Epigenetic effects of prenatal stress on 11β-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain.
Epigenetic effects of prenatal stress on 11β-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain.
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DOI：
10.1371/journal.pone.0039791
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Champagne FA
中科院分区：
文献类型：
--
作者：
Jensen Peña C;Monk C;Champagne FA
母亲在怀孕期间承受的压力与后代神经发育的显着改变有关，而母亲体内糖皮质激素的升高可能在调节这些影响中发挥着核心作用。胎盘 2 型 11β-羟基类固醇脱氢酶 (HSD11B2) 通过将皮质醇/皮质酮转化为无活性的代谢物来缓冲母体糖皮质激素暴露的影响。然而，之前的研究表明，产前的母亲逆境可能导致这种酶的下调。在当前的研究中，我们检查了 Long Evans 大鼠的产前应激（妊娠 14-20 天期间的慢性束缚应激）对胎盘和胎儿大脑 (E20) 中 HSD11B2 mRNA 的影响，并评估了表观遗传机制在这些应激诱导效应中的作用。在胎盘中，产前应激与 HSD11B2 mRNA 显着减少、DNA 甲基转移酶 DNMT3a mRNA 水平增加以及 HSD11B2 基因启动子内特定 CpG 位点 DNA 甲基化增加有关。在胎儿下丘脑中，虽然我们没有发现应激对 HSD11B2 mRNA 水平产生影响，但产前应激导致 HSD11B2 启动子内的 CpG 甲基化减少，并在外显子 1 内位点甲基化增加。在胎儿皮层中，HSD11B2 mRNA 和 DNA 甲基化水平并未因产前应激而改变，尽管我们确实发现应激诱导的 DNMT1 升高 该大脑区域的 mRNA。在个体中，我们鉴定了 HSD11B2 基因启动子和外显子 1 内的 CpG 位点，在该位点 DNA 甲基化水平在胎盘和胎儿皮质之间高度相关。总体而言，我们的研究结果表明 DNA 甲基化是产前应激改变 HSD11B2 基因表达的一种机制。这些发现强调了表观遗传效应的组织特异性，但也提出了利用胎盘的表观遗传状态来预测大脑相应变化的有趣可能性。
Maternal exposure to stress during pregnancy is associated with significant alterations in offspring neurodevelopment and elevated maternal glucocorticoids likely play a central role in mediating these effects. Placental 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2) buffers the impact of maternal glucocorticoid exposure by converting cortisol/corticosterone into inactive metabolites. However, previous studies indicate that maternal adversity during the prenatal period can lead to a down-regulation of this enzyme. In the current study, we examined the impact of prenatal stress (chronic restraint stress during gestational days 14–20) in Long Evans rats on HSD11B2 mRNA in the placenta and fetal brain (E20) and assessed the role of epigenetic mechanisms in these stress-induced effects. In the placenta, prenatal stress was associated with a significant decrease in HSD11B2 mRNA, increased mRNA levels of the DNA methyltransferase DNMT3a, and increased DNA methylation at specific CpG sites within the HSD11B2 gene promoter. Within the fetal hypothalamus, though we find no stress-induced effects on HSD11B2 mRNA levels, prenatal stress induced decreased CpG methylation within the HSD11B2 promoter and increased methylation at sites within exon 1. Within the fetal cortex, HSD11B2 mRNA and DNA methylation levels were not altered by prenatal stress, though we did find stress-induced elevations in DNMT1 mRNA in this brain region. Within individuals, we identified CpG sites within the HSD11B2 gene promoter and exon 1 at which DNA methylation levels were highly correlated between the placenta and fetal cortex. Overall, our findings implicate DNA methylation as a mechanism by which prenatal stress alters HSD11B2 gene expression. These findings highlight the tissue specificity of epigenetic effects, but also raise the intriguing possibility of using the epigenetic status of placenta to predict corresponding changes in the brain.
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