title: The roles of DNA damage-dependent signals and MAPK cascades in tributyltin-induced germline apoptosis in Caenorhabditis elegans.
abstract: The induction of apoptosis is recognized to be a major mechanism of tributyltin (TBT) toxicity. However, the underlying signaling pathways for TBT-induced apoptosis remain unclear. In this study, using the nematode Caenorhabditis elegans, we examined whether DNA damage response (DDR) pathway and mitogen-activated protein kinase (MAPK) signaling cascades are involved in TBT-induced germline apoptosis and cell cycle arrest. Our results demonstrated that exposing worms to TBT at the dose of 10nM for 6h significantly increased germline apoptosis in N2 strain. Germline apoptosis was absent in strains that carried ced-3 or ced-4 loss-of-function alleles, indicating that both caspase protein CED-3 and Apaf-1 protein CED-4 were required for TBT-induced apoptosis. TBT-induced apoptosis was blocked in the Bcl-2 gain-of-function strain ced-9(n1950), whereas TBT induced a minor increase in the BH3-only protein EGL-1 mutated strain egl-1(n1084n3082). Checkpoint proteins HUS-1 and CLK-2 exerted proapoptotic effects, and the null mutation of cep-1, the homologue of tumor suppressor gene p53, significantly inhibited TBT-induced apoptosis. Apoptosis in the loss-of-function strains of ERK, JNK and p38 MAPK signaling pathways were completely or mildly suppressed under TBT stress. These results were supported by the results of mRNA expression levels of corresponding genes. The present study indicated that TBT-induced apoptosis required the core apoptotic machinery, and that DDR genes and MAPK pathways played essential roles in signaling the processes.
authors.affiliation: Department of Life Sciences, Huainan Normal University, Huainan, Anhui 232001, PR China. Electronic address: yunwang2001@163.com.
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Life Sciences, Huainan Normal University, Huainan, Anhui 232001, PR China.
authors.forename: Shunchang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Life Sciences, Huainan Normal University, Huainan, Anhui 232001, PR China.
authors.forename: Xun
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Life Sciences, Huainan Normal University, Huainan, Anhui 232001, PR China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Life Sciences, Huainan Normal University, Huainan, Anhui 232001, PR China.
authors.forename: Fenglei
authors.initials: F
authors.lastname: Jian
authors.affiliation: Department of Life Sciences, Huainan Normal University, Huainan, Anhui 232001, PR China.
authors.forename: Xuemin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Life Sciences, Huainan Normal University, Huainan, Anhui 232001, PR China.
authors.forename: Lucheng
authors.initials: L
authors.lastname: Xie
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D017173:Caenorhabditis elegans / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D005854:Germ Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D015398:Signal Transduction / Q000187:drug effects; D034501:Telomere-Binding Proteins / Q000378:metabolism; D014220:Trialkyltin Compounds / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C438244:CEP-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D034501:Telomere-Binding Proteins; D014220:Trialkyltin Compounds; D016159:Tumor Suppressor Protein p53; C438752:clk-2 protein, C elegans; C011559:tributyltin; D020928:Mitogen-Activated Protein Kinases
keywords: Apoptosis; Caenorhabditis elegans; DNA damage response; MAPK; Tributyltin