Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan.
Department of Pharmacy, Faculty of Pharmacy, Gifu University of Medical Science, Kani, Japan.
J Appl Toxicol. 2024 Dec;44(12):1986-1996. doi: 10.1002/jat.4690. Epub 2024 Aug 26.
Methylmercury (MeHg) is an environmental toxin known to damage the central nervous system. When pregnant women ingest seafood, which may contain accumulated MeHg, fetal development may be affected. The embryonic period, a time of major epigenetic change, is susceptible to epigenetic disruptions due to chemical exposure. Therefore, understanding the molecular mechanism underlying MeHg's effects on neuronal development requires consideration of epigenetic factors. In this study, we investigated epigenetic modifications in the synaptophysin (SYP) and discs large MAGUK scaffold protein 4 (DLG4) genes. LUHMES cells were exposed to 1 nM MeHg for 6 days during days 2-8 of neural differentiation. MeHg exposure significantly reduced the number of spikes observed on day 16 of differentiation. Both mRNA and protein expression levels of SYP and DLG4 were significantly decreased by MeHg exposure. Additionally, MeHg treatment reduced acetyl histone H3 levels associated with transcriptional activity in the SYP gene while increasing histone H3 lysine 27 tri-methylation (H3K27me3) levels related to transcriptional repression. Conversely, regarding the DLG4 gene, MeHg exposure increased H3K27me3 levels. Differential changes in DNA methylation (high and low methylation states) were observed in the SYP and DLG4 genes due to MeHg exposure depending on CpG site position. In conclusion, this study suggests that epigenetic changes, particularly histone modifications, contribute to decreased MeHg exposure-induced SYP and DLG4 expression during neuronal differentiation.
甲基汞（MeHg）是一种环境毒素，已知会损害中枢神经系统。当孕妇摄入可能含有累积 MeHg 的海鲜时，胎儿发育可能会受到影响。胚胎期是表观遗传变化的主要时期，由于化学暴露，易受表观遗传干扰。因此，了解 MeHg 对神经元发育的影响的分子机制需要考虑表观遗传因素。在这项研究中，我们研究了突触小体蛋白（SYP）和盘状结构域蛋白 4（DLG4）基因的表观遗传修饰。在神经分化的第 2-8 天，将 LUHMES 细胞暴露于 1 nM MeHg 中 6 天。MeHg 暴露显著减少了分化第 16 天观察到的尖峰数量。SYP 和 DLG4 的 mRNA 和蛋白表达水平均因 MeHg 暴露而显著降低。此外，MeHg 处理降低了与 SYP 基因转录活性相关的乙酰化组蛋白 H3 水平，同时增加了与转录抑制相关的组蛋白 H3 赖氨酸 27 三甲基化（H3K27me3）水平。相反，对于 DLG4 基因，MeHg 暴露增加了 H3K27me3 水平。由于 MeHg 暴露，SYP 和 DLG4 基因中的 DNA 甲基化（高和低甲基化状态）发生了差异变化，这取决于 CpG 位点的位置。总之，这项研究表明，表观遗传变化，特别是组蛋白修饰，导致 MeHg 暴露诱导的神经元分化过程中 SYP 和 DLG4 表达降低。
