title: 4-Nonylphenol induces disruption of spermatogenesis associated with oxidative stress-related apoptosis by targeting p53-Bcl-2/Bax-Fas/FasL signaling.
abstract: 4-Nonylphenol (NP) is a ubiquitous environmental chemical with estrogenic activity. Our aim was to test the hypothesis that pubertal exposure to NP leads to testicular dysfunction. Herein, 24 7-week-old rats were randomly divided into four groups and treated with NP (0, 25, 50, or 100 mg/kg body weight every 2 days for 20 consecutive days) by intraperitoneal injection. Compared to untreated controls, the parameters of sperm activation rate, curvilinear velocity, average path velocity, and swimming velocity were significantly lower at doses of 100 mg/kg, while sperm morphological abnormalities were higher, indicating functional disruption and reduced fertilization potential. High exposure to NP (100 mg/kg) resulted in disordered arrangement of spermatoblasts and reduction of spermatocytes in seminiferous tubules, while tissues exhibited a marked decline in testicular fructose content and serum FSH, LH, and testosterone levels. Oxidative stress was induced by NP (50 or 100 mg/kg) as evidenced by elevated MDA, decreased SOD and GSH-Px, and inhibited antioxidant gene expression (CAT, GPx, SOD1, and CYP1B1). In addition, NP treatment decreased proportions of Ki-67-positive cells and increased apoptosis in a dose-dependent manner. Rats treated with 100 mg/kg NP exhibited significantly increased mRNA expression of caspase-1, -2, -9, and -11, decreased caspase-8 and PCNA1 mRNA expression, downregulation of Bcl-2/Bax ratios and upregulation of Fas, FasL, and p53 at the protein and mRNA levels. Taken together, NP-induced apoptosis, hormonal deficiencies, and depletion of fructose potentially impairs spermatogenesis and sperm function. p53-independent Fas/FasL-Bax/Bcl-2 pathways may be involved in NP-induced oxidative stress-related apoptosis. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 739-753, 2017.
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: Centre for Biophotonics, Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster, LA1 4YQ, United Kingdom.
authors.forename: Holly J
authors.initials: HJ
authors.lastname: Butler
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: 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: 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: Sha
authors.initials: S
authors.lastname: Tang
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: Centre for Biophotonics, Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster, LA1 4YQ, United Kingdom.
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.
authors.forename: Kedi
authors.initials: K
authors.lastname: Yang
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000235:genetics / Q000378:metabolism; D053222:Fas Ligand Protein / Q000235:genetics / Q000378:metabolism; D005632:Fructose / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D018384:Oxidative Stress / Q000187:drug effects*; D010636:Phenols / Q000633:toxicity*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D013091:Spermatogenesis / Q000187:drug effects*; D013094:Spermatozoa / Q000187:drug effects / Q000502:physiology; D013737:Testis / Q000378:metabolism / Q000648:ultrastructure; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D053222:Fas Ligand Protein; D010636:Phenols; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D005632:Fructose; D020169:Caspases; C041594:4-nonylphenol
keywords: 4-nonylphenol; apoptosis; endocrine disruptor; oxidative stress; spermatogenesis; testicular dysfunction