Embryonic caffeine exposure acts via A1 adenosine receptors to alter adult cardiac function and DNA methylation in mice.
Embryonic caffeine exposure acts via A1 adenosine receptors to alter adult cardiac function and DNA methylation in mice.
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DOI：
10.1371/journal.pone.0087547
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Wendler CC
中科院分区：
文献类型：
--
作者：
Buscariollo DL;Fang X;Greenwood V;Xue H;Rivkees SA;Wendler CC
有证据表明，正常的产前发育中断会影响一个人成年后患肥胖症和心血管疾病的风险。因此，了解子宫内暴露于化学制剂如何导致对成人疾病的易感性增加是一个关键的健康相关问题。我们的目的是确定腺苷A1受体（A1 ARs）是否介导子宫内咖啡因暴露对心脏功能的长期影响，以及这些长期影响是否是成年心脏DNA甲基化模式变化的结果。在胚胎第8.5天，用咖啡因（20 mg/kg）或溶媒（0.09% NaCl）腹膜内处理妊娠A1 AR敲除小鼠。这种咖啡因治疗导致血清水平相当于人类消耗2-4杯咖啡。母鼠分娩后，在8-10周龄时检查后代。在子宫内用咖啡因处理的A1 AR +/+后代比载体对照重10%。利用超声心动图，我们观察到在子宫内暴露于咖啡因的成年小鼠心脏功能和形态的改变。咖啡因治疗使心输出量减少11%，左室壁厚度增加29%。使用DNA甲基化阵列，我们确定了A1 AR +/+咖啡因治疗心脏中改变的DNA甲基化模式，包括基因组内7719个差异甲基化区域（DMR）和26%的DNA甲基化总体下降。与DMR相关的基因分析显示，许多与心脏肥大相关。这些数据表明，A1 ARs介导子宫内咖啡因对心脏功能和生长的影响，咖啡因暴露导致DNA甲基化的变化。
Evidence indicates that disruption of normal prenatal development influences an individual's risk of developing obesity and cardiovascular disease as an adult. Thus, understanding how in utero exposure to chemical agents leads to increased susceptibility to adult diseases is a critical health related issue. Our aim was to determine whether adenosine A1 receptors (A1ARs) mediate the long-term effects of in utero caffeine exposure on cardiac function and whether these long-term effects are the result of changes in DNA methylation patterns in adult hearts. Pregnant A1AR knockout mice were treated with caffeine (20 mg/kg) or vehicle (0.09% NaCl) i.p. at embryonic day 8.5. This caffeine treatment results in serum levels equivalent to the consumption of 2–4 cups of coffee in humans. After dams gave birth, offspring were examined at 8–10 weeks of age. A1AR+/+ offspring treated in utero with caffeine were 10% heavier than vehicle controls. Using echocardiography, we observed altered cardiac function and morphology in adult mice exposed to caffeine in utero. Caffeine treatment decreased cardiac output by 11% and increased left ventricular wall thickness by 29% during diastole. Using DNA methylation arrays, we identified altered DNA methylation patterns in A1AR+/+ caffeine treated hearts, including 7719 differentially methylated regions (DMRs) within the genome and an overall decrease in DNA methylation of 26%. Analysis of genes associated with DMRs revealed that many are associated with cardiac hypertrophy. These data demonstrate that A1ARs mediate in utero caffeine effects on cardiac function and growth and that caffeine exposure leads to changes in DNA methylation.
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影响因子：
29
作者：
Barres, Romain;Yan, Jie;Zierath, Juleen R.
通讯作者：
Zierath, Juleen R.
DOI：
10.1073/pnas.161292398
发表时间：
2001-07-31
影响因子：
11.1
作者：
Johansson, B;Halldner, L;Fredholm, BB
通讯作者：
Fredholm, BB
影响因子：
20.1
作者：
IMAMURA, S;KIMURA, M;MATSUOKA, R
通讯作者：
MATSUOKA, R
影响因子：
4.3
作者：
Fang X;Thornton C;Scheffler BE;Willett KL
通讯作者：
Willett KL
影响因子：
4.8
作者：
Cline, GW;Vidal-Puig, AJ;Shulman, GI
通讯作者：
Shulman, GI