title: Nonylphenol-induced apoptotic cell death in mouse TM4 Sertoli cells via the generation of reactive oxygen species and activation of the ERK signaling pathway.
abstract: Nonylphenol (NP), a representative endocrine disruptor, interferes with reproductive function in aquatic organisms and animals. Although many previous studies have focused on apoptotic cell death by NP, the fundamental mechanism of NP on apoptosis remains poorly understood. Here, we investigated the molecular mechanism on NP-induced apoptotic cell death in mouse TM4 Sertoli cells. To evaluate NP treatment on cell viability, formazan and lactate dehydrogenase (LDH) assays were performed. Results indicate that NP reduced cell viability and increased the release of LDH in dose- and time-dependent manners. The reduction of cell viability by NP treatment appeared to involve necrosis as well as apoptosis based on nuclear fragmentation, an increase in the sub G1 population, and the detection of poly(ADP ribose) polymerase and caspase-3 cleavage. Additionally, the anti-apoptotic protein Bcl-2 diminished, whereas the pro-apoptotic protein Bax increased in a time-dependent manner. Note that NP-induced apoptotic cell death was enhanced by the generation of reactive oxygen species (ROS) and activation of extracellular signal-regulated kinase (ERK) signaling. Pretreatment with N-acetylcysteine, an antioxidant, attenuated NP-induced apoptotic cell death. Moreover, NP caused a transient activation of the MAPK pathway. In particular, NP-induced cell death was significantly suppressed by U0126, a specific inhibitor of ERK. Taken together, our results suggest that NP induces apoptosis in mouse TM4 Sertoli cells via ROS generation and ERK activation.
authors.affiliation: Division of Toxicological Research, Korea Institute of Toxicology, Daejeon, 305-343, Korea.
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Choi
authors.forename: Han-Jin
authors.initials: HJ
authors.lastname: Park
authors.forename: Jung-Hwa
authors.initials: JH
authors.lastname: Oh
authors.forename: Eun-Hee
authors.initials: EH
authors.lastname: Lee
authors.forename: Se-Myo
authors.initials: SM
authors.lastname: Park
authors.forename: Seokjoo
authors.initials: S
authors.lastname: Yoon
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects*; D010636:Phenols / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012708:Sertoli Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000975:Antioxidants; D052244:Endocrine Disruptors; D010636:Phenols; D047428:Protein Kinase Inhibitors; D017382:Reactive Oxygen Species; C025256:nonylphenol; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: MAPK signaling; ROS; Sertoli cells; TM4; apoptosis; nonylphenol