 and P<0.0001, respectively) and the average of 4 CpG sites (P=0.0176, P=0.0063 and P=0.003, respectively) compared with the HC group. The results revealed that both NTD and TD patients had significantly decreased DNA methylation levels compared with healthy controls, which indicated a significant association between the DNA methylation levels of the IRS1 gene with SCZ and TD.
... The environment affects DNA methylation signatures, and exposures to toxicants, pharmaceutical agents, exercise, stress, and other factors have been shown to associate with changes in epigenetic marks, such as DNA methylation [72][73][74][75]. Our findings suggest that being born at high altitude leaves a persistent mark on the epigenome through adulthood by leaving lasting effects on global levels of DNA methylation measured at LINE-1. ...
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Recent discoveries indicate a genetic basis for high-altitude adaptation among human groups who have resided at high altitude for millennia, including Andeans, Tibetans, and Ethiopians. Yet, genetics alone does not explain the extent of variation in altitude-adaptive phenotypes. Current and past environments may also play a role, and one way to determine the effect of the environment is through the epigenome. To characterize if Andean adaptive responses to high altitude have an epigenetic component, we analyzed DNA methylation of the promoter region of EPAS1 and LINE-1 repetitive element among 572 Quechua individuals from high- (4,388 m) and low-altitude (0 m) in Peru. Participants recruited at high altitude had lower EPAS1 DNA methylation and higher LINE-1 methylation. Altitude of birth was associated with higher LINE-1 methylation, not with EPAS1 methylation. The number of years lived at high altitude was negatively associated with EPAS1 methylation and positively associated with LINE-1 methylation. We found four one-carbon metabolism SNPs (MTHFD1 rs2236225, TYMS rs502396, FOLH1 rs202676, GLDC rs10975681) that cumulatively explained 11.29% of the variation in average LINE-1 methylation. And identified an association between LINE-1 methylation and genome-wide SNP principal component 1 that distinguishes European from Indigenous American ancestry suggesting that European admixture decreases LINE-1 methylation. Our results indicate that both current and lifetime exposure to high-altitude hypoxia have an effect on EPAS1 and LINE-1 methylation among Andean Quechua, suggesting that epigenetic modifications may play a role in high-altitude adaptation.
... We assessed the predictive power of these models via the area under the receiver operating characteristic curve (AUC) [82,83]. As these epigenetic loci could be associated with post-MI medication usage [84,85], we used KORA to associate each medication type commonly prescribed post-MI with the CpGs retained in the NAS elastic net model. The CpGs in the model had already been assessed for associates with MI independent of age, body mass index, smoking, alcohol consumption, type 2 diabetes, and hypertension in the EWAS; thus, those confounders were not retested here. ...
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Background Most research into myocardial infarctions (MIs) have focused on preventative efforts. For survivors, the occurrence of an MI represents a major clinical event that can have long-lasting consequences. There has been little to no research into the molecular changes that can occur as a result of an incident MI. Here, we use three cohorts to identify epigenetic changes that are indicative of an incident MI and their association with gene expression and metabolomics. Results Using paired samples from the KORA cohort, we screened for DNA methylation loci (CpGs) whose change in methylation is potentially indicative of the occurrence of an incident MI between the baseline and follow-up exams. We used paired samples from the NAS cohort to identify 11 CpGs which were predictive in an independent cohort. After removing two CpGs associated with medication usage, we were left with an “epigenetic fingerprint” of MI composed of nine CpGs. We tested this fingerprint in the InCHIANTI cohort where it moderately discriminated incident MI occurrence (AUC = 0.61, P = 6.5 × 10⁻³). Returning to KORA, we associated the epigenetic fingerprint loci with cis-gene expression and integrated it into a gene expression-metabolomic network, which revealed links between the epigenetic fingerprint CpGs and branched chain amino acid (BCAA) metabolism. Conclusions There are significant changes in DNA methylation after an incident MI. Nine of these CpGs show consistent changes in multiple cohorts, significantly discriminate MI in independent cohorts, and were independent of medication usage. Integration with gene expression and metabolomics data indicates a link between MI-associated epigenetic changes and BCAA metabolism. Electronic supplementary material The online version of this article (10.1186/s13148-018-0588-7) contains supplementary material, which is available to authorized users.
... In a previous experiment (Dalla Bona et al., 2016), exposure to enrofloxacin (EFX), another veterinary fluoroquinolone, which may exert genotoxic (Thomé et al., 2012) or epigenetic (Csoka and Szyf, 2009) effects in eukaryotes, led to an increasing toxicity over Daphnia magna generations. Toxic effects (mortality and reproduction inhibition) were detected even in daphnids no longer exposed to EFX for two consecutive generations. ...
Article
In this study, the effects of both continuous and alternate exposure to 2 mg L⁻¹ of flumequine (FLU) on survival, growth and reproduction of Daphnia magna were evaluated over four generations. Mortality was the most evident effect, with an average mortality rate of 23 ± 14% across generations. Individuals destined to succumb were identifiable well in advance through their discolouration and lack of development, and limited or zero reproductive capacity. Inhibition of reproduction in surviving mothers varied across the four generations (14.3 ± 17%) without an apparent correlation with the duration of exposure over generations. Significant reproductive inhibition was observed in the generation that followed three non-exposed generations (the fourth generation), pointing to a transgenerational toxicity of FLU. In another experiment, in vitro exposure of 72 D. magna embryos to 2 mg L⁻¹ FLU caused 14% mortality (versus 7% in the control). Among the 62 individuals that hatched alive, six showed birth defects and only one was able to survive the next few days. The other, apparently healthy newborns were randomly assigned to two groups and submitted to a reproduction test, either in the absence or in the presence of 2 mg L⁻¹ FLU. A high mortality rate and/or strongly significantly inhibited reproduction were detected in both groups. As with previously run analogous tests with enrofloxacin, the multigenerational and embryonic tests showed a clear disruption to this crustacean population which would not be evidenced by the standard official acute and chronic tests. This indicates the necessity of taking a different and more comprehensive approach to the evaluation of substances having an inherent ability to interact with genetic material.
... However, no study has been found to quantify DNA methylation levels of the DLGAP2 gene using pyrosequencing in NTD and to examine the methylation of DLGAP2 gene in TD. Previous studies suggested that the occurrence of TD may be the result of the interactions between genetics, environment, and epigenetics [8][9][10][11] . Furthermore, it is proposed that antipsychotics are epigenetic modifiers with widespread effects on site-specific and global DNA methylation 38 . ...
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Abstract Tardive dyskinesia (TD) is a side effect of antipsychotic medications used to treat schizophrenia (SCZ) and other mental health disorders. No study has previously used pyrosequencing to quantify DNA methylation levels of the DLGAP2 gene; while the quantitative methylation levels among CpG sites within a gene may be correlated. To deal with the correlated measures among three CpG sites within the DLGAP2 gene, this study analyzed DNA methylation levels of the DLGAP2 gene using a linear mixed model (LMM) in a Chinese sample consisting of 35 SCZ patients with TD, 35 SCZ without TD (NTD) and 34 healthy controls (HCs) collected in Beijing, China. The initial analysis using the non-parametric Kruskal-Wallis test revealed that three groups (TD, NTD and HC) had significant differences in DNA methylation level for CpG site 2 (p = 0.0119). Furthermore, the average methylation levels among the three CpG sites showed strong correlations (all p values
... As with every observational study design, the causal attribution of epigenetic associations in eating disorders is extremely difficult. The epigenetic dysregulation could potentially have causally contributed to the disease or have arisen as a consequence of the disease, its symptoms or even treatments, such as medication; [81] or, in a third scenario, there could be a third factor driving both the disease and the epigenetic alteration, which have no direct link between one another. One important approach to addressing causality is to consider temporal factors [26,27]. ...
Article
Eating disorders are complex heritable conditions influenced by both genetic and environmental factors. Given the progress of genomic discovery in anorexia nervosa, with the identification of the first genome-wide significant locus, as well as animated discussion of epigenetic mechanisms in linking environmental factors with disease onset, our goal was to conduct a systematic review of the current body of evidence on epigenetic factors in eating disorders to inform future directions in this area. Following PRISMA guidelines, two independent authors conducted a search within PubMed and Web of Science and identified 18 journal articles and conference abstracts addressing anorexia nervosa (n = 13), bulimia nervosa (n = 6), and binge-eating disorder (n = 1), published between January 2003 and October 2017. We reviewed all articles and included a critical discussion of field-specific methodological considerations. The majority of epigenetic analyses of eating disorders investigated methylation at candidate genes (n = 13), focusing on anorexia and bulimia nervosa in very small samples with considerable sample overlap across published studies. Three studies used microarray-based technologies to examine DNA methylation across the genome of anorexia nervosa and binge-eating disorder patients. Overall, results were inconclusive and were primarily exploratory in nature. The field of epigenetics in eating disorders remains in its infancy. We encourage the scientific community to apply methodologically sound approaches using genome-wide designs including epigenome-wide association studies (EWAS), to increase sample sizes, and to broaden the focus to include all eating disorder types.
... Interestingly, changes in epigenome homeostasis are not only responsive to environmental signals, but also commonly-used pharmaceutical drugs [8]. These drugs can modify epigenetic and epigenomic homeostasis by direct or indirect mechanisms [9]. In this perspective, the cytidine analog molecule, 5-aza-2 -deoxycytidine (5AZ), initially used as a chemotherapeutic agent for acute myelogenous leukemia and myelodysplastic syndrome, acts as a demethylating agent [10]. ...
