Neonatal dexamethasone treatment leads to alterations in cell signaling cascades controlling hepatic and cardiac function in adulthood
Neonatal dexamethasone treatment leads to alterations in cell signaling cascades controlling hepatic and cardiac function in adulthood
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DOI：
10.1016/j.ntt.2009.10.002
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发表时间：
2010-03-01
影响因子：
2.9
通讯作者：
Slotkin, Theodore A.
中科院分区：
文献类型：
--
作者：
Adigun, Abayomi A.;Wrench, Nicola;Slotkin, Theodore A.
越来越多的证据表明，早期生活中糖皮质激素的暴露，无论是涉及压力或早产的治疗，有助于成年后的代谢和心血管疾病。我们通过在出生后（PN）1-3或7-9天对新生大鼠给予地塞米松（DEX），使用跨越躯体生长障碍阈值的剂量（0.05、0.2和0.8 mg/kg），研究了这些效应的细胞机制。在成年期，我们评估了通过腺苷酸环化酶（AC）信号级联介导的对肝脏和心脏细胞功能的影响，该信号级联控制调节肝脏葡萄糖代谢和心脏收缩力的神经元和激素输入。对PN 1 -3的处理产生了肝脏信号传导的异源致敏，AC本身的上调导致对β-肾上腺素能或胰高血糖素受体刺激的反应平行增加，或通过氟化物激活G蛋白。在最低剂量下观察到这些效应，但增加DEX超过躯体生长障碍点导致雌性动物的效应丧失。心脏中也存在非单调效应，其中雄性动物在最低剂量下显示AC致敏作用，随着剂量增加效应降低;雌性动物显示心脏AC活动进行性缺陷。将暴露转移到PN 7 -9仍然引起AC致敏，但在较高剂量下具有更大的抵消贡献。我们的研究结果表明，与生长受限相比，与压力或早产治疗相关的糖皮质激素对随后的代谢和心血管功能障碍相关的细胞异常更敏感，也更重要。(C)2009 Elsevier Inc. All rights reserved.
Increasing evidence indicates that early-life glucocorticoid exposure, either involving stress or the therapy of preterm labor, contributes to metabolic and cardiovascular disorders in adulthood. We investigated cellular mechanisms underlying these effects by administering dexamethasone (DEX) to neonatal rats on postnatal (PN) days 1-3 or 7-9, using doses spanning the threshold for somatic growth impairment: 0.05, 0.2 and 0.8 mg/kg. In adulthood, we assessed the effects on hepatic and cardiac cell function mediated through the adenylyl cyclase (AC) signaling cascade, which controls neuronal and hormonal inputs that regulate hepatic glucose metabolism and cardiac contractility. Treatment on PN1-3 produced heterologous sensitization of hepatic signaling, with upregulation of AC itself leading to parallel increases in the responses to beta-adrenergic or glucagon receptor stimulation, or to activation of G-proteins by fluoride. The effects were seen at the lowest dose but increasing DEX past the point of somatic growth impairment led to loss of the effect in females. Nonmonotonic effects were also present in the heart, where males showed AC sensitization at the lowest dose, with decreasing effects as the dose was raised; females showed progressive deficits of cardiac AC activity. Shifting the exposure to PN7-9 still elicited AC sensitization but with a greater offsetting contribution at the higher doses. Our findings show that, in contrast to growth restriction, the glucocorticoids associated with stress or the therapy of preterm labor are more sensitive and more important contributors to the cellular abnormalities underlying subsequent metabolic and cardiovascular dysfunction. (C) 2009 Elsevier Inc. All rights reserved.