U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Toxicity Assessment Division, Endocrine Toxicology Branch, Research Triangle Park, North Carolina, NC, 27711, USA.
Oak Ridge Institute for Science Education, Oak Ridge, TN, 37830, USA.
Sci Rep. 2019 Mar 15;9(1):4662. doi: 10.1038/s41598-019-40249-7.
Cortical heterotopias are clusters of ectopic neurons in the brain and are associated with neurodevelopmental disorders like epilepsy and learning disabilities. We have previously characterized the robust penetrance of a heterotopia in a rat model, induced by thyroid hormone (TH) disruption during gestation. However, the specific mechanism by which maternal TH insufficiency results in this birth defect remains unknown. Here we first determined the developmental window susceptible to endocrine disruption and describe a cellular mechanism responsible for heterotopia formation. We show that five days of maternal goitrogen treatment (10 ppm propylthiouracil) during the perinatal period (GD19-PN2) induces a periventricular heterotopia in 100% of the offspring. Beginning in the early postnatal brain, neurons begin to aggregate near the ventricles of treated animals. In parallel, transcriptional and architectural changes of this region were observed including decreased Sonic hedgehog (Shh) expression, abnormal cell adhesion, and altered radial glia morphology. As the ventricular epithelium is juxtaposed to two sources of brain THs, the cerebrospinal fluid and vasculature, this progenitor niche may be especially susceptible to TH disruption. This work highlights the spatiotemporal vulnerabilities of the developing brain and demonstrates that a transient period of TH perturbation is sufficient to induce a congenital abnormality.
皮质异位是大脑中异位神经元的簇集,与神经发育障碍有关,如癫痫和学习障碍。我们之前已经描述了一种在甲状腺激素(TH)在妊娠期间破坏诱导的大鼠模型中存在的异位现象的强穿透性。然而,母体 TH 不足导致这种出生缺陷的确切机制尚不清楚。在这里,我们首先确定了易受内分泌干扰的发育窗口,并描述了导致异位形成的细胞机制。我们表明,在围产期(GD19-PN2)期间,对母体进行 5 天的致甲状腺肿剂(10ppm 丙基硫氧嘧啶)处理会导致 100%的后代出现脑室周围异位。从早期的产后大脑开始,神经元开始在接受治疗的动物的脑室附近聚集。与此同时,该区域的转录和结构变化也被观察到,包括 Sonic hedgehog(Shh)表达减少、异常细胞黏附和放射状胶质形态改变。由于脑室上皮毗邻两种脑 TH 的来源,即脑脊液和血管,这个祖细胞龛可能特别容易受到 TH 破坏的影响。这项工作强调了发育中大脑的时空脆弱性,并表明短暂的 TH 干扰足以诱导先天性异常。