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A generation of induced pluripotent stem cells (iPSC) by ectopic expression of OCT4, SOX2, KLF4, and c-MYC has established promising opportunities for stem cell research, drug discovery, and disease modeling. While this forced genetic expression represents an advantage, there will always be an issue with genomic instability and transient pluripotency genes reactivation that might preclude their clinical application. During the reprogramming process, a somatic cell must undergo several epigenetic modifications to induce groups of genes capable of reactivating the endogenous pluripotency core. Here, looking to increase the reprograming efficiency in somatic cells, we evaluated the effect of epigenetic molecules 5-aza-2′-deoxycytidine (5AZ) and valproic acid (VPA) and two small molecules reported as reprogramming enhancers, CHIR99021 and A83-01, on the expression of pluripotency genes and the methylation profile of the OCT4 promoter in a human dermal fibroblasts cell strain. The addition of this cocktail to culture medium increased the expression of OCT4, SOX2, and KLF4 expression by 2.1-fold, 8.5-fold, and 2-fold, respectively, with respect to controls; concomitantly, a reduction in methylated CpG sites in OCT4 promoter region was observed. The epigenetic cocktail also induced the expression of the metastasis-associated gene S100A4. However, the epigenetic cocktail did not induce the morphological changes characteristic of the reprogramming process. In summary, 5AZ, VPA, CHIR99021, and A83-01 induced the expression of OCT4 and SOX2, two critical genes for iPSC. Future studies will allow us to precise the mechanisms by which these compounds exert their reprogramming effects.
... Given that Wnt/β-catenin signaling remained activated in chronic HCV infection despite virus clearance by DAA, there would be two possibilities for this phenomenon. One possibility is that chronic HCV infection promotes the addition or removal of epigenetic tags on DNA and/or chromatin, leading to a permanent change in the epigenetic profile and/or gene expression of specific genes affected by that epigenetic changes to remain activated Wnt/β-catenin signaling even after HCV clearance [56,57]. The other would be that DAA eradicates HCV and simultaneously activates Wnt/β-catenin signaling. ...
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Chronic hepatitis C virus (HCV) infection causes hepatocellular carcinoma (HCC). Although HCV clearance has been improved by the advent of direct-acting antiviral agents (DAA), retrospective studies have shown that the risk of subsequent HCC, while considerably decreased compared with active HCV infection, persists after DAA regimens. However, either the mechanisms of how chronic HCV infection causes HCC or the factors responsible for HCC development after viral eradication in patients with DAA treatments remain elusive. We reported an in vitro model of chronic HCV infection and determined Wnt/β-catenin signaling activation due to the inhibition of GSK-3β activity via serine 9 phosphorylation (p-ser9-GSK-3β) leading to stable non-phosphorylated β-catenin. Immunohistochemical staining demonstrated the upregulation of both β-catenin and p-Ser9-GSK-3β in HCV-induced HCC tissues. Chronic HCV infection increased proliferation and colony-forming ability, but knockdown of β-catenin decreased proliferation and increased apoptosis. Unexpectedly, Wnt/β-catenin signaling remained activated in chronic HCV-infected cells after HCV eradication by DAA, but metformin reversed it through PKA/GSK-3β-mediated β-catenin degradation, inhibited colony-forming ability and proliferation, and increased apoptosis, suggesting that DAA therapy in combination with metformin may be a novel therapy to treat HCV-associated HCC where metformin suppresses Wnt/β-catenin signaling for HCV-infected patients.
... Likewise, other FDA-approved preparations, including the anti-cancer drug (methotrexate), the antiarrhythmic agent (procainamide), the anti-acne (isotretinoin), anti-diabetes (metformin) in addition to various antibiotics, antipsychotics, synthetic hormones, beta-blockers, and general anesthetics are expected to have epigenetic mechanisms of action (Csoka and Szyf 2009a). ...
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The microbiome is a community of various microorganisms that inhabit or live on the skin of humans/animals, sharing the body space with their hosts. It is a sort of complex ecosystem of trillions of commensals, symbiotic, and pathogenic microorganisms, including trillions of bacteria, archaea, protozoa, fungi, and viruses. The microbiota plays a role in the health and disease status of the host. Their number, species dominance, and viability are dynamic. Their long-term disturbance is usually accompanied by serious diseases such as metabolic disorders, cardiovascular diseases, or even cancer. While epigenetics is a term that refers to different stimuli that induce modifications in gene expression patterns without structural changes in the inherited DNA sequence, these changes can be reversible or even persist for several generations. Epigenetics can be described as cell memory that stores experience against internal and external factors. Results from multiple institutions have contributed to the role and close interaction of both microbiota and epigenetics in disease induction. Understanding the mechanisms of both players enables a better understanding of disease induction and development and also opens the horizon to revolutionary therapeutic approaches. The present review illustrates the roles of diet, microbiome, and epigenetics in the induction of several chronic diseases. In addition, it discusses the application of epigenetic data to develop diagnostic biomarkers and therapeutics and evaluate their safety for patients. Understanding the interaction among all these elements enables the development of innovative preventive/therapeutic approaches for disease control.
... Since taking specific pharmaceuticals (e.g., antidiabetics, antihypertensives, or antilipidemic) reduces the severity or risk of developing aging-related diseases, it is possible that using these medications may also lead to decreases in DNAm age acceleration through deceleration of the biological aging process caused by relevant health conditions. On the other hand, recent evidence suggests that exposure to commonly used pharmaceuticals may also contribute to age-related chronic diseases, including CVD, cancer, neurological disorders, and diabetes, through epigenetic side effects [25,26]. Thus, it is critical to comprehensively investigate how commonly used pharmaceuticals are associated with biological aging and examine which drugs may have preventive or adverse effects on DNAm age acceleration. ...
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DNA methylation age acceleration, the discrepancy between epigenetic age and chronological age, is associated with mortality and chronic diseases, including diabetes, hypertension, and hyperlipidemia. In this study, we investigate whether medications commonly used to treat these diseases in 15 drug categories are associated with four epigenetic age acceleration measures: HorvathAge acceleration (HorvathAA), HannumAge acceleration (HannumAA), PhenoAge acceleration, and GrimAge acceleration (GrimAA) using cross-sectional (Phase 1, N=1,100) and longitudinal (Phases 1 and 2, N=266) data from African Americans in the Genetic Epidemiology Network of Arteriopathy (GENOA) study. In cross-sectional analyses, the use of calcium channel blockers was associated with 1.27 years lower HannumAA after adjusting for covariates including hypertension (p=0.001). Longitudinal analyses showed that, compared to those who never used antihypertensives, those who started to take antihypertensives after Phase 1 had a 0.97-year decrease in GrimAA (p=0.007). In addition, compared to those who never used NSAID analgesics, those who started to take them after Phase 1 had a 2.61-year increase in HorvathAA (p=0.0005). Our study demonstrates that three commonly used medications are associated with DNAm age acceleration in African Americans and sheds light on the potential epigenetic effects of pharmaceuticals on aging at the cellular level.
... As methylation reflects both environmental influences and individual genetic variation, the thoughtful and pragmatic control of confounding variables is particularly important and should be considered in the study design. Age (Bell et al., 2012;Hernandez et al., 2011;Horvath & Raj, 2018), ancestry (Galanter et al., 2017;Yuan et al., 2019), sex (Chung & Auger, 2013;Nugent & McCarthy, 2011), infectious disease (Gornalusse et al., 2015;Nakayama-Hosoya et al., 2015;Nelson et al., 2017), psychiatric disorders (Klengel et al., 2014;Vinkers et al., 2015) and pharmaceutical (Csoka & Szyf, 2009) exposure have all been associated with differential methylation. ...
Article
Childhood trauma (CT) is well‐established as a potent risk factor for the development of mental disorders. However, the potential of adverse early experiences to exert chronic and profound effects on physical health, including aberrant metabolic phenotypes, has only been more recently explored. Among these consequences is metabolic syndrome (MetS), which is characterised by at least three of five related cardiometabolic traits: hypertension, insulin resistance/hyperglycaemia, raised triglycerides, low high‐density lipoprotein, and central obesity. The deleterious effects of CT on health outcomes may be partially attributable to dysregulation of the hypothalamic‐pituitary‐adrenal (HPA) axis, which coordinates the response to stress, and the consequent fostering of a pro‐inflammatory environment. Epigenetic tags, such as DNA methylation, which are sensitive to environmental influences provide a means whereby the effects of CT can be biologically embedded and persist into adulthood to affect health and wellbeing. The methylome regulates the transcription of genes involved in the stress response, metabolism, and inflammation. This narrative review examines the evidence for DNA methylation in CT and MetS in order to identify shared neuroendocrine and immune correlates that may mediate the increased risk of MetS following CT exposure. Our review specifically highlights differential methylation of FKBP5, the gene that encodes FK506‐binding protein 51 and has pleiotropic effects on stress responding, inflammation and energy metabolism, as a central candidate to understand the molecular aetiology underlying CT‐associated MetS risk.
