Excessive exposure to manganese (Mn) through drinking water and food during pregnancy significantly heightens the likelihood of neurodevelopmental damage in offspring. Multiple studies have indicated that melatonin (Mel) may help to relieve neurodevelopmental disorders caused by Mn, but potential mechanisms underlying this effect require further exploration. Here, we utilized primary neural stem cells (NSCs) as a model to elucidate the molecular mechanism underlying the protective function of Mel on Mn‐induced cell proliferation dysfunction and cycle arrest. Our results showed that Mn disrupted the cell cycle in NSCs by suppressing positive regulatory proteins (CDK2, Cyclin A, Cyclin D1, and E2F1) and enhancing negative ones (p27KIP1 and p57KIP2), leading to cell proliferation dysfunction. Mel inhibited the Mn‐dependent changes to these proteins and the cell cycle through nuclear receptor‐related protein 1 (Nurr1), thus alleviating the proliferation dysfunction. Knockdown of Nurr1 using lentivirus‐expressed shRNA in NSCs resulted in a diminished protective effect of Mel. We concluded that Mel mitigated Mn‐induced proliferation dysfunction and cycle arrest in NSCs through Nurr1.

中文翻译：

---

褪黑素通过 Nurr1 促进锰处理神经干细胞的细胞周期进程

怀孕期间通过饮用水和食物过量接触锰 (Mn) 会显着增加后代神经发育损害的可能性。多项研究表明，褪黑激素（Mel）可能有助于缓解锰引起的神经发育障碍，但这种作用的潜在机制需要进一步探索。在这里，我们利用原代神经干细胞（NSC）作为模型来阐明 Mel 对 Mn 诱导的细胞增殖功能障碍和周期停滞的保护功能的分子机制。我们的结果表明，Mn 通过抑制正调节蛋白（CDK2、Cyclin A、Cyclin D）来破坏 NSC 的细胞周期。1，和E2F1）并增强负面的（p27关键IP1和p57关键IP2），导致细胞增殖功能障碍。 Mel 通过核受体相关蛋白 1 (Nurr1) 抑制这些蛋白和细胞周期的 Mn 依赖性变化，从而减轻增殖功能障碍。在 NSC 中使用慢病毒表达的 shRNA 敲低 Nurr1 会导致 Mel 的保护作用减弱。我们得出结论，Mel 通过 Nurr1 减轻了 Mn 诱导的 NSC 增殖功能障碍和周期停滞。