Manganese induces oxidative damage in the hippocampus by regulating the expression of oxidative stress-related genes via modulation of H3K18 acetylation.
Manganese induces oxidative damage in the hippocampus by regulating the expression of oxidative stress-related genes via modulation of H3K18 acetylation.
复制标题
DOI：
10.1002/tox.24102
复制
发表时间：
2023-12
影响因子：
4.5
通讯作者：
Zhi Chen;Chunyan Ao;Yan Liu;Yue Yang;Ying Liu;Q. Ming;Changzhe Li;Hua Zhao;Jiaqi Ban;Jun Li
中科院分区：
文献类型：
--
作者：
Zhi Chen;Chunyan Ao;Yan Liu;Yue Yang;Ying Liu;Q. Ming;Changzhe Li;Hua Zhao;Jiaqi Ban;Jun Li
长期暴露于锰会导致海马锰的蓄积，从而导致称为锰中毒的神经退行性疾病。然而，其潜在的分子机制仍不清楚，也没有理想的生物标志物。氧化应激是锰相关神经毒性的基本机制。此外，组蛋白乙酰化已被证实参与神经退行性疾病的发生和发展。因此，本工作旨在从组蛋白乙酰化修饰的角度来理解锰暴露所致海马区氧化损伤的分子机制，并评估外周血中H3K18乙酰化(H3K18ac)的修饰水平是否反映了锰所致的海马区氧化损伤。我们将60只雄性大鼠随机分为4组，每周5天，每天1次，每周5天，每周1次，连续16周，给予无菌纯净水和MnCl2⋅4H2O(5，10，15 mg/kg)。数据证实，锰暴露可下调大鼠海马区和血浆中超氧化物歧化酶活性和谷胱甘肽水平，上调丙二醛水平，且这些指标在海马区和血浆中呈正相关。此外，我们注意到，锰处理上调了海马区和外周血中H3K18ac的修饰水平，并且H3K18ac的修饰水平与氧化应激有关。进一步的研究表明，锰处理降低了锰超氧化物歧化酶(SOD2)和谷胱甘肽转移酶omega 1(GSTO1)基因启动子区H3K18ac的富集量，从而导致了海马区的氧化损伤。总之，我们的结果表明，锰通过调节H3K18ac抑制SOD2和GSTO1基因的表达，从而诱导海马区的氧化损伤。在评价锰诱导的海马神经毒性时，血浆中的氧化损伤可能反映了锰暴露组的海马区氧化损伤。
Prolonged exposure to manganese (Mn) contributes to hippocampal Mn accumulation, which leads to neurodegenerative diseases called manganese poisoning. However, the underlying molecular mechanisms remain unclear and there are no ideal biomarkers. Oxidative stress is the essential mechanisms of Mn‐related neurotoxicity. Furthermore, histone acetylation has been identified as being engaged in the onset and development of neurodegenerative diseases. Therefore, the work aims to understand the molecular mechanisms of oxidative damage in the hippocampus due to Mn exposure from the aspect of histone acetylation modification and to assess whether H3K18 acetylation (H3K18ac) modification level in peripheral blood reflect Mn‐induced oxidative damage in the hippocampus. Here, we randomly divided 60 male rats into four groups and injected them intraperitoneally with sterile pure water and MnCl2⋅4H2O (5, 10, and 15 mg/kg) for 16 weeks, 5 days a week, once a day. The data confirmed that Mn exposure down‐regulated superoxide dismutase activity and glutathione level as well as up‐regulated malondialdehyde level in the hippocampus and plasma, and that there was a positive correlation between these indicators in the hippocampus and plasma. Besides, we noted that Mn treatment upregulated H3K18ac modification levels in the hippocampus and peripheral blood and that H3K18ac modification levels correlated with oxidative stress. Further studies demonstrated that Mn treatment decreased the amounts of H3K18ac enrichment in the manganese superoxide dismutase (SOD2) and glutathione transferase omega 1 (GSTO1) gene promoter regions, contributing to oxidative damage in the hippocampus. In short, our results demonstrate that Mn induces oxidative damage in the hippocampus by inhibiting the expression of SOD2 and GSTO1 genes via modulation of H3K18ac. In assessing Mn‐induced hippocampal neurotoxicity, oxidative damage in plasma may reflect hippocampal oxidative damage in Mn‐exposed groups.