... Moreover, recent studies suggested that statins modulate miRNA activity [10]. Likewise, several others FDA-approved drugs has been raising the hypothesis of modulate the epigenetic status, including methotrexate, procainamide, thalidomide, isotretinoin, neuroleptics, general anesthetics, synthetic estrogens, beta-blockers, chloroquine and fluoroquinolone antibiotics, and Cox-2 inhibitors [11]. The aforementioned show only a few examples of drugs that modulate the epigenetic network and may lead to patients either beneficial or side effects. ...
... Countless different drugs are used in pregnancies (Briggs et al. 2017), Environmental and Molecular Mutagenesis. DOI 10.1002/em with many known to exert epigenetic impacts (Csoka and Szyf 2009), and germline risks for all of them cannot possibly be ascertained in any simple fashion. Instead, priorities must be made based on informed guesses as to pharmacokinetics and degree of epigenomic activity. ...
Article
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Millions of women and their fetuses were exposed to the toxic pregnancy drug diethylstilbestrol (DES) from the 1940s into the 1970s, a time when the medical profession had little knowledge about potential developmental consequences of fetal drug exposures. Pathological consequences of DES exposure to the pregnant mothers and their offspring are well documented, but now generational research is finding that the grandchildren of women given DES in pregnancy are also at risk. This commentary summarizes presentations on this subject from the Beyond Genes panel “Heritable Impacts of Diethylstilbestrol (DES).”
... 19 Thus, there is concern that chemotherapeutics may induce epigenetically-mediated multigenerational reproductive and developmental toxicity via the male germline. 20 The production of mature male germ cells (spermatogenesis) takes place within the seminiferous tubules of the testis and involves proliferation and differentiation of diploid spermatogonia into haploid spermatozoa. [21][22][23][24] Spermatogenesis is a complex developmental process supported by the secretion of hormones and other cellular signals from Leydig and Sertoli cells. ...
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We have previously shown that in addition to its widely recognised cardiotoxicity, the chemotherapeutic doxorubicin (DOX) is able to induce transcriptional, microRNA (miRNA) and DNA methylation changes in the mouse testis. These changes perturb pathways involved in stress/cell death and survival and testicular function and lead to germ cell loss and reproductive organ damage. Here, we further investigated the differential miRNA expression induced by DOX in mouse spermatogonial (GC1), Leydig (TM3) and Sertoli (TM4) cell lines in vitro. We began by performing cell cycle analysis of the three mouse testicular cell lines to evaluate their sensitivity to DOX and thus select suitable doses for miRNA profiling. In keeping with our in vivo data, the spermatogonial cell line was the most sensitive, and the Sertoli cell line the most resistant to DOX-induced cell cycle arrest. We then further demonstrated that each cell line has a distinct miRNA profile, which is perturbed upon treatment with DOX. Pathway analysis identified changes in the miRNA-mediated regulation of specialised signalling at germ–Sertoli and Sertoli–Sertoli cell junctions following treatment with DOX. Amongst the most significant disease categories associated with DOX-induced miRNA expression were organismal injury and abnormalities, and reproductive system disease. This suggests that miRNAs play significant roles in both normal testicular function and DOX-induced testicular toxicity. Comparison of our in vitro and in vivo data highlights that in vitro cell models can provide valuable mechanistic information, which may also help facilitate the development of biomarkers of testicular toxicity and high-throughput in vitro screening methods to identify potential testicular toxicants.
... The second one is the direct or indirect effect of the drugs in current therapeutic practice on epigenomic status that in turn can influence the treatment response: as an example, several antidepressant drugs and mood stabilizers (i.e. valproate, imipramine, amitriptyline, clomipramine, fluoxetine, escitalopram, phenelzine, and tranylcypromine) were shown to exert part of their therapeutic action by targeting DNA methyltransferase I (DNMT1), histone deacetylase, or altering methylation levels, which in turn can affect gene expression [52][53][54]. Hence, targeting selective epigenetic mechanisms with DNMT modulators or histone deacetylase (HDAC) inhibitors is being considered as a possible new avenue for the development of novel antidepressant drugs [54][55][56][57]. On these bases, we will next discuss if and how epigenetic processes, and in particular DNA methylation, histone modifications, and miRNAs, can be used as biomarkers for treatment response. ...
Article
Introduction: Millions of people worldwide suffer from depression, but despite advances in pharmacological therapies, many patients do not experience symptomatic remission or treatment response, even after treatments with several medications. As such, there is an urgent need to identify biomarkers that can not only predict the treatment response, but also allow a rational selection of optimal therapy for each patient. Areas covered: This review examines the recent findings, coming from different “omic sciences”, in human blood-based biomarkers associated with antidepressant treatment response with particular attention on genetic/epigenetic and biochemical biomarkers. Specific emphasis will be placed on key molecules related to neuroplasticity and inflammation because of their involvement in the pathophysiology of depression and antidepressant response. Expert commentary: Biomarker identification is still an ongoing work. Indeed, to date, no biomarkers have sufficiently proven specificity, sensitivity and reproducibility to be used in the clinical setting. However, “omic” approaches hold great promise in identifying multiple features for predicting antidepressant response, making a personalized treatment strategy possible for each patient, and thereby assist with quick and efficacious responsiveness. It is thus necessary that future studies take an integrative approach that include clinical assessment, environment influences and molecular and biological biomarkers.
... Anorgasmia and ejaculatory anhedonia are the most frequent symptoms of PSSD. 16,30,52 PSSD-mediated dysfunction commonly results in weakened or pleasure-less orgasms, or complete orgasmic anhedonia. Abnormally low release of oxytocin and b-endorphin are key neuro-endocrinological features of these symptoms, mediated through poor post-synaptic 5HT1A signaling. ...
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Introduction Post-SSRI sexual-dysfunction (PSSD) is an iatrogenicsyndrome, the underlying neurobiological mechanisms of which areunclear. Symptom onset follows cessation of serotonergicantidepressants i.e. Selective Serotonin and Norepinephrine ReuptakeInhibitors (SSRI's, SNRI's), and Tricyclic antidepressants (TCA's). PSSDsymptoms include genital anesthesia, erectile dysfunction andorgasmic/ejaculatory anhedonia, and should be differentiated fromdepression-related sexual-dysfunction. Recently, accumulated data of numerous case-reports suggest additional non-sexual symptoms including, anhedonia, apathy, and blunted affect. PSSD gained official recognition after the European medical agency concluded that PSSD is a medical condition that persists after discontinuation of SSRI's and SNRI's. Objective To review possible underlying neurobiological mechanisms ofthis syndrome, update information on the pathophysiology, present a listof potential risk-factors and discuss potential management options forPSSD. Methods Extensive literature review on the main symptom-patterns ofthis disorder was undertaken using PubMed. It includes introductoryexplications of relevant neurobiology with the objective of generatinghypothesis. Results Precipitating factors for PSSD include previous exposure to certain drugs, genetic predisposition, psychological stress or chemical stressful reaction to antidepressants along pre-existing medical conditions affecting neuroplasticity. Different theories have been proposed to explain the pathophysiology of PSSD: epigenetic gene expression, dopamine-serotonin interactions, serotonin neurotoxicity and hormonal changes. The diagnosis of PSSD is by excluding all other etiologies of sexual-dysfunction. Treatment is challenging, and many strategies have been suggested without definitive outcomes. We offerthe contours of a future neurobiological research agenda, and propose several underlying mechanisms for the various symptoms of PSSD which could be the foundation for a future treatment algorithm. Conclusion There is a need for well-designed neurobiological research in this domain, as well as in the prevalence, pathophysiology, and treatment of PSSD. Practitioners should be alert to the distinctive features of PSSD. Misdiagnosing this syndrome might lead to harmful Sexual Medicine Reviews. Peleg LC, Rabinovitch D, Lavie Y, et al. Post-SSRI Sexual Dysfunction (PSSD): Biological Plausibility, Symptoms, Diagnosis, and Presumed Risk Factors. Sex Med Rev 2021;XX:XXX–XXX
... Countless different drugs are used in pregnancies (Briggs et al. 2017), Environmental and Molecular Mutagenesis. DOI 10.1002/em with many known to exert epigenetic impacts (Csoka and Szyf 2009), and germline risks for all of them cannot possibly be ascertained in any simple fashion. Instead, priorities must be made based on informed guesses as to pharmacokinetics and degree of epigenomic activity. ...
Article
Drugs taken during pregnancy can affect three generations at once: the gestating woman (F0), her exposed fetus (F1), and the fetal germ cells that confer heritable information for the grandchildren (F2). Unfortunately, despite growing evidence for connections between F0 drug exposures and F2 pathology, current approaches to risk assessment overlook this important dimension of risk. In this commentary, we argue that the uniquemolecular vulnerabilities of the fetal germline, particularly with regard to global epigenomic reprogramming, combined withempirical evidence for F2 effects of F1 in utero drug and other exposures, should change the way we consider potential long‐term consequences of pregnancy drugs and alter toxicology's standard somatic paradigm. Specifically, we(1) suggest that pregnancy drugs common in the post‐war decades should be investigated as potential contributorsto the “missing heritability” of many pathologies now surging in prevalence; (2) call for inclusion of fetal germline risks in pregnancy drugsafety assessment; and (3) highlight the need for intensified research to ascertain generational impacts of diethylstilbestrol (DES), a vanguard question of human germline toxicity. Only by fully addressing this important dimension of transplacental exposure can we responsibly evaluate safety of drug exposures during pregnancy and convey the full scope of risks, while also retrospectively comprehending the generational legacy of recent history's unprecedented glut of evolutionarily novel intrauterine exposures. This article is protected by copyright. All rights reserved.
