Rivkees Scott A, Wendler Christopher C
Child Health Research Institute, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Child Health Research Institute, Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
Mol Aspects Med. 2017 Jun;55:110-117. doi: 10.1016/j.mam.2017.02.001. Epub 2017 Feb 13.
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.
越来越多的证据表明，产前环境的干扰会对个体成年后的健康产生长期影响。对包括心血管疾病在内的成人疾病的胎儿编程研究，聚焦于表观突变，这种突变会改变诸如DNA甲基化、miRNA表达或染色质修饰等表观遗传因子的正常模式，而非传统的基因改变。因此，了解子宫内化学物质暴露如何改变表观遗传学并导致成人疾病，是一个相当受公众关注的健康问题。很少有信号分子像核苷腺苷那样有潜力影响发育中的哺乳动物。腺苷水平会随着组织缺氧和炎症而迅速升高。包括甲基黄嘌呤咖啡因和茶碱在内的腺苷拮抗剂在孕期被广泛使用。转导腺苷作用的受体是A1、A2a、A2b和A3腺苷受体（ARs）。我们研究了子宫内腺苷信号传导中断对成年后代心脏基因表达、形态和功能的长期影响。胎儿经常接触的一种物质是咖啡因，它是一种非选择性腺苷受体拮抗剂。在过去几年里，我们研究了腺苷信号传导在胚胎发生和心脏发育过程中的作用。我们发现子宫内腺苷作用的改变会对胚胎和成年小鼠心脏产生不利影响。我们发现心脏A1ARs可保护胚胎免受子宫内缺氧应激的影响，这种情况会导致腺苷水平升高。在小鼠出生后，我们观察到子宫内咖啡因暴露会导致成年小鼠心脏功能和形态异常，包括对β-肾上腺素能刺激的反应受损。最近，我们观察到子宫内咖啡因暴露会对心脏形态、功能和基因表达产生跨代影响。我们的研究结果表明，腺苷信号改变的影响取决于通过A1ARs的信号传导以及中断的时间。此外，腺苷信号改变的长期影响似乎是由DNA甲基化的改变介导的，DNA甲基化是正常发育所必需的一种表观遗传过程。
