title: 4-Nonylphenol induces apoptosis, autophagy and necrosis in Sertoli cells: Involvement of ROS-mediated AMPK/AKT-mTOR and JNK pathways.
abstract: 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 20-30μM NP decreased cell viability, caused G2/M arrest, triggered ΔΨm loss, increased ROS production and induced caspase-dependent apoptosis, 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 (Thr172)p-AMPK/AMPK and (Thr183/185)p-JNK/JNK ratios. This was followed by the down-regulation of (Ser473)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.
authors.affiliation: MOE (Ministry of Education) Key Lab of Environment and Health, Department of Occupational and Environmental Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Duan
authors.affiliation: Department of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine Shiyan, Hubei 442000, China.
authors.forename: Chunhui
authors.initials: C
authors.lastname: Hu
authors.affiliation: MOE (Ministry of Education) Key Lab of Environment and Health, Department of Occupational and Environmental Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Quan
authors.affiliation: MOE (Ministry of Education) Key Lab of Environment and Health, Department of Occupational and Environmental Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Yu
authors.affiliation: MOE (Ministry of Education) Key Lab of Environment and Health, Department of Occupational and Environmental Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: MOE (Ministry of Education) Key Lab of Environment and Health, Department of Occupational and Environmental Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Yuan
authors.affiliation: Department of Epidemiology and Health Statistics, School of Public Health, Medical College, Wuhan University of Science and Technology, Wuhan 430030, China.
authors.forename: Yuqin
authors.initials: Y
authors.lastname: Shi
authors.affiliation: MOE (Ministry of Education) Key Lab of Environment and Health, Department of Occupational and Environmental Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: yangkd@mails.tjmu.edu.cn.
authors.forename: Kedi
authors.initials: K
authors.lastname: Yang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D053612:Janus Kinases / Q000187:drug effects; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D009336:Necrosis; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D010636:Phenols / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012708:Sertoli Cells / Q000166:cytology* / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D010636:Phenols; D017382:Reactive Oxygen Species; C546845:mTOR protein, rat; D053612:Janus Kinases; D051058:Oncogene Protein v-akt; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C041594:4-nonylphenol
keywords: 4-Nonylphenol; AMPK/Akt/JNK signalling; Apoptosis; Autophagy; ROS; Sertoli cells