PMID- 30502697 OWN - NLM STAT- MEDLINE DCOM- 20190225 LR - 20190225 IS - 1879-1298 (Electronic) IS - 0045-6535 (Linking) VI - 218 DP - 2019 Mar TI - RIP1 and RIP3 contribute to Tributyltin-induced toxicity in vitro and in vivo. PG - 589-598 LID - S0045-6535(18)32248-3 [pii] LID - 10.1016/j.chemosphere.2018.11.140 [doi] AB - Tributyltin (TBT), a widely distributed environmental pollutant, is toxic to animals and human beings. Although its toxicity, especially the immunosuppressive effect, has been reported a lot, the underlying molecular mechanisms are still unclear. In this study, we investigated the mechanisms of TBT-induced cytotoxicity both in vitro and in vivo. TBT induced cell death in both J774A.1 macrophages and mouse bone marrow-derived macrophages (BMDMs) as measured by the LDH and Annexin V-FITC/PI dual staining assays. Pretreatment with RIP1 inhibitor Necrostatin-1 (Nec-1) or transfection with Rip1 siRNA significantly suppressed TBT-induced cytotoxicity in J774A.1 macrophages or human embryonic kidney cell line (HEK293 cells). TBT-induced cell death was also markedly inhibited in RIP3(-/-) BMDMs. In agreement with in vitro results, TBT-induced in vivo immunotoxic effects including leukocyte depletion and thymus atrophy were significantly attenuated in RIP3(-/-) mice or WT mice treated with Nec-1. Notably, the mortality rate induced by TBT was remarkably reduced in RIP3(-/-) mice (100% vs. 12.5% lethality) or Nec-1-treated mice (100% vs. 59.2% lethality) respectively. These results reveal a critical role of RIP1 and RIP3 in TBT-induced toxicity both in vitro and in vivo. CI - Copyright (c) 2018 Elsevier Ltd. All rights reserved. FAU - Ling, Ling AU - Ling L AD - School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China. FAU - Wen, Jingjing AU - Wen J AD - School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China. FAU - Tao, Liang AU - Tao L AD - School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China. FAU - Zhao, Mengshu AU - Zhao M AD - School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China. FAU - Ge, Wenhao AU - Ge W AD - School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China. FAU - Wang, Lei AU - Wang L AD - School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China. FAU - Zhang, Jianfa AU - Zhang J AD - School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China. FAU - Weng, Dan AU - Weng D AD - School of Environmental and Biological Engineering, Nanjing University of Science & Technology, 200 Xiaolingwei Street, Nanjing, 210094, China. Electronic address: danweng@njust.edu.cn. LA - eng PT - Journal Article DEP - 20181124 PL - England TA - Chemosphere JT - Chemosphere JID - 0320657 RN - 0 (AGFG1 protein, human) RN - 0 (GTPase-Activating Proteins) RN - 0 (Imidazoles) RN - 0 (Immunosuppressive Agents) RN - 0 (Indoles) RN - 0 (Nuclear Pore Complex Proteins) RN - 0 (RNA-Binding Proteins) RN - 0 (Ralbp1 protein, mouse) RN - 0 (Trialkyltin Compounds) RN - 0 (necrostatin-1) RN - 4XDX163P3D (tributyltin) RN - EC 2.7.11.1 (Receptor-Interacting Protein Serine-Threonine Kinases) RN - EC 2.7.11.1 (Ripk3 protein, mouse) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Cell Death/drug effects/physiology MH - GTPase-Activating Proteins/antagonists & inhibitors/genetics/*metabolism MH - HEK293 Cells MH - Humans MH - Imidazoles/pharmacology MH - Immunosuppressive Agents/toxicity MH - Indoles/pharmacology MH - Macrophages/drug effects MH - Mice, Inbred C57BL MH - Mice, Mutant Strains MH - Nuclear Pore Complex Proteins/antagonists & inhibitors/genetics/metabolism MH - RNA-Binding Proteins/antagonists & inhibitors/genetics/metabolism MH - Receptor-Interacting Protein Serine-Threonine Kinases/genetics/*metabolism MH - Trialkyltin Compounds/*toxicity EDAT- 2018/12/05 06:00 MHDA- 2019/02/26 06:00 CRDT- 2018/12/04 06:00 PHST- 2018/10/19 00:00 [received] PHST- 2018/11/21 00:00 [revised] PHST- 2018/11/22 00:00 [accepted] PHST- 2018/12/05 06:00 [pubmed] PHST- 2019/02/26 06:00 [medline] PHST- 2018/12/04 06:00 [entrez] AID - S0045-6535(18)32248-3 [pii] AID - 10.1016/j.chemosphere.2018.11.140 [doi] PST - ppublish SO - Chemosphere. 2019 Mar;218:589-598. doi: 10.1016/j.chemosphere.2018.11.140. Epub 2018 Nov 24.