Global S&T Development Trend Analysis Platform of Resources and Environment
DOI | 10.1289/EHP4949 |
Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both | |
Akiyama, Masahiro1; Unoki, Takamitsu1,2; Shinkai, Yasuhiro1; Ishii, Isao3; Ida, Tomoaki4; Akaike, Takaaki4; Yamamoto, Masayuki5; Kumagai, Yoshito1 | |
2019-06-01 | |
发表期刊 | ENVIRONMENTAL HEALTH PERSPECTIVES |
ISSN | 0091-6765 |
EISSN | 1552-9924 |
出版年 | 2019 |
卷号 | 127期号:6 |
文章类型 | Article |
语种 | 英语 |
国家 | Japan |
英文摘要 | BACKGROUND: Transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2) plays a key role in detoxification of electrophiles via formation of glutathione (GSH) adducts and subsequent excretion into extracellular spaces. We found that reactive sulfur species (RSS), such as cysteine persulfides produced by cystathionine gamma-lyase (CSE), capture environmental electrophiles through formation of sulfur adducts. However, contributions of Nrf2 and CSE to the blockage of environmental electrophile-mediated toxicity remain to be evaluated. OBJECTIVES: The aim of this study was to clarify roles that CSE and Nrf2 play in the protection against various environmental electrophiles. We also wished to clarify the molecular basis of the developmental window of toxicity through investigating expression levels of Nrf2, RSS-producing enzymes, and sulfur nucleophiles during developmental stages of mice. METHODS: Wild-type (WT), CSE knockout (KO), Nrf2 KO, Nrf2/CSE double KO (DKO) mice, and their primary hepatocytes were analyzed in this studey. Cadmium (Cd), methylmercury (MeHg), 1,4-naphthoquinone, crotonaldehyde, and acrylamide were used. We conducted Western blotting, real-time polymerase chain reaction (PCR), 3-(4,5-dimethylthiazol-2-yl)-2,5-triphenyl tetrazolium bromide (MTT) assays, liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) analysis, alanine transaminase (ALT) activity. histopathological analysis, and rotarod test. RESULTS: Primary hepatocytes from DKO mice were significantly more sensitive to the environmental electrophiles than each single KO counterpart. Both Nrf2 and CSE single KO mice were highly susceptible to Cd and MeHg, and such sensitivity was further exacerbated in the DKO mice. Lower-level expressions of CSE and sulfur nucleophiles than those in adult mice were observed in a window of developmental stage. CONCLUSIONS: Our mouse model provided new insights into the response to environmental electrophiles; while Nrf2 is recognized as a key transcription factor for detoxification of environmental electrophiles, CSE is crucial factor to repress their toxicity in a parallel mode. In addition, the sensitivity of fetuses to MeHg appears to be, at least. in part, associated with the restricted production of RSS due to low-level expression of CSE. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000474528700011 |
WOS关键词 | CYSTATHIONINE-GAMMA-LYASE ; ERYTHROID 2-RELATED FACTOR-2 ; CHEMICAL BIOLOGY ; HSP90/HSF1 PATHWAY ; ENDOTHELIAL-CELLS ; KEAP1-NRF2 SYSTEM ; HYDROGEN-SULFIDE ; OXIDATIVE STRESS ; METHYLMERCURY ; GLUTATHIONE |
WOS类目 | Environmental Sciences ; Public, Environmental & Occupational Health ; Toxicology |
WOS研究方向 | Environmental Sciences & Ecology ; Public, Environmental & Occupational Health ; Toxicology |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/183720 |
专题 | 资源环境科学 |
作者单位 | 1.Univ Tsukuba, Fac Med, Environm Biol Lab, 1-1 Tennodai, Tsukuba, Ibaraki 3058575, Japan; 2.Natl Inst Minamata Dis, Dept Basic Med Sci, Minamata, Japan; 3.Showa Pharmaceut Univ, Lab Hlth Chem, Tokyo, Japan; 4.Tohoku Univ, Grad Sch Med, Dept Environm Hlth Sci & Mol Toxicol, Sendai, Miyagi, Japan; 5.Tohoku Univ, Grad Sch Med, Dept Med Biochem, Sendai, Miyagi, Japan |
推荐引用方式 GB/T 7714 | Akiyama, Masahiro,Unoki, Takamitsu,Shinkai, Yasuhiro,et al. Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both[J]. ENVIRONMENTAL HEALTH PERSPECTIVES,2019,127(6). |
APA | Akiyama, Masahiro.,Unoki, Takamitsu.,Shinkai, Yasuhiro.,Ishii, Isao.,Ida, Tomoaki.,...&Kumagai, Yoshito.(2019).Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both.ENVIRONMENTAL HEALTH PERSPECTIVES,127(6). |
MLA | Akiyama, Masahiro,et al."Environmental Electrophile-Mediated Toxicity in Mice Lacking Nrf2, CSE, or Both".ENVIRONMENTAL HEALTH PERSPECTIVES 127.6(2019). |
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