Prenatal ethanol exposure-induced adrenal developmental abnormality of male offspring rats and its possible intrauterine programming mechanisms
Prenatal ethanol exposure-induced adrenal developmental abnormality of male offspring rats and its possible intrauterine programming mechanisms
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DOI：
10.1016/j.taap.2015.07.005
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发表时间：
2015-10-01
影响因子：
3.8
通讯作者：
Wang, Hui
中科院分区：
文献类型：
--
作者：
Huang, Hegui;He, Zheng;Wang, Hui
胎儿肾上腺发育状况是胎儿组织成熟和后代生长的主要决定因素。我们以前提出，产前乙醇暴露（PEE）抑制胎儿肾上腺皮质酮（CURT）合成。本研究以pee诱导的雄性子代大鼠出生前后肾上腺发育异常为研究对象，探讨其宫内编程机制。采用4 g/kg.d PEE建立宫内生长迟缓大鼠模型。PEE胎儿血清CURT浓度升高，胰岛素样生长因子1 （IGF1）浓度降低，体重降低，结构异常，肾上腺皮质Ki67（增殖标志物）表达降低。肾上腺糖皮质激素（GC）代谢激活系统增强，IGF1与类固醇急性调节蛋白（StAR）、3 β -羟基类固醇脱氢酶（3 β - hsd）信号通路基因表达降低。此外，PEE雄性成年后代血清CURT水平降低，IGF1升高，部分追赶生长，Ki67表达无明显变化。成人肾上腺gc -代谢激活系统被抑制，IGF1信号通路和3 β - hsd被甾体生成因子1 （SF1）增强，StAR下调。基于这些发现，我们提出了pee诱导肾上腺发育毒性的“双编程”机制：“第一编程”是肾上腺甾体生成的低功能编程，“第二编程”是gc -代谢激活系统相关的GC-IGF1轴编程。(C) 2015爱思唯尔公司版权所有。
Fetal adrenal developmental status is the major determinant of fetal tissue maturation and offspring growth. We have previously proposed that prenatal ethanol exposure (PEE) suppresses fetal adrenal corticosterone (CURT) synthesis. Here, we focused on PEE-induced adrenal developmental abnormalities of male offspring rats before and after birth, and aimed to explore its intrauterine programming mechanisms. A rat model of intrauterine growth retardation (IUGR) was established by PEE (4 g/kg.d). In PEE fetus, increased serum CURT concentration and decreased insulin-like growth factor 1 (IGF1) concentration, with lower bodyweight and structural abnormalities as well as a decreased Ki67 expression (proliferative marker), were observed in the male fetal adrenal cortex. Adrenal glucocorticoid (GC)-metabolic activation system was enhanced while gene expression of IGF1 signaling pathway with steroidogenic acute regulatory protein (StAR), 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) was decreased. Furthermore, in the male adult offspring of PEE, serum CURT level was decreased but IGF1 was increased with partial catch-up growth, and Ki67 expression demonstrated no obvious change. Adrenal GC-metabolic activation system was inhibited, while IGF1 signaling pathway and 3 beta-HSD was enhanced with the steroidogenic factor 1 (SF1), and StAR was down-regulated in the adult adrenal. Based on these findings, we propose a "two-programming" mechanism for PEE-induced adrenal developmental toxicity: "the first programming" is a lower functional programming of adrenal steroidogenesis, and "the second programming" is GC-metabolic activation system-related GC-IGF1 axis programming. (C) 2015 Elsevier Inc. All rights reserved.