title: 4-Nonylphenol induces autophagy and attenuates mTOR-p70S6K/4EBP1 signaling by modulating AMPK activation in Sertoli cells.
abstract: The estrogenic chemical 4-nonylphenol (NP) is known to impair testicular devolopment and spermatogenesis in rodents. The objective of this study was to explore the effects of NP on autophagy induction and AMPK-mTOR signaling pathway in Sertoli cells (SCs), which are the "nursemaid cells" for meiosis of spermatocytes. In this study we exposed 7-week-old male rats to NP by intra-peritoneal injection at 0, 20, 50 or 100mg/kg body weight/2days for 20 consecutive days. Our results showed that exposure to NP dose-dependently induces the formation of autophagosomes in SCs, increases the expression of Beclin-1, the conversion of LC3-I to LC3-II and the mRNA expression of Atg3, Atg5, Atg7 and Atg12 in testis, and these effects are concomitant with the activation of AMPK, and the suppression of TSC2-mTOR-p70S6K/4EBP1 signaling cascade in testis. Furthermore, 10μM Compound C or AMPKα1 siRNA pre-treatment effectively attenuated autophagy and reversed AMPK-mTOR-p70S6K/4EBP1 signaling in NP-treated SCs. Co-treatment with 1mM AICAR remarkably strengthened NP-induced autophagy and mTOR inhibition in SCs. Together, these data suggest that NP stimulates Sertoli cell autophagy and inhibits mTOR-p70S6K/4EBP1 activity through AMPK activation, which is the potential mechanism responsible for the regulation of testis function and differentiation following NP exposure.
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; Research Center for Environment and Health, Hubei University of Medicine, Shiyan 442000, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Duan
authors.affiliation: Department of Clinical Laboratories, Taihe Hospital, Hubei University of Medicine, Shiyan 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: Wenting
authors.initials: W
authors.lastname: Huang
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: Chen
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: Sha
authors.initials: S
authors.lastname: Tang
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: School of Pharmacy and Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK.
authors.forename: Francis L
authors.initials: FL
authors.lastname: Martin
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 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D002352:Carrier Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004789:Enzyme Activation; D020536:Enzyme Activators; D004967:Estrogens / Q000633:toxicity*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D010636:Phenols / Q000633:toxicity*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D012708:Sertoli Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: D002352:Carrier Proteins; C499526:Eif4ebp1 protein, rat; D052244:Endocrine Disruptors; D020536:Enzyme Activators; D004967:Estrogens; D047908:Intracellular Signaling Peptides and Proteins; D010636:Phenols; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; C546845:mTOR protein, rat; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D055372:AMP-Activated Protein Kinases; C568305:Prkaa1 protein, rat; C041594:4-nonylphenol
keywords: 4-nonylphenol; AMPK; Autophagy; Sertoli cells; mTOR-p70S6K/4EBP1