Article
Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric condition that has been strongly associated with changes in sleep and circadian rhythms. Circadian rhythms are near 24-h cycles that are primarily generated by an endogenous circadian timekeeping system, encoded at the molecular level by a panel of clock genes. Stimulant and non-stimulant medication used in the management of ADHD has been shown to potentially impact on circadian processes and their behavioral outputs. In the current study, we have analyzed circadian rhythms in daily activity and sleep, and the circadian gene expression in a cohort of healthy controls (N = 22), ADHD participants not using ADHD-medication (N = 17), and participants with ADHD and current use of ADHD medication (N = 17). Rhythms of sleep/wake behavior were assessed via wrist-worn actigraphy, whilst rhythms of circadian gene expression were assessed ex-vivo in primary human-derived dermal fibroblast cultures. Behavioral data indicate that patients with ADHD using ADHD-medication have lower relative amplitudes of diurnal activity rhythms, lower sleep efficiency, more nocturnal activity but not more nocturnal wakenings than both controls and ADHD participants without medication. At the molecular level, there were alterations in the expression of PER2 and CRY1 between ADHD individuals with no medication compared to medicated ADHD patients or controls, whilst CLOCK expression was altered in patients with ADHD and medication. Analysis of fibroblasts transfected with a BMAL1:luc reporter showed changes in the timing of the peak expression across the three groups. Taken together, these data support the contention that both ADHD and medication status impact on circadian processes.
Article
The article describes up-to-date data on mechanics of epigenetic effects of system retinoid - isotretinoin (Roaccutane). It is noted, that modern acne therapy is able not only to pathogenetically influence consequences of the process, but effect genetical causes of desease, leading to persistant changes and normalization of regulatory segments DNA structure under influence of isotretinoin. Also this article lists data on the use of isotretinoin (Roaccutane) for acne treatment of 237 adolescents. Studies were performed on frequency of occurrence, degree of manifestation of secondary effects and methods of levereging this effects in practical use. Authors state that correctly prescribed treatments are safe and do not cause serious secondary effects with in case of long treatmetns.
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Background: Bleomycin, etoposide and cisplatin (BEP) are three chemotherapeutic agents widely used individually or in combination with each other or other chemotherapeutic agents in the treatment of various cancers. These chemotherapeutic agents are cytotoxic; hence, along with killing cancerous cells, they also damage stem cell pools in the body, which causes various negative effects on patients. The epigenetic changes due to the individual action of BEP on stem cells are largely unknown. Methods: Human amniotic fluid stem cells (hAFSCs) were treated with our in-vitro standardized dosages of BEP individually, for seven days. The cells were harvested after the treatment and extraction of DNA and RNA were performed. Real-time PCR and flow cytometry were conducted for cell markers analysis. The global DNA methylation was quantified using 5mC specific kit and promoter and CpG methylation % through bisulfite conversion and pyrosequencing. Micro- RNAs (miRNAs) were quantified with real-time qPCR. Results: The cytotoxic nature of BEP was observed even at low dosages throughout the experiment. We also investigated the change in the expression of various pluripotent and germline markers and found a significant change in the properties of the cells after the treatments. The methylation of DNA at global, promoter and individual CpG levels largely get fluctuated due to the BEP treatment. Several tested miRNAs showed differential expression. No positive correlation between mRNA and protein expression was observed for some markers. Conclusion: Cytotoxic chemotherapeutic agents such as BEP were found to alter stem cell properties of hAFSCs. Different methylation profiles change dynamically, which may explain such changes in cellular properties. Data also suggests that the fate of hAFSCs after treatment may depend upon the interplay between the miRNAs. Finally, our results demonstrate that hAFSCs might prove to be a suitable in-vitro model of stem cells to predict genetic and epigenetic modification due to the action of various drugs.
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Blood transfusions are sometimes necessary after a high loss of blood due to injury or surgery. Some people need regular transfusions due to medical conditions such as haemophilia or cancer. Studies have suggested that extracellular DNA present in the extracellular milieu of transfused blood products has biological actions that are capable of activating the innate immune systems and potentially contribute to some adverse reactions in transfusion. Extracellular mitochondrial DNA encompassed in extracellular DNA has also been found in blood products. From the present work, it becomes increasingly clear that extracellular DNA is far from being biologically inert in blood products. It has been demonstrated to be present in eligible blood products and thus can be transfused to blood recipients. Although the presence of extracellular DNA in human plasma was initially detected in 1948, some aspects have not been fully elucidated. In this review, we summarize the potential origins, clearance mechanisms, relevant structures, and potential role of extracellular DNA in the innate immune responses and its relationship with individual adverse reactions in transfusion.
Article
The release of pharmaceuticals and personal care products (PPCPs) into aquatic environments has been a major concern for the health of ecosystems. Transgenerational plasticity is a potential mechanism for organisms to respond to changing environmental conditions, including climate change and environmental contaminants. The purpose of the present study was to determine the long-term transgenerational effects of an abundant freshwater zooplankton, Daphnia magna, to acute embryonic exposures of serotonin re-uptake inhibitors (SSRI - fluoxetine and sertraline). Both SSRIs have been used extensively to treat depression and anxiety disorders for decades and persist in freshwater ecosystems at physiologically relevant concentrations. Our results revealed that even short (72 h) embryonic exposures of D. magna embryos had long lasting consequences on life history and expression of 5HT related genes in the unexposed generation (F3). Moreover, we identified direct effects of SSRIs on heart rate and swimming behavior in the first generation that carried over from embryonic exposure. We also found that SSRI exposure resulted in a transient increase of ephippia formation in the F1 and F2 in addition to previously well-established increases in parthenogenic egg production. Our results suggest that SSRI exposure has transgenerational consequences to the unexposed generation and potentially beyond, even at low concentration (10-100× lower than what can be found in natural ecosystems) and as a result of embryonic exposure. Because of the short reproductive period of D. magna and their integral role in aquatic food webs, these findings have population-level implications and deserve further investigation.
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The rapidly changing trend of science has yielded novel fronts in many fields of medicine including anesthesiology and perioperative medicine. The traditional approach of medicine would not fulfill the twenty-first century needs of the patient care. Personalized anesthesia and perioperative medicine has been thrived during the last years with many practical ongoing example leading to real paradigm shifts (Kharasch 2018; Sezari and Dabbagh 2019). There is no doubt that the current knowledge in OMICS sciences has impressed our current medical research and has created an avant-garde medical ideology covering research, education, patient care, pharmaceuticals, and all other socioeconomic aspects. Coining the name “Anesthesiomics” as one of the “Clinical Products” of the OMICS sciences is not just a game of words, instead, it represents a real change in the process of development in Anesthesiology and Perioperative Medicine. This is one of the most important reasons why anesthesiologists and perioperative medicine specialists have to be more familiar with these fields since this trend is growing with an everyday changing novel pattern (Iravani et al. 2017; Dabbagh 2020). In this chapter, the cellular and molecular basis for the most related OMICS fields are discussed with a wealth of their anesthesia-related examples. Meanwhile, thanks to the dazzling improvements in cellular and molecular techniques from one side and artificial intelligence from the other side, a detailed list of single-cell multi-OMICS techniques are in the way which would exponentially augment these research fields with resulting clinical applications (Hu et al. 2018). There would be many paths in front which would be doors to novel fields in anesthesiology and perioperative medicine. A great paradigm shift seems to be on the way.
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Maternal exposure to the valproate short-chain fatty acid (SCFA) during pregnancy is known to possibly induce autism spectrum disorders (ASDs) in the offspring. By contrast, case studies have evidenced positive outcomes of this anticonvulsant drug in children with severe autism. Interestingly, the same paradoxical pattern applies to the IL-17a inflammatory cytokine involved in the immune system regulation. Such joint apparent contradictions can be overcome by pointing out that, among their respective signaling pathways, valproate and IL-17a share an enhancement of the “type A monoamine oxidase” (MAOA) enzyme carried by the X chromosome. In the Guided Propagation (GP) model of autism, such enzymatic rise triggers a prenatal epigenetic downregulation, which, without possible X-inactivation, and when coinciding with genetic expression variants of other brain enzymes, results in the delayed onset of autistic symptoms. The underlying imbalance of synaptic monoamines, serotonin in the first place, would reflect a mismatch between the environment to which the brain metabolism was prepared during gestation and the postnatal actual surroundings. Following a prenatal exposure to molecules that significantly elicit the MAOA gene expression, a daily treatment with the same metabolic impact would tend to recreate the fetal environment and contribute to rebalance monoamines, thus allowing proper neural circuits to gradually develop, provided behavioral re-education. Given the multifaceted other players than MAOA that are involved in the regulation of serotonin levels, potential compensatory effects are surveyed, which may underlie the autism heterogeneity. This explanatory framework opens up prospects regarding autism prevention and treatment, strikingly in line with current advances along the gut microbiome–brain axis.
