Arsenic activates the expression of 3β-HSD in mouse Leydig cells through repression of histone H3K9 methylation
Arsenic activates the expression of 3β-HSD in mouse Leydig cells through repression of histone H3K9 methylation
复制标题
砷通过抑制组蛋白 H3K9 甲基化激活小鼠 Leydig 细胞中 3β-HSD 的表达
DOI：
10.1016/j.taap.2017.04.012
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发表时间：
2017-07-01
影响因子：
3.8
通讯作者：
Shen, Heqing
中科院分区：
文献类型：
--
作者：
Alamdar, Ambreen;Xi, Guochen;Shen, Heqing
砷暴露与男性生殖功能障碍有关，破坏类固醇生成;然而，表观遗传驱动因素，特别是组蛋白甲基化在砷诱导的类固醇毒性中的作用仍然没有很好的记录。在这项研究中，我们研究了组蛋白H3赖氨酸9（H3 K9）甲基化的作用，在类固醇激素合成障碍的小鼠Leydig细胞（MLTC-1）由于砷暴露。我们的研究结果表明，3 β-羟基类固醇脱氢酶（3 β-HSD）的mRNA和蛋白质表达水平都显着上调，而参与类固醇合成的其他关键基因下调。此外，砷暴露显着降低组蛋白H3 K9的二甲基化和三甲基化（H3 K9 me 2/3）在MLTC-1细胞的水平。由于H3 K9去甲基化导致基因活化，我们进一步研究了3 β-HSD表达的诱导是否归因于H3 K9甲基化的降低。结果表明，H3 K9 me 2/3去甲基化酶（JMJD 2A）抑制剂槲皮素（Que）可显著抑制砷诱导的H3 K9 me 2/3表达的降低和3 β-HSD表达的升高。为了进一步阐明3 β-HSD的激活机制，我们测定了砷暴露后Hsd 3b基因启动子区组蛋白H3 K9甲基化水平，结果也显示砷暴露后研究区域H3 K9 me 2/3显著降低。考虑到这些结果，我们得出结论，砷暴露诱导3 β-HSD上调通过抑制H3 K9 me 2/3状态，这被认为是MLTC-1细胞中类固醇合成障碍的补偿机制。(C)2017爱思唯尔公司All rights reserved.
Arsenic exposure has been associated with male reproductive dysfunction by disrupting steroidogenesis; however, the roles of epigenetic drivers, especially histone methylation in arsenic-induced steroidogenic toxicity remain not well documented. In this study, we investigated the role of histone H3 lysine 9 (H3K9) methylation in steroidogenesis disturbance in mouse Leydig cells (MLTC-1) due to arsenic exposure. Our results indicated that mRNA and protein expression levels of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) were both significantly up-regulated while the rest of key genes involved in steroidogenesis were down-regulated. Moreover, arsenic exposure significantly decreased the histone H3K9 di- and tri-methylation (H3K9me2/3) levels in MLTC-1 cells. Since H3K9 demethylation leads to gene activation, we further investigated whether the induction of 3 beta-HSD expression was ascribed to reduced H3K9 methylation. The results showed that H3K9me2/3 demethylase (JMJD2A) inhibitor, quercetin (Que) significantly attenuated the decrease of H3K9me2/3 and increase of 3 beta-HSD expression induced by arsenic. To further elucidate the mechanism for the activation of 3 beta-HSD, we determined the histone H3K9 methylation levels in Hsd3b gene promoter, which also showed significant decrease of H3K9me2/3 in the investigated region after arsenic exposure. Considering these results, we conclude that arsenic exposure induced 3 beta-HSD up-regulation by suppressing H3K9me2/3 status, which is suggested as a compensatory mechanism for steroidogenic disturbance in MLTC-1 cells. (C) 2017 Elsevier Inc. All rights reserved.