title: Microcystin-Leucine Arginine Causes Cytotoxic Effects in Sertoli Cells Resulting in Reproductive Dysfunction in Male Mice.
abstract: Microcystin-leucine arginine (MC-LR) is a potent toxin for Sertoli cells. However, the specific molecular mechanisms of MC-induced cytotoxicity still remain unclear. In this study, we performed a comprehensive analyses of changes of miRNAs and mRNAs in Sertoli cells treated with MC-LR. Through computational approaches, we showed the pivotal roles of differentially expressed miRNAs that were associated with cell metabolism, cellular growth and proliferation, cell-to-cell signaling and interaction and cellular movement. Ingenuity Pathway Analyses (IPA) revealed some differentially expressed miRNAs and mRNAs that may cause reproductive system diseases. Target gene analyses suggested that destruction in tight junctions (TJ) and adherens junctions (AJ) in testes may be mediated by miRNAs. Consistent with a significant enrichment of chemokine signaling pathways, we observed numerous macrophages in the testes of mice following treatment with MC-LR, which may cause testicular inflammation. Moreover, miR-98-5p and miR-758 were predicted to bind the 3'-UTR region of the mitogen-activated protein kinase 11 (MAPK11, p38 β isoform) gene which stimulates tumor necrosis factor-α (TNF-α) expression in Sertoli cells. TNF-α could interact with the tumor necrosis factor receptor 1 (TNFR1) on germ cells leading to induction of germ cell apoptosis. Collectively, our integrated miRNA/mRNA analyses provided a molecular paradigm, which was experimentally validated, for understanding MC-LR-induced cytotoxicity.
authors.affiliation: Immunology and Reproduction Biology Laboratory &State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, China.|Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
authors.forename: Yabing
authors.initials: Y
authors.lastname: Chen
authors.affiliation: School of Basic Medicine, Nanjing University of Chinese Medicine, Nanjing, 210093, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Immunology and Reproduction Biology Laboratory &State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, China.|Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Immunology and Reproduction Biology Laboratory &State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, China.|Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Health Technology and Informatics, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China.
authors.forename: Zou
authors.initials: Z
authors.lastname: Xiang
authors.affiliation: Immunology and Reproduction Biology Laboratory &State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, China.|Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
authors.forename: Dongmei
authors.initials: D
authors.lastname: Li
authors.affiliation: Immunology and Reproduction Biology Laboratory &State Key Laboratory of Analytical Chemistry for Life Science, Medical School, Nanjing University, Nanjing, 210093, China.|Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Han
mesh_terms: D022005:Adherens Junctions / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D053263:Gene Regulatory Networks / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D052998:Microcystins / Q000633:toxicity*; D048290:Mitogen-Activated Protein Kinase 11 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012098:Reproduction / Q000187:drug effects*; D012708:Sertoli Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013737:Testis / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D019108:Tight Junctions / Q000187:drug effects / Q000378:metabolism; D059467:Transcriptome / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D052998:Microcystins; D016760:Proto-Oncogene Proteins c-fos; D014409:Tumor Necrosis Factor-alpha; C078588:microcystin; D048031:JNK Mitogen-Activated Protein Kinases; D048290:Mitogen-Activated Protein Kinase 11