Department of Psychology, Columbia University, New York, New York, United States of America.
PLoS One. 2012;7(6):e39791. doi: 10.1371/journal.pone.0039791. Epub 2012 Jun 26.
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.
母体在怀孕期间暴露于压力与后代神经发育的显著改变有关，而升高的母源性皮质醇可能在介导这些影响中起核心作用。胎盘 11β-羟类固醇脱氢酶 2 型（HSD11B2）通过将皮质醇/皮质酮转化为无活性代谢物来缓冲母源性皮质醇暴露的影响。然而，先前的研究表明，产前期间的母体逆境会导致这种酶的下调。在当前的研究中，我们检查了产前应激（妊娠第 14-20 天的慢性束缚应激）对 Long Evans 大鼠胎盘和胎儿大脑（E20）中 HSD11B2mRNA 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，产前应激与 HSD11B2mRNA 的显著减少、DNA 甲基转移酶 DNMT3a 的 mRNA 水平增加以及 HSD11B2 基因启动子内特定 CpG 位点的 DNA 甲基化增加有关。在胎儿下丘脑内，尽管我们没有发现 HSD11B2mRNA 水平的应激诱导效应，但产前应激诱导 HSD11B2 启动子内的 CpG 甲基化减少和外显子 1 内的甲基化增加。在胎儿皮质中，产前应激未改变 HSD11B2mRNA 和 DNA 甲基化水平，但我们确实发现该脑区的 DNMT1mRNA 应激诱导升高。在个体内，我们鉴定了 HSD11B2 基因启动子和外显子 1 内的 CpG 位点，这些位点的 DNA 甲基化水平在胎盘和胎儿皮质之间高度相关。总的来说，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。这些发现突出了表观遗传效应的组织特异性，但也提出了一个有趣的可能性，即利用胎盘的表观遗传状态来预测大脑中相应的变化。
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