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Evidence is emerging that paternal effects, the nongenetic influence of fathers on their offspring, can be transgenerational, spanning several generations. Methylphenidate hydrochloride (MPH; e.g. Ritalin) is a dopaminergic drug that is highly prescribed to adolescent males for the treatment of Attention-deficit/hyperactivity disorder. It has been suggested that MPH could cause transgenerational effects because MPH can affect the male germline in rodents and because paternal effects have been observed in individuals taking similar drugs (e.g. cocaine). Despite these concerns, the transgenerational effects of paternal MPH exposure are unknown. Therefore, we exposed male and female Trinidadian guppies (Poecilia reticulata) to a low, chronic dose of MPH and observed that MPH affected the anxiety/exploratory behaviour of males, but not females. Because of this male-specific effect, we investigated the transgenerational effects of MPH through the paternal line. We observed behavioural effects of paternal MPH exposure on offspring and great-grandoffspring that were not directly administered the drug, making this the first study to demonstrate that paternal MPH exposure can affect descendants. These effects were not due to differential mortality or fecundity between control and MPH lines. These results highlight the transgenerational potential of MPH.
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Adenosine kinase (ADK) is the key regulator of adenosine and catalyzes the metabolism of adenosine to 5'-adenosine monophosphate. The enzyme exists in two isoforms: a long isoform (ADK-long, ADK-L) and a short isoform (ADK-short, ADK-S). The two isoforms are developmentally regulated and are differentially expressed in distinct subcellular compartments with ADK-L localized in the nucleus and ADK-S localized in the cytoplasm. The nuclear localization of ADK-L and its biochemical link to the transmethylation pathway suggest a specific role for gene regulation via epigenetic mechanisms. Recent evidence reveals an adenosine receptor-independent role of ADK in determining the global methylation status of DNA and thereby contributing to epigenomic regulation. Here we summarize recent progress in understanding the biochemical interactions between adenosine metabolism by ADK-L and epigenetic modifications linked to transmethylation reactions. This review will provide a comprehensive overview of ADK-associated changes in DNA methylation in developmental, as well as in pathological conditions including brain injury, epilepsy, cancer, and diabetes. Challenges in investigating the epigenetic role of ADK for therapeutic gains are briefly discussed.
Chapter
The pharmacologically mediated mechanism is defined as the interaction of the drug with its intended target or relevant receptor, which can result in an anticipated biological effect or in a previously unanticipated adverse effect. An understanding of the pathomechanism of drug-induced neurologic disorders may be useful for treating these complications.
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Stroke, also known as cerebral stroke or cerebrovascular accident, refers to acute ischemic or hemorrhagic encephalopathy caused by a disturbance to cerebral blood flow. Ischemic stroke is the most common type of cerebral stroke, accounting for approximately 80% of the total incidence of clinical stroke. High morbidity, disability, and mortality rates place heavy burdens on the families of patients and society. An increasing number of studies have shown that histone modification plays an important role in the pathogenesis of ischemic stroke, but most studies on histone modification focus on acetylation, and studies on the role of histone methylation in the pathogenesis of ischemic stroke are limited. Here, we review the role of histone methylation and related histone methyltransferase (HMT) inhibitors in the pathogenesis of ischemic stroke and related HMT inhibitors in the treatment of ischemic stroke, which may open up a new avenue to the study of ischemic stroke.
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Epigenetic alterations such as DNA methylation have been associated with the etiology of inflammation-related diseases. The present study evaluated the association between the methylation levels of LPL , ADRB3 and MTHFR genes and the stage of inflammation in individuals with isolated or associated morbidities, as well as in individuals without morbidities. This is a cross-sectional population-based study, in which 261 adults, between 20 and 59 years, individuals of both sex were selected. Inflammatory parameters were evaluated in blood, and the evaluation of methylation levels in the promoter of LPL , ADRB3 and MTHFR genes was performed in peripheral blood leukocytes. For statistical treatment, normality analysis was performed using the Lilliefors test, multiple linear regression, in addition to odds ratio. For all tests, the significance level adopted was 5%. In individuals with isolated morbidities, a positive association was observed between CRP values (2.49mg/L±3.7) and LPL gene methylation levels (35%±18) (p=.003) and with associated morbidities, females had higher levels of LPL gene methylation (40% ± 20) (p = 0.041) and for MTHFR gene methylation levels (35% ± 18) a positive association was found with MDA values (3.02µmol/L± 0.8) (p=.032). In addition, the use of medications did not influence the level of methylation for any of the three genes analyzed. Among individuals with isolated or associated morbidities, there was an association between the methylation levels of the LPL gene with the CRP values and females, and furthermore with the MTHFR gene and MDA. This study could help to understand the etiology and treatment of different morbidities, enabling the discovery of new combats resources.
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Background: The rapid and major advances being made in epigenetics are impacting pharmacology, giving rise to new sub-disciplines in pharmacology, pharmacoepigenetics, the study of the epigenetic basis of variation in response to drugs; and pharmacoepigenomics, the application of pharmacoepigenetics on a genome-wide scale. Methods: This article highlights the following aspects of pharmacoepigenetics and pharmacoepigenomics: epigenetic therapy, the role of epigenetics in pharmacokinetics, the relevance of epigenetics to adverse drug reactions, personalized medicine, drug addiction, and drug resistance, and the use of epigenetic biomarkers in drug therapy. Results: Epigenetics is having an increasing impact on several areas of pharmacology. Conclusion: Pharmacoepigenetics and pharmacoepigenomics are new sub-disciplines in pharmacology and are likely to have an increasing impact on the use of drugs in clinical practice.
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OBJECTIVE: To analyze selective COX 2 inhibitor nonsteroidal anti-inflammatory drugs (NSAID) in terms of their mechanism of action, principal indications, posology and most common adverse effects. SOURCES: MEDLINE and LILACS databases and Food and Drug Administration (FDA) and National Agency for Sanitary Vigilance (ANVISA - Agência Nacional de Vigilância Sanitária) websites. The most important articles were selected and preference was given to articles published within the last 5 years. SUMMARY OF THE FINDINGS: The principal indications for NSAID are for control of pain and acute and chronic inflammation. There is no overwhelming evidence that demonstrates the superiority of one NSAID over another in terms of effectiveness. To date none of the COX 2 inhibitors has been liberated for use in the pediatric age group. Only meloxicam and etoricoxib can be prescribed for adolescents (13 and 16 years, respectively). Selective COX 2 inhibitors are indicated for patients with adverse effects that have proven to be associated with nonselective NSAID use. Selective COX 2 inhibitors can be prescribed in some cases of allergy to aspirin, but they must be used with care. Principal adverse effects include cardiovascular events and thrombotic phenomena. CONCLUSIONS: Selective COX 2 inhibitors are medicines that have been used in certain well-defined clinical situations and which may offer certain advantages over nonselective NSAID. Nevertheless, taking into consideration the higher cost involved and the potential for adverse cardiovascular effects, they should be employed only in accordance with strict criteria.
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SSRI therapy is commonly associated with sexual side effects, but it is assumed that these distressing symp-toms resolve with termination of therapy. The atypical antidepressant nefazodone is infrequently associated with sexual dysfunction and may be substituted for SSRI's when sexual symptoms are intolerable. Recently, scattered case reports of persistent sexual dysfunction and genital anesthesia persisting well after termination of SSRI antidepressant therapy have surfaced. In each case, the underlying depressive disorder was in remission. Case: A 32-year old women with major depression was treated with citalopram but switched to nefazodone after 4 weeks of therapy due to genital anesthesia and orgasmic dysfunction. These symptoms continued following institution of nefa-zodone therapy and have persisted for over a year since termination of antidepressant treatment. Her depression remains in full remission. Discussion: It is likely that persistent post-treatment genital anesthesia and other sexual side effects are underreported, and physicians should be aware of this bothersome phenomenon. Formal post-treatment surveillance for this condition is war-ranted. Pharmacogenomic research may ultimately allow physicians to predict who is at risk for antidepressant induced sexual side effects.
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Long-term administration of antipsychotic drugs can induce differential expression of a variety of genes in the brain, which may underscore the molecular mechanism of the clinical efficacy and/or side effects of antipsychotic drugs. We used cDNA microarray analysis to screen differentially expressed genes in rat frontal cortex under 4 weeks' treatment of risperidone (1 mg/kg). Using real-time quantitative PCR, we were able to verify eight genes, whose expression were significantly upregulated in rat frontal cortex under chronic risperidone treatment when compared with control animals. These genes include receptor for activated protein kinase C, amida, cathepsin D, calpain 2, calcium-independent receptor for alpha-latrotoxin, monoamine oxidase B, polyubiquitin, and kinesin light chain. In view of the physiological function of these genes, the results of our study suggest that chronic risperidone treatment may affect the neurotransmission, synaptic plasticity, and proteolysis of brain cells. This study also demonstrates that cDNA microarray analysis is useful for uncovering genes that are regulated by chronic antipsychotic drugs treatment, which may help bring new insight into the molecular mechanism of antipsychotic drugs.
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The current goal of diabetes therapy is to reduce time-averaged mean levels of glycemia, measured as HbA1c, to prevent diabetic complications. However, HbA1c only explains <25% of the variation in risk of developing complications. Because HbA1c does not correlate with glycemic variability when adjusted for mean blood glucose, we hypothesized that transient spikes of hyperglycemia may be an HbA1c-independent risk factor for diabetic complications. We show that transient hyperglycemia induces long-lasting activating epigenetic changes in the promoter of the nuclear factor kappaB (NF-kappaB) subunit p65 in aortic endothelial cells both in vitro and in nondiabetic mice, which cause increased p65 gene expression. Both the epigenetic changes and the gene expression changes persist for at least 6 d of subsequent normal glycemia, as do NF-kappaB-induced increases in monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 expression. Hyperglycemia-induced epigenetic changes and increased p65 expression are prevented by reducing mitochondrial superoxide production or superoxide-induced alpha-oxoaldehydes. These results highlight the dramatic and long-lasting effects that short-term hyperglycemic spikes can have on vascular cells and suggest that transient spikes of hyperglycemia may be an HbA1c-independent risk factor for diabetic complications.
