Embryonic Caffeine Exposure Acts via A1 Adenosine Receptors to Alter Adult Cardiac Function and DNA Methylation in Mice

Buscariollo, Daniela L.; Fang, Xiefan; Greenwood, Victoria; Xue, Huiling; Rivkees, Scott A.; Wendler, Christopher C.

doi:10.1371/journal.pone.0087547

Cited by 51 publications

(41 citation statements)

References 56 publications

(72 reference statements)

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“…An accompanying editorial expressed concern that 'We must now heed the wake-up call sounded by Silva et al (2013) that exposure to psychoactive substances, even a seemingly innocuous, socially well-integrated substance like caffeine, before or soon after birth can alter brain development' (Kabir et al, 2013). Another team has suggested that embryonic caffeine exposure produces an increase in body weight (B10%), alters cardiac function and morphology, and produces long-lasting alterations in DNA methylation (Buscariollo et al, 2014). A third group has focused on the neuroendocrine consequences and found that prenatal caffeine ingestion induces an increased susceptibility to metabolic syndrome with alterations of glucose and lipid metabolic phenotypes that then propagate transgenerationally (Katayama et al, 1987;Xu et al, 2012a;Xu et al, 2012b).…”

Section: Caffeinementioning

confidence: 99%

Developmental Consequences of Fetal Exposure to Drugs: What We Know and What We Still Must Learn

Ross

Graham

Money

et al. 2014

Neuropsychopharmacol

340

241

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Most drugs of abuse easily cross the placenta and can affect fetal brain development. In utero exposures to drugs thus can have long-lasting implications for brain structure and function. These effects on the developing nervous system, before homeostatic regulatory mechanisms are properly calibrated, often differ from their effects on mature systems. In this review, we describe current knowledge on how alcohol, nicotine, cocaine, amphetamine, Ecstasy, and opiates (among other drugs) produce alterations in neurodevelopmental trajectory. We focus both on animal models and available clinical and imaging data from cross-sectional and longitudinal human studies. Early studies of fetal exposures focused on classic teratological methods that are insufficient for revealing more subtle effects that are nevertheless very behaviorally relevant. Modern mechanistic approaches have informed us greatly as to how to potentially ameliorate the induced deficits in brain formation and function, but conclude that better delineation of sensitive periods, dose-response relationships, and long-term longitudinal studies assessing future risk of offspring to exhibit learning disabilities, mental health disorders, and limited neural adaptations are crucial to limit the societal impact of these exposures.

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Section: Caffeinementioning

confidence: 99%

Developmental Consequences of Fetal Exposure to Drugs: What We Know and What We Still Must Learn

Ross

Graham

Money

et al. 2014

Neuropsychopharmacol

340

241

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“…Epigenetic changes not only affect the exposed embryo, but may also affect subsequent generations and contribute to the development of disease, as shown by endocrine disruptors vinclozolin and bisphenol A 14, 15 . Research in our laboratory has demonstrated that in utero caffeine exposure disrupts adenosine action and leads to long-term adverse effects on cardiac function 16–18 . Furthermore, depending on the timing of exposure, caffeine has transgenerational effects on cardiac function 16 .…”

Section: Fetal Programming Of Adult Diseasementioning

confidence: 99%

“…Research in our laboratory has demonstrated that in utero caffeine exposure disrupts adenosine action and leads to long-term adverse effects on cardiac function 16–18 . Furthermore, depending on the timing of exposure, caffeine has transgenerational effects on cardiac function 16 .…”

Section: Fetal Programming Of Adult Diseasementioning

confidence: 99%

Long-term consequences of disrupting adenosine signaling during embryonic development

