Manganese induces oxidative damage in the hippocampus by regulating the expression of oxidative stress-related genes via modulation of H3K18 acetylation

Abstract

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 ⋅4H₂ O (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.

Keywords: H3K18 acetylation; biomarkers; manganese; neurodegenerative diseases; oxidative stress.