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Genomic imprinting results in the expression of genes in a parent-of-origin-dependent manner. The mechanism and developmental consequences of genomic imprinting are most well characterized in mammals, plants, and certain insect species (e.g., sciarid flies and coccid insects). However, researchers have observed imprinting phenomena in species in which imprinting of endogenous genes is not known to exist or to be developmentally essential. In this review, I survey the known mechanisms of imprinting, focusing primarily on examples from mammals, where imprinting is relatively well characterized. Where appropriate, I draw attention to imprinting mechanisms in other organisms to compare and contrast how diverse organisms employ different strategies to perform the same process. I discuss how the various mechanisms come into play in the context of the imprint life cycle. Finally, I speculate why imprinting may be more widely prevalent than previously thought.
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The nervous system contains a multitude of cell types which are specified during development by cascades of transcription factors acting combinatorially. Some of these transcription factors are only active during development, whereas others continue to function in the mature nervous system to maintain appropriate gene-expression patterns in differentiated cells. Underpinning the function of the nervous system is its plasticity in response to external stimuli, and many transcription factors are involved in regulating gene expression in response to neuronal activity, allowing us to learn, remember and make complex decisions. Here we review some of the recent findings that have uncovered the molecular mechanisms that underpin the control of gene regulatory networks within the nervous system. We highlight some recent insights into the gene-regulatory circuits in the development and differentiation of cells within the nervous system and discuss some of the mechanisms by which synaptic transmission influences transcription-factor activity in the mature nervous system. Mutations in genes that are important in epigenetic regulation (by influencing DNA methylation and post-translational histone modifications) have long been associated with neuronal disorders in humans such as Rett syndrome, Huntington's disease and some forms of mental retardation, and recent work has focused on unravelling their mechanisms of action. Finally, the discovery of microRNAs has produced a paradigm shift in gene expression, and we provide some examples and discuss the contribution of microRNAs to maintaining dynamic gene regulatory networks in the brain.
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The National Cancer Institute is supporting a study of vaginal cancer and other noncancerous genital tract irregularities in offspring of mothers who received synthetic estrogens during pregnancy. The study, entitled the DESAD Project (DES and Adenosis), seeks to provide answers concerning the risk to exposed offspring born after 1940 of developing cancer or other medically important conditions, including vaginal adenosis and cervical abnormalities. Each of 4 participating institutions is identifying 500 or more subjects with documented in utero exposure. Exposed daughters of different ages are being examined and followed to determine incidence and natural history of vaginal adenosis and other irregularities.
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Genomic sequencing was used to study the in vivo methylation pattern of two CpG sites in the promoter region of the avian vitellogenin gene. The CpG at position +10 was fully methylated in DNA isolated from tissues that do not express the gene but was unmethylated in the liver of mature hens and estradiol-treated roosters. In the latter tissue, this site became demethylated and DNase I hypersensitive after estradiol treatment. A second CpG (position -52) was unmethylated in all tissues examined. In vivo genomic footprinting with dimethyl sulfate revealed different patterns of DNA protection in silent and expressed genes. In rooster liver cells, at least 10 base pairs of DNA, including the methylated CpG, were protected by protein(s). Gel-shift assays indicated that a protein factor, present in rooster liver nuclear extract, bound at this site only when it was methylated. In hen liver cells, the same unmethylated CpG lies within a protected region of approximately equal to 20 base pairs. In vitro DNase I protection and gel-shift assays indicate that this sequence is bound by a protein, which binds both double- and single-stranded DNA. For the latter substrate, this factor was shown to bind solely the noncoding (i.e., mRNA-like) strand.
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Most antibacterial agents do not affect human lymphocyte function, but a few are inhibitory. In contrast, a pronounced increase in the incorporation of [3H]thymidine in the presence of 4-quinolones was observed in these studies. The uptake of [3H]thymidine into DNA (trichloroacetic acid precipitable) was significantly increased in phytohemagglutinin-stimulated human lymphocytes when they were exposed to eight new 4-quinolone derivatives, ciprofloxacin, norfloxacin, ofloxacin, A-56619, A-56620, amifloxacin, enoxacin, and pefloxacin, at 1.6 to 6.25 micrograms/ml for 5 days. Four less antibacterially active 4-quinolones (nalidixic acid, cinoxacin, flumequine, and pipemidic acid) stimulated [3H]thymidine incorporation only at higher concentrations or not at all. Kinetic studies showed that incorporation of [3H]thymidine was not affected or slightly inhibited by ciprofloxacin 2 days after phytohemagglutinin stimulation but was increased on days 3 to 6. The total incorporation of [3H]thymidine from day 1 to day 6 after phytohemagglutinin stimulation was increased by 42 to 45% at 5 to 20 micrograms of ciprofloxacin per ml. Increased [3H]thymidine incorporation was also seen when human lymphocytes were stimulated with mitogens other than phytohemagglutinin. Ciprofloxacin added at the start of the culture had a more pronounced effect on [3H]thymidine incorporation than when added later. In spite of the apparent increase in DNA synthesis, lymphocyte growth was inhibited by 20 micrograms of ciprofloxacin per ml, and cell cycle analysis showed that ciprofloxacin inhibited progression through the cell cycle. In addition, immunoglobulin secretion by human lymphocytes stimulated by pokeweed mitogen for Epstein-Barr virus was inhibited by approximately 50% at 5 micrograms of ciprofloxacin per ml. These results suggest that the 4-quinolone drugs may also affect eucaryotic cell function in vitro, but additional studies are needed to establish an in vivo relevance.
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PURPOSE: The primary purpose of this study was to compare the neuropsychologic functioning of long-term survivors of breast cancer and lymphoma who had been treated with standard-dose systemic chemotherapy or local therapy only. PATIENTS AND METHODS: Long-term survivors (5 years postdiagnosis, not presently receiving cancer treatment, and disease-free) of breast cancer or lymphoma who had been treated with systemic chemotherapy (breast cancer: n = 35, age, 59.1 ± 10.7 years; lymphoma: n = 36, age, 55.9 ± 12.1 years) or local therapy only (breast cancer: n = 35, age, 60.6 ± 10.5 years; lymphoma: n = 22, age, 48.7 ± 11.7 years) completed a battery of neuropsychologic and psychologic tests (Center for Epidemiological Study–Depression, Spielberger State-Trait Anxiety Inventory, and Fatigue Symptom Inventory). RESULTS: Multivariate analysis of variance, controlling for age and education, revealed that survivors who had been treated with systemic chemotherapy scored significantly lower on the battery of neuropsychologic tests compared with those treated with local therapy only (P < .04), particularly in the domains of verbal memory (P < .01) and psychomotor functioning (P < .03). Survivors treated with systemic chemotherapy were also more likely to score in the lower quartile on the Neuropsychological Performance Index (39% v 14%, P < .01) and to self-report greater problems with working memory on the Squire Memory Self-Rating Questionnaire (P < .02). CONCLUSION: Data from this study support the hypothesis that systemic chemotherapy can have a negative impact on cognitive functioning as measured by standardized neuropsychologic tests and self-report of memory changes. However, analysis of the Neuropsychological Performance Index suggests that only a subgroup of survivors may experience long-term cognitive deficits associated with systemic chemotherapy.
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This article was undertaken to review the history of professional awareness of tardive dyskinesia (TD) and to address reasons for the delay in such recognition. The literature was reviewed, and selections are included to highlight some of the major issues. Personal recollections are deliberately emphasized since they may reflect the phenomenon of personal discovery familiar to others and the now widespread professional awareness of TD. TD is indeed well recognized by psychiatrists and neurologists, and most general practitioners are also aware that the syndrome exists. Physicians were once unfamiliar with the concept of a drug reaction that was so long delayed as is possible with TD, nor did they know that a drug side effect could present in this manner. The historical delay in initial recognition of TD, and the reason for such delay, remain of interest. The lack of a perfect therapy and the uncertainty regarding the precise pathophysiologic basis of TD remain as challenges. Most psychiatrists, and many neurologists, probably have vivid memories of specific patients with TD. This author, a neurologist, was blessed to work with George Crane and other investigators in the early days of TD and was witness to some of the original uncertainty regarding what seemed to be a new phenomenon. TD has reshaped our concepts of disease and our awareness that diseases can originate from deleterious late effects of beneficial agents.
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Hyperhomocysteinemia, a risk factor for cardiovascular disease, is caused by nutritional and/or genetic disruptions in homocysteine metabolism. The most common genetic cause of hyperhomocysteinemia is the 677C→T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene. This variant, with mild enzymatic deficiency, is associated with an increased risk for neural tube defects and pregnancy complications and with a decreased risk for colon cancer and leukemia. Although many studies have reported that this variant is also a risk factor for vascular disease, this area of investigation is still controversial. Severe MTHFR deficiency results in homocystinuria, an inborn error of metabolism with neurological and vascular complications. To investigate the in vivo pathogenetic mechanisms of MTHFR deficiency, we generated mice with a knockout of Mthfr. Plasma total homocysteine levels in heterozygous and homozygous knockout mice are 1.6- and 10-fold higher than those in wild-type littermates, respectively. Both heterozygous and homozygous knockouts have either significantly decreased S-adenosylmethionine levels or significantly increased S-adenosylhomocysteine levels, or both, with global DNA hypomethylation. The heterozygous knockout mice appear normal, whereas the homozygotes are smaller and show developmental retardation with cerebellar pathology. Abnormal lipid deposition in the proximal portion of the aorta was observed in older heterozygotes and homozygotes, alluding to an atherogenic effect of hyperhomocysteinemia in these mice.