Rivkees

Wendler

2017

Molecular Aspects of Medicine

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There is growing evidence that disruption in the prenatal environment can have long-lasting effects on an individual’s health in adulthood. Research on the fetal programming of adult diseases, including cardiovascular disease, focuses on epi-mutations, which alter the normal pattern of epigenetic factors such as DNA methylation, miRNA expression, or chromatin modification, rather than traditional genetic alteration. Thus, understanding how in utero chemical exposures alter epigenetics and lead to adult disease is of considerable public health concern. Few signaling molecules have the potential to influence the developing mammal as the nucleoside adenosine. Adenosine levels increase rapidly with tissue hypoxia and inflammation. Adenosine antagonists including the methlyxanthines caffeine and theophylline are widely consumed during pregnancy. The receptors that transduce adenosine action are the A1, A2a, A2b, and A3 adenosine receptors (ARs). We examined the long-term effects of in utero disruption of adenosine signaling on cardiac gene expression, morphology, and function in adult offspring. One substance that fetuses are frequently exposed to is caffeine, which is a non-selective adenosine receptor antagonist. Over the past several years, we examined the role of adenosine signaling during embryogenesis and cardiac development. We discovered that in utero alteration in adenosine action leads to adverse effects on embryonic and adult murine hearts. We find that cardiac A1ARs protect the embryo from in utero hypoxic stress, a condition that causes an increase in adenosine levels. After birth in mice, we observed that in utero caffeine exposure leads to abnormal cardiac function and morphology in adults, including an impaired response to β-adrenergic stimulation. Recently, we observed that in utero caffeine exposure induces transgenerational effects on cardiac morphology, function, and gene expression. Our findings indicate that the effects of altered adenosine signaling are dependent on signaling through the A1ARs and timing of disruption. In addition, the long-term effects of altered adenosine signaling appear to be mediated by alterations in DNA methylation, an epigenetic process critical for normal development.

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“…Genomic DNA was isolated with the DNeasy Blood & Tissue Kit (Qiagen) and treated with RNase to remove RNA contaminants. The MethylFlash Methylated DNA Quantification Kit (Colorimetric; Epigentek, Farmingdale, NY) and MethylFlash Hydroxymethylated DNA Quantification Kit (Colorimetric; Epigentek) were used to quantitate the percentage of 5mC and 5hmC in genomic DNA samples, respectively (4,16). After colorimetric reaction, the methylated cytosine was measured with a Synergy HT Multi-Mode Microplate Reader (BioTek, Winooski, VT).…”

Section: Materials Nmentioning

confidence: 99%

cAMP induces hypertrophy and alters DNA methylation in HL-1 cardiomyocytes

Fang

Robinson

Wang-Hu

et al. 2015

American Journal of Physiology-Cell Physiology

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-cAMP is a highly regulated secondary messenger involved in many biological processes. Chronic activation of the cAMP pathway by catecholamines results in cardiac hypertrophy and fibrosis; however, the mechanism by which elevated cAMP leads to cardiomyopathy is not fully understood. To address this issue, we increased intracellular cAMP levels in HL-1 cardiomyocytes, a cell line derived from adult mouse atrium, using either the stable cAMP analog N 6 ,2=-O-dibutyryladenosine 3=,5=-cyclic monophosphate (DBcAMP) or phosphodiesterase (PDE) inhibitors caffeine and theophylline. Elevated cAMP levels increased cell size and altered expression levels of cardiac genes and micro-RNAs associated with hypertrophic cardiomyopathy (HCM), including Myh6, Myh7, Myh7b, Tnni3, Anp, Bnp, Gata4, Mef2c, Mef2d, Nfatc1, miR208a, and miR208b. In addition, DBcAMP altered the expression of DNA methyltransferases (Dnmts) and Tet methylcytosine dioxygenases (Tets), enzymes that regulate genomic DNA methylation levels. Changes in expression of DNA methylation genes induced by elevated cAMP led to increased global DNA methylation in HL-1 cells. In contrast, inhibition of DNMT activity with 5-azacytidine treatment decreased global DNA methylation levels and blocked the increased expression of several HCM genes (Myh7, Gata4, Mef2c, Nfatc1, Myh7b, Tnni3, and Bnp) observed with DBcAMP treatment. These results demonstrate that cAMP induces cardiomyocyte hypertrophy and altered HCM gene expression in vitro and that DNA methylation patterns mediate the upregulation of HCM genes induced by cAMP. These data identify a previously unknown mechanism by which elevated levels of cAMP lead to increased expression of genes associated with cardiomyocyte hypertrophy.

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Embryonic Caffeine Exposure Acts via A1 Adenosine Receptors to Alter Adult Cardiac Function and DNA Methylation in Mice

Cited by 51 publications

References 56 publications

Developmental Consequences of Fetal Exposure to Drugs: What We Know and What We Still Must Learn

Developmental Consequences of Fetal Exposure to Drugs: What We Know and What We Still Must Learn

Long-term consequences of disrupting adenosine signaling during embryonic development

cAMP induces hypertrophy and alters DNA methylation in HL-1 cardiomyocytes

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