Cytotoxic mechanism related to dihydrolipoamide dehydrogenase in Leydig cells exposed to heavy metals
Cytotoxic mechanism related to dihydrolipoamide dehydrogenase in Leydig cells exposed to heavy metals
复制标题
重金属暴露间质细胞二氢硫辛酰胺脱氢酶相关的细胞毒性机制
DOI：
10.1016/j.tox.2015.05.003
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发表时间：
2015-08-06
期刊：
影响因子：
4.5
通讯作者：
Zhang, Qihao
中科院分区：
文献类型：
--
作者：
Ji, Xunmin;Li, Zhiliang;Zhang, Qihao
重金属是一种常见的环境毒物，对甾体生物合成有不良影响。线粒体在重金属对Leydig细胞的毒性机制中的重要性近年来得到了广泛的重视。但它仍然鲜为人知。我们前期的研究发现，镉暴露后，Leydig细胞线粒体上的二氢硫辛酰胺脱氢酶（DLD）活性显著降低，提示DLD可能参与镉的细胞毒性作用。因此，在大鼠和R2 C细胞暴露于镉，锰和铅，DLD的表达的改变进行了验证，并在本研究中的类固醇合成途径cAMP/PKA-ERK 1/2中的作用进行了研究。在OLD低表达的情况下，重金属通过抑制cAMP/PKA、PKC信号通路和类固醇生成酶星星、CYP 11 A1和3 β-HSD的活化而显著降低类固醇激素水平。在R2 C细胞中敲低DLD后，孕酮合成减少40%，并且细胞内cAMP浓度、星星、3 β-HSD、PICA的蛋白表达以及ERK 112的磷酸化也降低。这些结果表明，DLD在Leyig细胞中被下调，并与重金属暴露的类固醇生物合成有关; cAMP/PKA作为OLD的下游效应分子，激活ERK 1/2的磷酸化，启动类固醇合成。(C)2015爱思唯尔爱尔兰有限公司版权所有。
Heavy metals are common environmental toxicants with adverse effects on steroid biosynthesis. The importance of mitochondria has been recognized in cytotoxic mechanism of heavy metals on Leydig cells these years. But it is still poorly known. Our previous study reported that dihydrolipoamide dehydrogenase (DLD) located on the mitochondria was significantly decreased in Leydig cells exposed to cadmium, which suggested that DLD might be involved in the cytotoxic effects. Therefore, the altered expression of DLD was validated in rats and R2C cells exposed to cadmium, manganese and lead, and the role of DLD in the steroid synthesis pathway cAMP/PKA-ERK1/2 was investigated in this study. With a low expression of OLD, heavy metals dramatically reduced the levels of steroid hormone by inhibiting the activation of cAMP/PKA, PKC signaling pathway and the steroidogenic enzymes StAR, CYP11A1 and 3 beta-HSD. After knockdown of DLD in R2C cells, progesterone synthesis was reduced by 40%, and the intracellular concentration of cAMP, protein expression of StAR, 3 beta-HSD, PICA, and the phosphorylation of ERK1 12 were also decreased. These results highlight that DLD is down-regulation and related to steroid biosynthesis in Leyig cells exposed to heavy metals; cAMP/PKA act as downstream effector molecules of OLD, which activate phosphorylation of ERK1/2 to initiate the steroidogenesis. (C) 2015 Elsevier Ireland Ltd. All rights reserved.