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Administration of methylphenidate (MPH, Ritalin®) to children with attention deficit hyperactivity disorder (ADHD) is an elective therapy, but raises concerns for public health, due to possible persistent neurobehavioral alterations. Wistar adolescent rats (30 to 46 day old) were administered MPH or saline (SAL) for 16 days, and tested for reward-related and motivational-choice behaviors. When tested in adulthood in a drug-free state, MPH-pretreated animals showed increased choice flexibility and economical efficiency, as well as a dissociation between dampened place conditioning and more marked locomotor sensitization induced by cocaine, compared to SAL-pretreated controls. The striatal complex, a core component of the natural reward system, was collected both at the end of the MPH treatment and in adulthood. Genome-wide expression profiling, followed by RT-PCR validation on independent samples, showed that three members of the postsynaptic-density family and five neurotransmitter receptors were upregulated in the adolescent striatum after subchronic MPH administration. Interestingly, only genes for the kainate 2 subunit of ionotropic glutamate receptor (Grik2, also known as KA2) and the 5-hydroxytryptamine (serotonin) receptor 7 (Htr7) (but not GABAA subunits and adrenergic receptor α1b) were still upregulated in adulthood. cAMP responsive element-binding protein and Homer 1a transcripts were modulated only as a long-term effect. In summary, our data indicate short-term changes in neural plasticity, suggested by modulation of expression of key genes, and functional changes in striatal circuits. These modifications might in turn trigger enduring changes responsible for the adult neurobehavioral profile, that is, altered processing of incentive values and a modified flexibility/habit balance.
A retrospective analysis is presented of a clinician's 10-year experience using isotretinoin as a treatment for severe nodulocystic acne and the spectrum of side effects experienced by patients on a 20 week course of 1 mg/kg/day of the drug.
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Drug addiction involves potentially life-long behavioral abnormalities that are caused in vulnerable individuals by repeated exposure to a drug of abuse. The persistence of these behavioral changes suggests that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. Work over the past decade has demonstrated a crucial role for epigenetic mechanisms in driving lasting changes in gene expression in diverse tissues, including brain. This has prompted recent research aimed at characterizing the influence of epigenetic regulatory events in mediating the lasting effects of drugs of abuse on the brain in animal models of drug addiction. This review provides a progress report of this still early work in the field. As will be seen, there is robust evidence that repeated exposure to drugs of abuse induces changes within the brain's reward regions in three major modes of epigenetic regulation-histone modifications such as acetylation and methylation, DNA methylation, and non-coding RNAs. In several instances, it has been possible to demonstrate directly the contribution of such epigenetic changes to addiction-related behavioral abnormalities. Studies of epigenetic mechanisms of addiction are also providing an unprecedented view of the range of genes and non-genic regions that are affected by repeated drug exposure and the precise molecular basis of that regulation. Work is now needed to validate key aspects of this work in human addiction and evaluate the possibility of mining this information to develop new diagnostic tests and more effective treatments for addiction syndromes.
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Genomic imprinting results in the deliberate silencing of alleles, dictated by their parental origin, but reversible on passage through the germ line. In this chapter, we shall consider the functional properties of imprinted genes, why these genes might have been singled out for the risky strategy of mono-allelic expression, and how imprinting is regulated. We shall look at how imprinted genes affect processes throughout our lifetimes, from the way we grow in the womb to the control of metabolism as adults. In contrast to the depth of our knowledge of the contributions of imprinted genes to growth of the fetus, our understanding of their roles in adult physiology is still rather poor. We shall look at those imprinted genes that have been implicated in diabetes and those which are known to help determine �-cell mass. It is likely that the effects of imprinted genes on these processes are more pervasive than currently recognised. The intention of this chapter is therefore to equip the readers with the general principles governing imprinting, so that they are able to comprehend this intriguing and important form of gene regulation when they encounter it next.
Article
Introduction: Approximately one out of four sexually active women in the United States uses some form of hormonal contraceptive method because they provide the most effective reversible method of birth control available. However, little attention has been paid to possible adverse effects of combined oral contraceptives (COCs) on sexual functioning. Aim: The aim of this study was to examine the potential effects of COCs on women with hypoactive sexual desire disorder (HSDD). It was hypothesized that female patients with generalized, acquired HSDD on COCs have lower androgen levels than those not on COCs. Methods: The patients were healthy premenopausal women with HSDD, aged 22-50 years. Subjects had a history of adequate sexual desire, interest, and functioning. Participants were required to be in a stable, monogamous, heterosexual relationship and were screened for any medication or medical or psychiatric disorders that impact desire. The patients met operational criteria for global, acquired HSDD. The 106 patients were divided into two groups: those on COCs (N = 43) and those not on COCs (N = 63). A two-tailed t-test comparison was made between the two groups comparing free and total testosterone and sex hormone-binding globulin (SHBG). Main outcome measures: The main outcome measures are the differences between the two groups comparing free testosterone, total testosterone, and SHBG. Results: These patients with HSDD on COCs had significantly lower free and total testosterone levels compared with those who were not on COCs. The SHBG was significantly higher in the group on COCs compared with those who were not on COCs. Conclusion: The result of this study suggests that COCs in premenopausal women with HSDD are associated with lower androgen levels than those not on COCs. Further research is required to determine if low androgen levels secondary to COCs impact female sexual desire.
Article
Introduction: Oral contraceptives (OCs) have been the preferred method of birth control because of their high rate of effectiveness. OC use, however, has been associated with women's sexual health complaints and androgen insufficiency. OC use is associated with a decrease of androgen ovarian synthesis and an increase in the production of sex hormone-binding globulin (SHBG). There have been limited studies assessing SHBG values after discontinuation of OC use. Aim: To retrospectively investigate SHBG levels before and after discontinuation of OC use. Main outcome measure: Sex hormone-binding globulin values were compared at baseline, while on the OC, and well beyond the 7-day half-life of SHBG at 49-120 (mean 80) days and >120 (mean 196) days after discontinuation of OCs. Methods: A total of 124 premenopausal women with sexual health complaints for >6 months met inclusion/exclusion criteria. Three groups of women were defined: (i) "Continued-Users" (N = 62; mean age 32 years) had been on OCs for >6 months and continued taking them; (ii) "Discontinued-Users" (N = 39; mean age 33 years) had been on OCs for >6 months and discontinued them; and (iii) "Never-Users" (N = 23; mean age 36 years) had never taken OCs. Results: Sex hormone-binding globulin values in the "Continued-Users" were four times higher than those in the "Never-User" group (mean 157 +/- 13 nmol/L vs. 41 +/- 4 nmol/L; P < 0.0001). Despite a decrease in SHBG values after discontinuation of OC use, SHBG levels in "Discontinued-Users" remained elevated in comparison with "Never-Users" (N = 26; P < 0.0001 for >120 days). Conclusion: In women with sexual dysfunction, SHBG changes in "Discontinued-Users" did not decrease to values consistent with "Never-Users." Long-term sexual, metabolic, and mental health consequences might result as a consequence of chronic SHBG elevation. Does prolonged exposure to the synthetic estrogens of OCs induce gene imprinting and increased gene expression of SHBG in the liver in some women? Prospective research is needed.
Chapter
DNA methylation is a post-replicative, or epigenetic, modification of the genome that is critical for proper mammalian embryonic development, gene silencing, X chromosome inactivation, and imprinting. Genome-wide DNA methylation patterns are nonrandomly distributed and undergo significant remodeling events during embryogenesis. DNA methylation patterns are also frequently ‘remodeled’ in tumor cells in a way that directly contributes to tumor suppressor gene inactivation and genomic instability. The mechanisms for the establishment and maintenance of genomic DNA methylation patterns during development and in somatic cells remains a very important and unanswered question in the DNA methylation field. Emerging evidence suggests that protein-protein interactions between components of the DNA methylation machinery (the DNA methyltransferases) and aspects of chromatin structure such as histone tail modifications and chromatin remodeling, directly determine which regions of the genome are to be methylated. By studying these mechanisms in detail we should be able gain insights into how DNA methylation patterns become disrupted in tumor cells and how these defects may be corrected.
Article
Inhaled anesthetics bind specifically to many proteins in the mammalian brain. Within the subgroup of proteins whose activity is substantially modulated by anesthetic binding, it is reasonable to expect anesthetic-induced alterations in host expression level. Thus, in an attempt to define the group of functional targets for these commonly used drugs, we examined changes in protein expression after anesthetic exposure in both intact rodent brains and in neuronal cell culture. Differential in-gel electrophoresis was used to minimize variance, in order to detect small changes. Quantitative analysis shows that 5 h exposures to 1 minimum alveolar concentration (1 MAC) halothane caused changes in the expression of approximately 2% of detectable proteins, but only at 2-24 h after awakening, and only in the cortex. An equipotent concentration of isoflurane altered the expression of only approximately 1% of detectable proteins, and only in the hippocampus. Primary cortical neurons were exposed to three-fold higher concentrations of anesthetics with no evidence of cytotoxicity. Small changes in protein expression were elicited by both drugs. Despite the fact that anesthetics produce profound changes in neurobiology and behavior, we found only minor changes in brain protein expression. A pronounced degree of regional selectivity was noted, indicating an under appreciated degree of specificity for these promiscuous drugs.
