Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development.
Prenatal arsenic exposure alters the programming of the glucocorticoid signaling system during embryonic development.
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DOI：
10.1016/j.ntt.2014.11.006
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发表时间：
2015-01
影响因子：
2.9
通讯作者：
Allan AM
中科院分区：
文献类型：
--
作者：
Caldwell KE;Labrecque MT;Solomon BR;Ali A;Allan AM
糖皮质激素系统在包括情绪障碍和学习记忆在内的一系列细胞功能中发挥着关键作用，据报道，砷会扰乱该系统。在以前的工作中，我们已经建立并表征了产前中度砷暴露(50 Ppb)的模型，并在青春期小鼠中发现了学习记忆和情绪障碍的几个缺陷，以及糖皮质激素受体信号系统的变化。在这些研究中，我们评估了砷对胎盘和胎脑中糖皮质激素受体(GR)途径的影响。这些研究的重点是在糖皮质激素合成中起关键作用的11个β-羟基类固醇脱氢酶(11个β-HSD1和11个β-HSD2)以及GR负反馈调节的表达和设定点。负反馈调节是在早期发展阶段建立起来的。在胚胎14d，我们发现砷暴露显著降低了GR和11个β-HSD1在脑中的蛋白和消息的表达，而在脑中11个β-HSD2酶的蛋白水平上升，而mR-NA水平下降。大脑蛋白质的这些变化持续到E18时间点，但mRNA水平不再有显著变化。胎盘组织HSD11B2mRNA未受砷处理的影响，但胎盘HSD11B2蛋白水平在胚胎第14天升高。在染砷条件下，胎盘GR蛋白水平在胎龄18时显著降低。这表明砷暴露可能会改变GR的表达水平，这是由于11β-HSD1和11β-HSD2蛋白表达的长期发育不平衡造成的，尽管11HSDB2mRNA表达下降。在胎儿发育过程中，GR的抑制和11β-HSD2蛋白表达的失败可能会导致整个成年期GR信号的设定点发生改变。据我们所知，这些研究首次证明，妊娠期暴露于中等水平的砷会导致胎儿糖皮质激素系统的编程改变。
The glucocorticoid system, which plays a critical role in a host of cellular functions including mood disorders and learning and memory, has been reported to be disrupted by arsenic. In previous work we have developed and characterized a prenatal moderate arsenic exposure (50 ppb) model and identified several deficits in learning and memory and mood disorders, as well as alterations within the glucocorticoid receptor signaling system in the adolescent mouse. In these present studies we assessed the effects of arsenic on the glucocorticoid receptor (GR) pathway in both the placenta and the fetal brain in response at two critical periods, embryonic days 14 and 18. The focus of these studies was on the 11β-hydroxysteroid dehydrogenase enzymes (11β-HSD1 and 11β-HSD2) which play a key role in glucorticoid synthesis, as well as the expression and set point of the GR negative feedback regulation. Negative feedback regulation is established early in development. At E14 we found arsenic exposure significantly decreased expression of both protein and message in brain of GR and the 11β-HSD1, while 11β-HSD2 enzyme protein levels were increased but mRNA levels were decreased in the brain. These changes in brain protein continued into the E18 time point, but mRNA levels were no longer significantly altered. Placental HSD11B2 mRNA was not altered by arsenic treatment but protein levels were elevated at E14. GR placental protein levels were decreased at E18 in the arsenic exposed condition. This suggests that arsenic exposure may alter GR expression levels as a consequence of a prolonged developmental imbalance between 11β-HSD1 and 11β-HSD2 protein expression despite decreased 11HSDB2 mRNA. The suppression of GR and the failure to turn down 11β-HSD2 protein expression during fetal development may lead to an altered set point for GR signaling throughout adulthood. To our knowledge, these studies are the first to demonstrate that gestational exposure to moderate levels of arsenic results in altered fetal programming of the glucocorticoid system.