Prenatal alcohol exposure causes fetal neurodevelopmental damage and growth restriction. Among regions of the brain, the cerebellum is the most vulnerable to developmental alcohol exposure. Despite vast research in the field, there is still a need to identify specific mechanisms by which alcohol causes this damage in order to design effective therapeutic interventions. The mammalian target of rapamycin (mTOR) is known to be associated with axonal regeneration, dendritic arborization, synaptic plasticity, cellular growth, autophagy, and many other cellular processes. Glutamine and glutamine-related amino acids play a key role in fetal development and are known to alter the mTOR pathway; recent research has shown that disturbances in their bioavailability and signaling pathways may mediate adverse effects of prenatal alcohol exposure. This study investigated the role of the mTOR signaling pathway in the fetal cerebellum and skeletal muscle after third trimester-equivalent prenatal alcohol exposure and maternal l-glutamine (GLN) supplementation using a sheep model. Fetal cerebella and skeletal muscles were sampled for Western blot analysis of mTOR and its downstream targets S6 kinase and eukaryotic initiation factor 4E-bindin protein (4E-BP1). The expression of cerebellar phosphorylated mTOR relative to the total mTOR was elevated in the alcohol+GLN group compared to the saline and GLN groups. Alcohol exposure increased the ratio of phosphorylated S6K to total S6K in fetal cerebellum, and no significant effect of GLN supplementation was observed. On contrary, maternal GLN supplementation reduced the activation of mTOR and S6K in fetal skeletal muscle, possibly to make GLN and other amino acids available for use by other organs. These findings suggest prenatal alcohol exposure and maternal GLN supplementation during the third trimester-equivalent alter the mTOR signaling cascade, which plays a possible key role in alcohol-induced developmental damage.

产前酒精暴露会导致胎儿神经发育损伤和生长受限。在大脑的各个区域中，小脑最容易受到发育性酒精暴露的影响。尽管在该领域进行了大量研究，但仍需要确定酒精造成这种损害的具体机制，以便设计有效的治疗干预措施。已知哺乳动物雷帕霉素靶点 (mTOR) 与轴突再生、树突分枝、突触可塑性、细胞生长、自噬和许多其他细胞过程有关。谷氨酰胺和谷氨酰胺相关氨基酸在胎儿发育中起着关键作用，并且已知会改变 mTOR 通路；最近的研究表明，其生物利​​用度和信号通路的紊乱可能会介导产前酒精暴露的不利影响。升使用绵羊模型补充 - 谷氨酰胺 (GLN)。对胎儿小脑和骨骼肌进行取样，用于 mTOR 及其下游靶标 S6 激酶和真核起始因子 4E-结合蛋白 (4E-BP1) 的蛋白质印迹分析。与盐水和 GLN 组相比，酒精 + GLN 组中小脑磷酸化 mTOR 相对于总 mTOR 的表达升高。酒精暴露增加了胎儿小脑中磷酸化 S6K 与总 S6K 的比例，并且没有观察到补充 GLN 的显着影响。相反，母体 GLN 补充剂降低了胎儿骨骼肌中 mTOR 和 S6K 的激活，可能使 GLN 和其他氨基酸可供其他器官使用。