Article
The authors hypothesized that inhalational anesthetics induced cell damage by causing abnormal calcium release from the endoplasmic reticulum via excessive activation of inositol 1,4,5-trisphosphate (IP3) receptors, with isoflurane having greater potency than sevoflurane or desflurane. The authors treated DT40 chicken B lymphocytes with total IP3 receptor knockout or their corresponding wild-type control cells with equipotent exposure to isoflurane, sevoflurane, and desflurane. The authors then determined the degree of cell damage by counting the percentage of annexin V- or propidium iodide-positively stained cells or measuring caspase-3 activity. They also studied the changes of calcium concentrations in the endoplasmic reticulum, cytosol, and mitochondria evoked by equipotent concentrations of isoflurane, sevoflurane, and desflurane in both types of DT40 cells. Prolonged use of 2 minimal alveolar concentration sevoflurane or desflurane (24 h) induced significant cell damage only in DT40 wild-type and not in IP3 receptor total knockout cells, but with significantly less potency than isoflurane. In accord, all three inhalational anesthetics induced significant decrease of calcium concentrations in the endoplasmic reticulum, accompanied by a subsequent significant increase in the cytosol and mitochondrial calcium concentrations only in DT40 wild-type and not in IP3 receptor total knockout cells. Isoflurane treatment showed significantly greater potency of effect than sevoflurane or desflurane. Inhalational anesthetics may induce cell damage by causing abnormal calcium release from the endoplasmic reticulum via excessive activation of IP3 receptors. Isoflurane has greater potency than sevoflurane or desflurane to cause calcium release from the endoplasmic reticulum and to induce cell damage.
Article
A spate of high-powered genome-wide association studies (GWAS) have recently identified numerous single-nucleotide polymorphisms (SNPs) robustly linked with complex disease. Despite interrogating the majority of common human variation, these SNPs only account for a small proportion of the phenotypic variance, which suggests genetic factors are acting in concert with non-genetic factors. Although environmental measures are logical covariants for genotype-phenotype investigations, another non-genetic intermediary exists: epigenetics. Epigenetics is the analysis of somatically-acquired and, in some cases, transgenerationally inherited epigenetic modifications that regulate gene expression, and offers to bridge the gap between genetics and environment to understand phenotype. The most widely studied epigenetic mark is DNA methylation. Aberrant methylation at gene promoters is strongly implicated in disease etiology, most notably cancer. This review will highlight the importance of DNA methylation as an epigenetic regulator, outline techniques to characterize the DNA methylome and present the idea of reverse phenotyping, where multiple layers of analysis are integrated at the individual level to create personalized digital phenotypes and, at a phenotype level, to identify novel molecular signatures of disease.
Article
Somatic cell nuclear transfer (SCNT, 'cloning') holds great potential for agricultural applications, generation of medical model animals, transgenic farm animals or by 'therapeutic cloning' for generating human embryonic stem cells for the treatment of human diseases. However, the low survival rate of SCNT-derived pregnancies represents a serious limitation of the current technology. In order to overcome this hurdle, a deeper understanding of the epigenetic reprogramming of the somatic cell nuclei and its effect on the pregnancy is needed. Here we review the literature on nuclear reprogramming by SCNT, including studies of gene expression, DNA methylation, chromatin remodelling, genomic imprinting and X chromosome inactivation. Reprogramming of genes expressed in the inner cell mass, from which the body of the foetus is formed, seems to be highly efficient. Defects in the extra-embryonic tissues are probably the major cause of the low success rate of reproductive cloning. Methods to partially overcome such problems exist, yet more future research is needed to find practical and efficient methods to remedy this problem. Improvement of the survival of foetuses is a central issue for the future of agricultural SCNT not only for its economic viability, but also because in lack of improvements in animal welfare current regulations can block the use of the method in the EU and several other countries.
Article
Changes in gene expression in brain reward regions are thought to contribute to the pathogenesis and persistence of drug addiction. Recent studies have begun to focus on the molecular mechanisms by which drugs of abuse and related environmental stimuli, such as drug-associated cues or stress, converge on the genome to alter specific gene programs. Increasing evidence suggests that these stable gene expression changes in neurons are mediated in part by epigenetic mechanisms that alter chromatin structure on specific gene promoters. This review discusses recent findings from behavioral, molecular and bioinformatic approaches being used to understand the complex epigenetic regulation of gene expression by drugs of abuse. This novel mechanistic insight might open new avenues for improved treatments of drug addiction.
Article
Most human diseases are related in some way to the loss or gain in gene functions. Regulation of gene expression is a complex process. In addition to genetic mechanisms, epigenetic causes are gaining new perspectives in human diseases related to gene deregulation. Most eukaryotic genes are packed into chromatin structures, which lead to high condensations of the genes that require dynamic chromatin remodeling processes to facilitate their transcription. DNA methylation and histone modifications represent two of the major chromatin remodeling processes. They also serve to integrate environmental signals for the cells to modulate the functional output of their genome. Complex human diseases such as cancer and type 2 diabetes are believed to have a strong environmental component in addition to genetic causes. Aberrancies in chromatin remodeling are associated with both genetically and environmentally-related diseases. We will focus on recent findings of the epigenetic basis of human metabolic disorders to facilitate further exploration of epigenetic mechanisms and better understandings of the molecular cues underlying such complex diseases.
Article
Addiction is a still an acute problem of nowadays. Drug addiction does not develop within the first taste of the drug and does not progress in each individual, who abuse drugs. Several factors play a role in this process, such as: factor of environment, stress and also genetic dispositions. This review summarizes all available findings about: what is addiction; how it develops; what brain structures and neurotransmitter systems play a role in it and what are the possibilities of its treatment in nowadays.
Article
The aim of this study was to analyze epigenetic (specifically, DNA methylation) participation in the mechanisms of cleft palate only induced by maternal exposure to all-trans retinoic acid in mice. Cleft palate only was induced in fetuses by maternal exposure to all-trans retinoic acid. Their secondary palates were excised for analysis. Cytosine extension assay and restriction landmark genomic scanning were performed to analyze DNA methylation status. The expression levels of the DNA methyltransferases were examined by real-time reverse transcriptase-polymerase chain reaction. Using cytosine extension assay, on gestation day 14.5, the status of DNA methylation within CpG islands and in global DNA was decreased significantly in all-trans retinoic acid-treated groups compared with the controls (p < .01 and p < .05). In the controls, the status within CpG islands on gestation day 14.5 was significantly increased compared with gestation days 13.5 and 18.5 (p < .01). Using real-time reverse transcriptase-polymerase chain reaction, there was no significant change in the expression of DNA methyltransferases, except on gestation day 18.5. Using restriction landmark genomic scanning on gestation day 18.5, five spots (0.49%) in the controls and one spot (0.1%) in all-trans retinoic acid-treated groups were specifically detected. These results indicate that changes in DNA methylation may play an important role in the manifestation of cleft palate only caused by environmental factors such as maternal exposure to all-trans retinoic acid.
Article
Embryonic stem (ES) cells are unique as they have the potential to be generated in large numbers and the ability to differentiate into the three germ layers via embryoid body (EB) formation. This property could be utilized as an index to study initial mammalian development. We have investigated the utility of a comprehensively characterized human ES (hES) cell line (ReliCellhES1) for testing the embryotoxic effects of compounds using cytotoxicity assays. Further, we performed real time gene expression analysis to check the alterations in germ layer markers expression upon drug treatment. The results show that assays using hES cells could serve as a reliable, sensitive and robust method to assess embryotoxic potential of compounds. They also provide a proof of concept that hES cells can be used as an in vitro model to demonstrate developmental toxicity, and to examine the germ layer-specific effects on differentiating EBs.
Article
While no single trigger can be identified as the leading cause of autoimmunity, an interplay of factors, including genetic susceptibility, infection and chemical exposure, are thought to play a role. Lupus can be caused by a wide array of medications taken for a variety of reasons in genetically predisposed individuals. Despite significant therapeutic progress, the precise mechanisms that lead to loss of lymphocyte tolerance to self-antigens in lupus remain under scrutiny. Mounting evidence supports the view that epigenetic alterations contribute to the emergence of pathogenic autoreactivity. In parallel, current research aims at understanding how different classes of biomolecules interact in response to exposure to drugs that induce lupus. Toxicogenomic evaluations could provide early indicators of potential safety assessment issues, and could permit the identification of diagnostic genetic and/or epigenetic expression patterns.
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Statins are widely used to treat hypercholesterolemia, a known risk factor for atherosclerosis. These drugs can lead to a number of side effects in muscle, including rhabdomyolysis; however, the mechanism of muscle injury is poorly defined. We review the clinical characteristics of this diverse syndrome, as well as the biochemical mechanisms that might provide an explanation for the toxicity of these agents. New findings implicating atrogin-1, a gene required for muscle atrophy, in the pathophysiology of statin-induced muscle injury are discussed, as well as implications of these novel discoveries.