Gilbert M E, Ramos R L, McCloskey D P, Goodman J H
Toxicity Assessment Division, Neurotoxicology Branch, US Environmental Protection Agency, Research Triangle Park, NC, USA.
J Neuroendocrinol. 2014 Aug;26(8):528-41. doi: 10.1111/jne.12169.
Thyroid hormones (TH) play crucial roles in brain maturation and are important for neuronal migration and neocortical lamination. Subcortical band heterotopia (SBH) represent a class of neuronal migration errors in humans that are often associated with childhood epilepsy. We have previously reported the presence of SBH in a rodent model of low level hypothyroidism induced by maternal exposure to the goitrogen, propylthiouracil (PTU). In the present study, we report the dose-response characteristics of this developmental malformation and the connectivity of heterotopic neurones with other brain regions, as well as their functionality. Pregnant rats were exposed to varying concentrations of PTU through the drinking water (0-10 p.p.m.) beginning on gestational day 6 to produce graded levels of TH insufficiency. Dose-dependent increases in the volume of the SBH present in the corpus callosum were documented in the adult offspring, with a clear presence at concentrations of PTU that resulted in minor (< 15%) reductions in maternal serum thyroxine as measured when pups were weaned. SBH contain neurones, oligodendrocytes, astrocytes and microglia. Monoaminergic and cholinergic processes were prevalent and many of the axons were myelinated. Anatomical connectivity of SBH neurones to cortical neurones and the synaptic functionality of these anatomical connections was verified by ex vivo field potential recordings. SBH persisted in adult offspring despite a return to euthyroid status on termination of exposure and these offspring displayed an increased sensitivity to seizures. Features of this model are attractive with respect to the investigation of the molecular mechanisms of cortical development, the effectiveness of therapeutic intervention in hypothyroxinaemia during pregnancy and the impact of the very modest TH imbalance that accompanies exposure to environmental contaminants.
甲状腺激素（TH）在大脑成熟过程中发挥着关键作用，对神经元迁移和新皮质分层非常重要。皮质下带状异位（SBH）是人类一类神经元迁移错误，常与儿童癫痫相关。我们之前报道过，在母体接触致甲状腺肿物质丙硫氧嘧啶（PTU）诱导的低水平甲状腺功能减退啮齿动物模型中存在SBH。在本研究中，我们报告了这种发育畸形的剂量反应特征、异位神经元与其他脑区的连接情况及其功能。从妊娠第6天开始，通过饮用水让怀孕大鼠接触不同浓度的PTU（0 - 10 ppm），以产生不同程度的TH不足。在成年后代中记录到胼胝体中SBH体积呈剂量依赖性增加，在导致幼崽断奶时母体血清甲状腺素轻微降低（< 15%）的PTU浓度下明显存在。SBH包含神经元、少突胶质细胞、星形胶质细胞和小胶质细胞。单胺能和胆碱能突起普遍存在，许多轴突有髓鞘。通过离体场电位记录验证了SBH神经元与皮质神经元的解剖连接以及这些解剖连接的突触功能。尽管在接触终止后恢复到甲状腺功能正常状态，但SBH在成年后代中持续存在，并且这些后代对癫痫发作的敏感性增加。该模型的特点对于研究皮质发育的分子机制、孕期甲状腺功能减退症治疗干预的有效性以及接触环境污染物所伴随的非常轻微的TH失衡的影响具有吸引力。
