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RIP1 and RIP3 contribute to Tributyltin-induced toxicity in vitro and in vivo

Author:
Ling, Ling, Wen, Jingjing, Tao, Liang, Zhao, Mengshu, Ge, Wenhao, Wang, Lei, Zhang, Jianfa, Weng, Dan
Source:
Chemosphere 2019 v.218 pp. 589-598
ISSN:
0045-6535
Subject:
atrophy, cell death, cytotoxicity, death, human cell lines, humans, immunosuppression, immunotoxicity, leukocytes, macrophages, mice, mortality, pollutants, small interfering RNA, staining, thymus gland, transfection, tributyltin
Abstract:
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.
Agid:
6232568