Endosulfan as a new member of persistent organic pollutants has been shown to induce apoptosis in various animal models. However, the mechanism underlying endosulfan-induced apoptosis has not been well elucidated thus far. Caenorhabditis elegans N2 wild type and mutant strains were used in the present study to clarify the roles of the mitochondria, the insulin/insulin-like growth factor-1 (IGF-1) signaling pathway, and mitogen-activated protein kinase (MAPK) cascades in α-endosulfan-induced apoptosis. Our results demonstrated a dose- and time-dependent increase of apoptosis in the meiotic zone of the gonad of C. elegans exposed to graded concentrations of endosulfan. The expression levels of sod-3, localized in the mitochondrial matrix, increased greatly after endosulfan exposure. A significant increase in germ cell apoptosis was observed in abnormal methyl viologen sensitivity-1 (mev-1(kn-1)) mutants (with abnormal mitochondrial respiratory chain complex II and higher ROS levels) compared to that in N2 at equal endosulfan concentrations. We found that the insulin/IGF-1 signaling pathway and its downstream Ras/ERK/MAPK did not participate in the endosulfan-induced apoptosis. However, the apoptosis in the loss-of-function strains of JNK and p38 MAPK signaling pathways was completely or mildly suppressed under endosulfan stress. The apoptotic effects of endosulfan were blocked in the mutants of jnk-1/JNK-MAPK, sek-1/MAP2K, and pmk-1/p38-MAPK, suggesting that these downstream genes play an essential role in endosulfan-induced germ cell apoptosis. In contrast, the mkk-4/MAP2K and nsy-1/MAP3K were only partially involved in the apoptosis induction. Our data provide evidence that endosulfan increases germ cell apoptosis, which is regulated by mitochondrial function, JNK and p38 MAPK cascades. These findings contribute to the understanding of the signal transduction pathways involved in endosulfan-induced apoptosis.

中文翻译：

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线粒体和MAPK级联调节线粒体秀丽隐杆线虫中硫丹诱导的种系凋亡。

硫丹作为持久性有机污染物的新成员已显示出在各种动物模型中诱导细胞凋亡。然而，到目前为止，硫丹引起的细胞凋亡的机制尚未得到很好的阐明。本研究使用秀丽隐杆线虫N2野生型和突变株来阐明线粒体，胰岛素/胰岛素样生长因子-1（IGF-1）信号通路和丝裂原激活的蛋白激酶（MAPK）级联的作用。在α-硫丹诱导的细胞凋亡中。我们的研究结果表明，暴露于浓度分级的硫丹的秀丽隐杆线虫性腺减数分裂区中凋亡的剂量和时间依赖性增加。暴露于硫丹后，位于线粒体基质中的sod-3的表达水平大大提高。与相同硫丹浓度下的N2相比，异常甲基甲基紫精敏感性-1（mev-1（kn-1））突变体（具有异常线粒体呼吸链复合物II和更高的ROS水平）的生殖细胞凋亡显着增加。我们发现胰岛素/ IGF-1信号通路及其下游的Ras / ERK / MAPK不参与硫丹诱导的细胞凋亡。然而，在硫丹胁迫下，功能丧失的JNK和p38 MAPK信号通路中的细胞凋亡被完全或轻度抑制。硫丹的凋亡在jnk-1 / JNK-MAPK，sek-1 / MAP2K和pmk-1 / p38-MAPK突变体中被阻断，表明这些下游基因在硫丹诱导的生殖细胞凋亡中起重要作用。相比之下，mkk-4 / MAP2K和nsy-1 / MAP3K仅部分参与细胞凋亡的诱导。我们的数据提供了硫丹增加生殖细胞凋亡的证据，这是由线粒体功能，JNK和p38 MAPK级联调节的。这些发现有助于理解与硫丹诱导的细胞凋亡有关的信号转导途径。