UNC Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA.
Department of Nutrition, University of North Carolina at Chapel Hill, Kannapolis, NC 28081, USA.
Cells. 2024 Mar 2;13(5):440. doi: 10.3390/cells13050440.
Prenatal alcohol exposure (PAE) is a leading cause of neurodevelopmental disability through its induction of neuronal growth dysfunction through incompletely understood mechanisms. Ribosome biogenesis regulates cell cycle progression through p53 and the nucleolar cell stress response. Whether those processes are targeted by alcohol is unknown. Pregnant C57BL/6J mice received 3 g alcohol/kg daily at E8.5-E17.5. Transcriptome sequencing was performed on the E17.5 fetal cortex. Additionally, primary neural stem cells (NSCs) were isolated from the E14.5 cerebral cortex and exposed to alcohol to evaluate nucleolar stress and p53/MDM2 signaling. Alcohol suppressed KEGG pathways involving ribosome biogenesis (rRNA synthesis/processing and ribosomal proteins) and genes that are mechanistic in ribosomopathies (, ; ; ); this was accompanied by nucleolar dissolution and p53 stabilization. In primary NSCs, alcohol reduced rRNA synthesis, caused nucleolar loss, suppressed proliferation, stabilized nuclear p53, and caused apoptosis that was prevented by dominant-negative p53 and MDM2 overexpression. Alcohol's actions were dose-dependent and rapid, and rRNA synthesis was suppressed between 30 and 60 min following alcohol exposure. The alcohol-mediated deficits in ribosomal protein expression were correlated with fetal brain weight reductions. This is the first report describing that pharmacologically relevant alcohol levels suppress ribosome biogenesis, induce nucleolar stress in neuronal populations, and involve the ribosomal/MDM2/p53 pathway to cause growth arrest and apoptosis. This represents a novel mechanism of alcohol-mediated neuronal damage.
产前酒精暴露（PAE）通过其诱导的神经元生长功能障碍，是神经发育障碍的主要原因，但其机制尚不完全清楚。核糖体生物发生通过 p53 和核仁细胞应激反应调节细胞周期进程。酒精是否靶向这些过程尚不清楚。在 E8.5-E17.5 期间，给怀孕的 C57BL/6J 小鼠每日接受 3 g/kg 酒精。对 E17.5 胎皮质进行转录组测序。此外，从 E14.5 大脑皮质分离原代神经干细胞（NSC）并暴露于酒精以评估核仁应激和 p53/MDM2 信号。酒精抑制了涉及核糖体生物发生（rRNA 合成/加工和核糖体蛋白）和核糖体病机制基因（，；；）的 KEGG 途径；这伴随着核仁溶解和 p53 稳定。在原代 NSC 中，酒精降低了 rRNA 合成，导致核仁丢失，抑制了增殖，稳定了核 p53，并引起了由显性失活的 p53 和 MDM2 过表达预防的凋亡。酒精的作用具有剂量依赖性和快速性，并且在暴露于酒精后 30 至 60 分钟内抑制 rRNA 合成。核糖体蛋白表达的酒精介导的缺陷与胎脑重量减轻相关。这是第一个描述药理相关酒精水平抑制核糖体生物发生，诱导神经元群体核仁应激，并涉及核糖体/MDM2/p53 途径导致生长停滞和凋亡的报告。这代表了酒精介导的神经元损伤的新机制。
