Many studies report that cadmium chloride (CdCl2)-induces oxidative stress is associated with male reproductive damage in the testes. CdCl2 also induces mitochondrial fission by increasing dynamin-related protein 1 (Drp1) expression as well as the mitochondria-dependent apoptosis pathway by extracellular signal-regulated kinase (ERK) activation. However, it remains unclear whether mechanisms linked to the mitochondrial damage signal via CdCl2-induced mitogen-activated protein kinases (MAPK) cause damage to spermatocytes. In this study, increased intracellular and mitochondrial reactive oxygen species (ROS) levels, mitochondrial membrane potential (∆Ψm) depolarization, and mitochondrial fragmentation and swelling were observed at 5 μM of CdCl2 exposure, resulting in increased apoptotic cell death. Moreover, CdCl2-induced cell death is closely associated with the ERK/Drp1/p38 signaling axis. Interestingly, SB203580, a p38 inhibitor, effectively prevented CdCl2-induced apoptotic cell death by reducing ∆Ψm depolarization and intracellular and mitochondrial ROS levels. Knockdown of Drp1 expression diminished CdCl2-induced mitochondrial deformation and ROS generation and protected GC-2spd cells from apoptotic cell death. In addition, electron microscopy showed that p38 inhibition reduced CdCl2-induced mitochondrial interior damage more effectively than N-acetyl-L-cysteine (NAC), an ROS scavenger; ERK inhibition; or Drp1 knockdown. Therefore, these results demonstrate that inhibition of p38 activity prevents CdCl2-induced apoptotic GC-2spd cell death by reducing depolarization of mitochondrial membrane potential and mitochondrial ROS levels via ERK phosphorylation in a signal pathway different from the CdCl2-induced ERK/Drp1/p38 axis and suggest a therapeutic strategy for CdCl2-induced male infertility.

中文翻译：

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通过抑制p38活性来增加ERK磷酸化，可防止精子细胞衍生的GC-2spd细胞中通过ERK / Drp1 / p38信号轴对镉诱导的凋亡细胞死亡。

许多研究报告说，氯化镉（CdCl2）引起的氧化应激与睾丸中的雄性生殖损伤有关。CdCl2还通过增加动力蛋白相关蛋白1（Drp1）的表达以及通过细胞外信号调节激酶（ERK）激活的线粒体依赖性凋亡途径来诱导线粒体裂变。但是，尚不清楚通过CdCl2诱导的丝裂原活化蛋白激酶（MAPK）与线粒体损伤信号相关的机制是否引起精细胞的损伤。在这项研究中，在5μMCdCl2暴露下观察到细胞内和线粒体活性氧（ROS）水平升高，线粒体膜电位（∆m）去极化以及线粒体破碎和肿胀，导致凋亡细胞死亡增加。而且，CdCl2诱导的细胞死亡与ERK / Drp1 / p38信号转导轴密切相关。有趣的是，p38抑制剂SB203580可通过降低∆mm去极化以及细胞内和线粒体ROS的水平来有效预防CdCl2诱导的凋亡细胞死亡。减少Drp1表达减少了CdCl2诱导的线粒体变形和ROS的产生，并保护GC-2spd细胞免于凋亡。此外，电子显微镜显示，p38抑制比ROS清除剂N-乙酰-L-半胱氨酸（NAC）更有效地减少了CdCl2诱导的线粒体内部损伤。抑制ERK; 或Drp1组合式。所以，