4-Nonylphenol induces apoptosis, autophagy and necrosis in Sertoli cells: Involvement of ROS-mediated AMPK/AKT-mTOR and JNK pathways
4-Nonylphenol induces apoptosis, autophagy and necrosis in Sertoli cells: Involvement of ROS-mediated AMPK/AKT-mTOR and JNK pathways
复制标题
4-壬基酚诱导支持细胞凋亡、自噬和坏死：ROS 介导的 AMPK/AKT-mTOR 和 JNK 通路的参与
DOI：
10.1016/j.tox.2016.01.004
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发表时间：
2016-02-03
期刊：
影响因子：
4.5
通讯作者：
Yang, Kedi
中科院分区：
文献类型：
--
作者：
Duan, Peng;Hu, Chunhui;Yang, Kedi
外源雌激素4-壬基酚（NP）引起雄性大鼠生殖功能障碍，但其根本机制尚未明确。支持细胞（SCs）是精子发生和男性生育的关键。研究了自噬在np诱导的细胞凋亡和坏死死亡中的作用。在本研究中，将SCs暴露于20-30 μ M NP 24小时会降低细胞活力，导致G2/M停滞，引发δ Psi M损失，增加ROS产生，诱导caspase依赖性凋亡、坏死和自噬体形成。单胺尸胺染色和LC3-I/LC3-II转化证实了np诱导的自噬。此外，NP上调（Thr）172p- AMPK/AMPK和（Thr183/185）p-JNK/JNK比值。随后是Ser(473)p-Akt/Akt, (Thr1462)p-TSC2/TSC2, (ser2448)p-mTOR/mTOR, (Thr389)p-p70S6K/p70S6K和（Thr37/45）p-4EBP1/4EBP1的下调。有趣的是，n -乙酰半胱氨酸可以通过阻断ROS的产生来抑制np诱导的细胞凋亡、自噬和坏死。自噬抑制剂3-MA增强np诱导的细胞凋亡和坏死。此外，NP诱导的AMPK/mTOR/p70s6k/4EBP1和JNK信号通路的激活可以通过n -乙酰半胱氨酸或3-MA预处理有效逆转。总的来说，我们的研究结果首次证明了NP同时促进SCs的凋亡、自噬和坏死，并且这一过程可能涉及ros依赖性的JNK-和Akt/AMPK/mTOR通路。NP诱导的自噬调节可能是抗细胞凋亡和坏死的生存机制。2016爱思唯尔爱尔兰有限公司版权所有。
The xenoestrogen 4-nonylphenol (NP) induces reproductive dysfunction of male rats, but the fundamental mechanism of this phenomenon is largely unexplored. Sertoli cells (SCs) are pivotal for spermatogenesis and male fertility. The involvement of autophagy in NP-induced apoptotic and necrotic death of SCs was investigated. In this study, 24-h exposure of SCs to 20-30 mu M NP decreased cell viability, caused G2/M arrest, triggered Delta Psi m loss, increased ROS production and induced caspase-dependent apoptsis, necrosis as well as autophagosome formation. NP-induced autophagy was confirmed by monodansylcadaverine-staining and LC3-I/LC3-II conversion. Furthermore, NP up-regulated the (Thr)172p- AMPK/AMPK and (Thr183/185)p-JNK/JNK ratios. This was followed by the down-regulation of Ser(473)p-Akt/Akt, (Thr1462)p-TSC2/TSC2, (ser2448)p-mTOR/mTOR, (Thr389)p-p70S6K/p70S6K and (Thr37/45)p-4EBP1/4EBP1. Intriguingly, NP-induced apoptosis, autophagy and necrosis could be inhibited through blocking ROS generation by N-acetylcysteine. Autophagy inhibitor 3-MA enhanced NP-induced apoptosis and necrosis. Moreover, The activation of AMPK/mTOR/p70s6k/4EBP1 and JNK signalling pathways induced by NP could be efficiently reversed by pretreatment of N-acetylcysteine or 3-MA. Collectively, our findings provide the first evidence that NP promotes apoptosis, autophagy and necrosis simultaneously in SCs and that this process may involve ROS-dependent JNK- and Akt/AMPK/mTOR pathways. Modulation of autophagy induced by NP may serve as a survival mechanism against apoptosis and necrosis. (C) 2016 Elsevier Ireland Ltd. All rights reserved.