Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A. 2014 Jul 1;111(26):9639-44. doi: 10.1073/pnas.1401203111. Epub 2014 Jun 16.
Maternal stress is a key risk factor in neurodevelopmental disorders, which often have a sex bias in severity and prevalence. We previously identified O-GlcNAc transferase (OGT) as a placental biomarker in our mouse model of early prenatal stress (EPS), where OGT levels were lower in male compared with female tissue and were further decreased following maternal stress. However, the function of placental OGT in programming the developing brain has not been determined. Therefore, we generated a transgenic mouse with targeted placental disruption of Ogt (Pl-OGT) and examined offspring for recapitulation of the adult EPS phenotype. Pl-OGT hemizygous and EPS male placentas showed similar robust changes in gene expression patterns suggestive of an altered ability to respond to endocrine and inflammatory signals, supporting placental OGT as an important mediator of EPS effects. ChIP-Seq for the O-GlcNAc mark identified the 17 beta hydroxysteroid dehydrogenase-3 (Hsd17b3) locus in male EPS placentas, which correlated with a reduction in Hsd17b3 expression and concordant reduced testosterone conversion. Remarkably, Pl-OGT adult offspring had reduced body weights and elevated hypothalamic-pituitary-adrenal stress axis responsivity, recapitulating phenotypes previously reported for EPS males. Further, hypothalamic microarray gene-set enrichment analyses identified reduced mitochondrial function in both Pl-OGT and EPS males. Cytochrome c oxidase activity assays verified this finding, linking reduced placental OGT with critical brain programming. Together, these studies confirm OGT as in important placental biomarker of maternal stress and demonstrate the profound impact a single placental gene has on long-term metabolic and neurodevelopmental programming that may be related to an increased risk for neurodevelopmental disorders.
母体应激是神经发育障碍的一个关键风险因素，而这些障碍在严重程度和患病率上常常存在性别偏向。我们之前在早期产前应激（EPS）的小鼠模型中发现 O-连接糖基化转移酶（OGT）是一种胎盘生物标志物，在雄性组织中 OGT 水平低于雌性，而在母体应激后进一步降低。然而，胎盘 OGT 在编程发育中大脑的功能尚未确定。因此，我们生成了一种靶向胎盘 Ogt 缺失的转基因小鼠（Pl-OGT），并检查了后代是否重现成年 EPS 表型。Pl-OGT 杂合子和 EPS 雄性胎盘显示出类似的基因表达模式的强烈变化，表明其对内分泌和炎症信号的反应能力发生改变，支持胎盘 OGT 是 EPS 效应的重要介导物。O-GlcNAc 标记的 ChIP-Seq 鉴定了雄性 EPS 胎盘中的 17 位羟类固醇脱氢酶-3（Hsd17b3）基因座，这与 Hsd17b3 表达的降低和一致的睾酮转化减少相关。值得注意的是，Pl-OGT 成年后代体重减轻，下丘脑-垂体-肾上腺应激轴反应性升高，重现了以前报道的 EPS 雄性的表型。此外，下丘脑微阵列基因集富集分析在 Pl-OGT 和 EPS 雄性中均发现线粒体功能降低。细胞色素 c 氧化酶活性测定验证了这一发现，将胎盘 OGT 的减少与关键的大脑编程联系起来。总之，这些研究证实了 OGT 是母体应激的重要胎盘生物标志物，并表明单个胎盘基因对长期代谢和神经发育编程的深远影响，这可能与神经发育障碍的风险增加有关。
