School of Health Sciences, Purdue University, West Lafayette, IN 47907, United States.
Department of Neurology, Indiana University School of Medicine, Indianapolis, IN 46202, United States.
Toxicol Sci. 2024 Nov 1;202(1):123-141. doi: 10.1093/toxsci/kfae100.
The corpus callosum is an oligodendrocyte-enriched brain region, replenished by newborn oligodendrocytes from oligodendrocyte progenitor cells (OPCs) in subventricular zone (SVZ). Lead (Pb) exposure has been associated with multiple sclerosis, a disease characterized by the loss of oligodendrocytes. This study aimed to investigate the effects of Pb exposure on oligodendrogenesis in SVZ and myelination in the corpus callosum. Adult female mice were used for a disproportionately higher prevalence of multiple sclerosis in females. Acute Pb exposure (one ip-injection of 27 mg Pb/kg as PbAc2 24 hr before sampling) caused mild Pb accumulation in the corpus callosum. Ex vivo assay using isolated SVZ tissues collected from acute Pb-exposed brains showed a diminished oligodendrogenesis in SVZ-derived neurospheres compared with controls. In vivo subchronic Pb exposure (13.5 mg Pb/kg by daily oral gavage 4 wk) revealed significantly decreased newborn BrdU+/MBP+ oligodendrocytes in the corpus callosum, suggesting demyelination. Mechanistic investigations indicated decreased Rictor in SVZ OPCs, defective self-defense pathways, and reactive gliosis in the corpus callosum. Given the interwined pathologies between multiple sclerosis and Alzheimer's disease, the effect of Pb on myelination was evaluated in AD-modeled APP/PS1 mice. Myelin MRI on mice following chronic exposure (1,000 ppm Pb in drinking water as PbAc2 for 20 wk) revealed a profound demyelination in the corpus callosum compared with controls. Immunostaining of the choroid plexus showed diminished signaling molecule (Klotho, OTX2) expressions in Pb-treated animals. These observations suggest that Pb caused demyelination in the corpus callosum, likely by disrupting oligodendrogenesis from SVZ OPCs. Pb-induced demyelination represents a crucial pathogenic pathway in Pb neurotoxicity, including multiple sclerosis.
胼胝体富含少突胶质细胞，由脑室下区（SVZ）中的少突胶质前体细胞（OPC）分化产生的新生少突胶质细胞补充。铅（Pb）暴露与多发性硬化症有关，这种疾病的特征是少突胶质细胞的丧失。本研究旨在探讨 Pb 暴露对 SVZ 中的少突胶质生成和胼胝体中的髓鞘形成的影响。成年雌性小鼠用于研究女性多发性硬化症的发病率更高。急性 Pb 暴露（在采样前 24 小时通过腹腔注射 27mg/kg 的 PbAc2 一次）导致胼胝体中出现轻度的 Pb 积累。从急性 Pb 暴露的大脑中分离的 SVZ 组织进行的离体实验显示，SVZ 来源的神经球中的少突胶质生成减少。体内亚慢性 Pb 暴露（通过每日口服灌胃 13.5mg/kg Pb 持续 4 周）显示，胼胝体中的新生 BrdU+/MBP+少突胶质细胞显著减少，提示脱髓鞘。机制研究表明 SVZ OPC 中的 Rictor 减少、自我防御途径缺陷和胼胝体中的反应性神经胶质增生。鉴于多发性硬化症和阿尔茨海默病之间的病理相互交织，评估了 Pb 对髓鞘形成的影响在 APP/PS1 型 AD 模型小鼠中。慢性暴露（在饮用水中添加 1000ppm 的 PbAc2 持续 20 周）后对小鼠进行髓鞘 MRI 显示，与对照组相比，胼胝体中出现严重的脱髓鞘。对脉络丛的免疫染色显示 Pb 处理动物中的信号分子（Klotho、OTX2）表达减少。这些观察结果表明，Pb 导致胼胝体脱髓鞘，可能是通过破坏 SVZ OPC 中的少突胶质生成引起的。Pb 诱导的脱髓鞘代表了 Pb 神经毒性中的一个关键致病途径，包括多发性硬化症。
