DNA methyltransferase- and histone deacetylase-mediated epigenetic alterations induced by low-level methylmercury exposure disrupt neuronal development
DNA methyltransferase- and histone deacetylase-mediated epigenetic alterations induced by low-level methylmercury exposure disrupt neuronal development
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DOI：
10.1007/s00204-021-02984-7
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发表时间：
2021-01-16
影响因子：
6.1
通讯作者：
Hozumi, Isao
中科院分区：
文献类型：
--
作者：
Go, Suzuna;Kurita, Hisaka;Hozumi, Isao
甲基汞（MeHg）是一种化学物质，会对胎儿发育造成不良影响。然而，环境甲基汞影响胎儿发育的分子机制尚未阐明。近年来，化学物质对胎儿发育的毒性作用被认为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神经元发育。孕鼠（C57 BL/6 J）从胚胎第12-14天开始每天经口给予3 mg/kg的甲基汞。在胚胎第19天取出胎仔并收集脑组织。LUHMES细胞用1 nM MeHg处理6天，并在处理的最后一天收集。在体内和体外样本中，甲基汞显着抑制神经突起的生长。乙酰化组蛋白H3（AcH 3）水平降低，组蛋白去乙酰化酶（HDAC）3和HDAC 6水平增加，在体内和体外实验中观察到甲基汞处理。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（DNMT 1）水平增加。与DNMT抑制剂或HDAC抑制剂的共同治疗恢复甲基汞暴露导致的神经突起生长的抑制。我们的研究结果表明，神经系统的影响，如减少神经突生长由于低水平的甲基汞暴露的结果从表观遗传变化，包括减少AcH 3通过增加HDAC水平和增加DNA甲基化通过增加DNMT 1水平。
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.