title: Integrated Transcriptional and Proteomic Analysis of Growth Hormone Suppression Mediated by Trichothecene T-2 Toxin in Rat GH3 Cells.
abstract: Chronic exposure to trichothecenes is known to disturb insulin-like growth factor 1 and signaling of insulin and leptin hormones and causes considerable growth retardation in animals. However, limited information was available on mechanisms underlying trichothecene-induced growth retardation. In this study, we employed an integrated transcriptomics, proteomics, and RNA interference (RNAi) approach to study the molecular mechanisms underlying trichothecene cytotoxicity in rat pituitary adenoma GH3 cells. Our results showed that trichothecenes suppressed the synthesis of growth hormone 1 (Gh1) and inhibited the eukaryotic transcription and translation initiation by suppressing aminoacyl-tRNA synthetases transcription, inducing eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) and reducing eukaryotic translation initiation factor 5 a. The sulfhydryl oxidases , protein disulfide isomerase,and heat shock protein 90 (were greatly reduced, which resulted in adverse regulation of protein processing and folding. Differential genes and proteins associated with a decline in energy metabolism and cell cycle arrest were also found in our study. However, use of RNAi to interfere with hemopoietic cell kinase (Hck) and EIF2AK2 transcriptions or use of chemical inhibitors of MAPK, p38, Ras, and JNK partially reversed the reduction of Gh1 levels induced by trichothecenes. It indicated that the activation of MAPKs, Hck, and EIF2AK2 were important for trichothecene-induced growth hormone suppression. Considering the potential hazards of exposure to trichothecenes, our findings could help to improve our understanding regarding human and animal health implications.
authors.affiliation: *National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China; Research Center of Healthy Livestock Institute of Subtropical Agriculture, Chinese Academy of Sciences, Changsha, China;
authors.forename: Dan
authors.initials: D
authors.lastname: Wan
authors.affiliation: *National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China;
authors.forename: Xu
authors.initials: X
authors.lastname: Wang
authors.affiliation: *National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues; College of Life Science, Yangtze University, Jingzhou, Hubei, China; and Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Hradec Kralove, Czech Republic.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Wu
authors.affiliation: MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China;
authors.forename: Pingping
authors.initials: P
authors.lastname: Lin
authors.affiliation: MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China;
authors.forename: Yuanhu
authors.initials: Y
authors.lastname: Pan
authors.affiliation: *National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China;
authors.forename: Adeel
authors.initials: A
authors.lastname: Sattar
authors.affiliation: *National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University;
authors.forename: Lingli
authors.initials: L
authors.lastname: Huang
authors.affiliation: *National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China;
authors.forename: Ijaz
authors.initials: I
authors.lastname: Ahmad
authors.affiliation: *National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University;
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: *National Reference Laboratory of Veterinary Drug Residues (HZAU) and MAO Key Laboratory for Detection of Veterinary Drug Residues; MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and Poultry Products, Huazhong Agricultural University; Hubei Collaborative Innovation Center for Animal Nutrition and Feed Safety, Wuhan, Hubei, China; yuan5802@mail.hzau.edu.cn.
authors.forename: Zonghui
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000604:Amino Acyl-tRNA Synthetases / Q000037:antagonists & inhibitors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D020869:Gene Expression Profiling; D013006:Growth Hormone / Q000037:antagonists & inhibitors*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D010088:Oxidoreductases / Q000037:antagonists & inhibitors; D010448:Peptide Initiation Factors / Q000037:antagonists & inhibitors; D014176:Protein Biosynthesis / Q000187:drug effects; D019704:Protein Disulfide-Isomerases / Q000037:antagonists & inhibitors; D040901:Proteomics; D034622:RNA Interference / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors; D051381:Rats; D013605:T-2 Toxin / Q000031:analogs & derivatives* / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors; D000097574:Eukaryotic Translation Initiation Factor 5A; D050862:Oxidoreductases Acting on Sulfur Group Donors
chemical_list: D000604:Amino Acyl-tRNA Synthetases; D013006:Growth Hormone; D018841:HSP90 Heat-Shock Proteins; D010088:Oxidoreductases; D010448:Peptide Initiation Factors; D019704:Protein Disulfide-Isomerases; D016601:RNA-Binding Proteins; D013605:T-2 Toxin; D019892:eIF-2 Kinase; D000097574:Eukaryotic Translation Initiation Factor 5A; D050862:Oxidoreductases Acting on Sulfur Group Donors; C055008:4'-hydroxy T-2 toxin
keywords: EIF2AK2; Gh1; Hck; growth retardation; trichothecene