Laboratory of Medical Therapeutics and Molecular Therapeutics, Department Biomedical Pharmaceutics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi Gifu city, Gifu, 501-1196, Japan.
Basic Medical Sciences, National Institute for Minamata Disease, 4058-18 Hama, Minamata, 867-0008, Japan.
Arch Toxicol. 2021 Apr;95(4):1227-1239. doi: 10.1007/s00204-021-02984-7. Epub 2021 Jan 16.
Methylmercury (MeHg) is a chemical substance that causes adverse effects on fetal development. However, the molecular mechanisms by which environmental MeHg affects fetal development have not been clarified. Recently, it has been suggested that the toxic effects of chemicals on fetal development are related alterations in epigenetics, such as DNA methylation and histone modification. In order to analyze the epigenetic effects of low-level MeHg exposure on neuronal development, we evaluated neuronal development both in vivo and in vitro. Pregnant mice (C57BL/6J) were orally administrated 3 mg/kg of MeHg once daily from embryonic day 12-14. Fetuses were removed on embryonic day 19 and brain tissues were collected. LUHMES cells were treated with 1 nM of MeHg for 6 days and collected on the last day of treatment. In both in vivo and in vitro samples, MeHg significantly suppressed neurite outgrowth. Decreased acetylated histone H3 (AcH3) levels and increased histone deacetylase (HDAC) 3 and HDAC6 levels were observed in response to MeHg treatment in both in vivo and in vitro experiments. In addition, increased DNA methylation and DNA methyltransferase 1 (DNMT1) levels were observed in both in vivo and in vitro experiments. The inhibition of neurite outgrowth resulting from MeHg exposure was restored by co-treatment with DNMT inhibitor or HDAC inhibitors. Our results suggest that neurological effects such as reduced neurite outgrowth due to low-level MeHg exposure result from epigenetic changes, including a decrease in AcH3 via increased HDAC levels and an increase in DNA methylation via increased DNMT1 levels.
甲基汞（MeHg）是一种对胎儿发育有不良影响的化学物质。然而，环境甲基汞影响胎儿发育的分子机制尚未阐明。最近，有人提出，化学物质对胎儿发育的毒性作用与表观遗传学的改变有关，如 DNA 甲基化和组蛋白修饰。为了分析低水平甲基汞暴露对神经元发育的表观遗传效应，我们评估了体内和体外的神经元发育。从胚胎第 12-14 天开始，每天给怀孕的 C57BL/6J 小鼠口服 3mg/kg 的甲基汞。在胚胎第 19 天取出胎儿，并收集脑组织。将 LUHMES 细胞用 1nM 的甲基汞处理 6 天，并在最后一天处理时收集。在体内和体外样本中，甲基汞均显著抑制神经突生长。在体内和体外实验中，甲基汞处理后观察到乙酰化组蛋白 H3（AcH3）水平降低，组蛋白去乙酰化酶（HDAC）3 和 HDAC6 水平升高。此外，在体内和体外实验中均观察到 DNA 甲基化和 DNA 甲基转移酶 1（DNMT1）水平升高。用 DNMT 抑制剂或 HDAC 抑制剂共同处理可恢复由甲基汞暴露引起的神经突生长抑制。我们的研究结果表明，由于低水平甲基汞暴露导致的神经发育迟缓等神经效应是由于表观遗传变化引起的，包括通过增加 HDAC 水平导致 AcH3 减少，以及通过增加 DNMT1 水平导致 DNA 甲基化增加。
