title: Involvement of CaM-CaMKII-ERK in bisphenol A-induced Sertoli cell apoptosis.
abstract: Bisphenol A (BPA), one of the most prevalent chemicals for daily use, has been reported as a xenoestrogen to induce reproductive toxicity, but its mechanism is poorly understood. In the present study, we aimed to explore whether CaM-CaMKII-ERK1/2 signaling pathway was involved in BPA-induced Sertoli cells injury via the mitochondrial apoptotic pathway. TM4 cells were cultured with 0, 0.02, 0.2, 2.0, 20μM BPA, and cell viability, mitochondrial function and CaM-CaMKII-ERK1/2 signal pathway were examined. With the MTT assay, BPA was found to suppress cell viability in a dose- and time-dependent manner. Moreover, mitochondrial mass loss, membrane potential decrease, cytochrome c release, Bcl-2 family members down-regulation and caspases-3 up-regulation were obviously observed when the TM4 cells were exposed to BPA. Additionally, the expression of calmodulin (CaM) and phosphorylation of calcium/calmodulin dependent kinase II (CaMKII) significantly increased, and pretreatment with 10μM antagonist of CaM (W-7) or CaMKII (KN62) prevented cell damage through mitochondrial apoptotic pathway. In parallel, ERK1/2 pathway was proved to participate in BPA-induced cell damage, since W-7 and KN62 partially suppressed ERK1/2 activation, and PD98059, the ERK1/2 antagonist, significantly attenuated BPA-induced cell damage. These data, taken together, indicated that CaM-CaMKII-ERK axis might transmit apoptotic signals to the mitochondria during BPA-induced cell apoptosis. By exploring the mechanisms of the Ca(2+) homeostasis and the corresponding proteins, our study provides new insight into BPA-induced reproductive toxicity.
authors.affiliation: Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Wenyi
authors.initials: W
authors.lastname: Qian
authors.affiliation: Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jingying
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China; Department of Oncology, Affiliated Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing 210000, China.
authors.forename: Changfei
authors.initials: C
authors.lastname: Mao
authors.affiliation: Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China; Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing 210000, China.
authors.forename: Jingli
authors.initials: J
authors.lastname: Liu
authors.affiliation: Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yixin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Preventive Medicine, School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang 212013, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Gao
authors.affiliation: Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hang
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Key Lab of Modern Toxicology (NJMU), Ministry of Education, Department of Toxicology, School of Public Health, Nanjing Medical University, Nanjing 210029, China. Electronic address: wangjun@njmu.edu.cn.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001559:Benzhydryl Compounds / Q000633:toxicity*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000633:toxicity*; D004789:Enzyme Activation; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010636:Phenols / Q000633:toxicity*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D012708:Sertoli Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D000098826:Bisphenol A Compounds
chemical_list: D001559:Benzhydryl Compounds; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002147:Calmodulin; D053148:Caspase 3; D045304:Cytochromes c; D052244:Endocrine Disruptors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010636:Phenols; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C535148:Mapk1 protein, mouse; C505409:Casp3 protein, mouse; C006780:bisphenol A; D000098826:Bisphenol A Compounds
keywords: Apoptosis; Bisphenol A; Calcium/calmodulin dependent protein kinase II; Calmodulin; ERK1/2