Global S&T Development Trend Analysis Platform of Resources and Environment
DOI | 10.1289/EHP5105 |
Using Collaborative Cross Mouse Population to Fill Data Gaps in Risk Assessment: A Case Study of Population-Based Analysis of Toxicokinetics and Kidney Toxicodynamics of Tetrachloroethylene | |
Luo, Yu-Syuan1; Cichocki, Joseph A.1; Hsieh, Nan-Hung1; Lewis, Lauren1; Wright, Fred A.2,3; Threadgill, David W.4; Chiu, Weihsueh A.1; Rusyn, Ivan1 | |
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 | USA |
英文摘要 | BACKGROUND: Interindividual variability in susceptibility remains poorly characterized for environmental chemicals such as tetrachloroethylene (PERC). Development of population-based experimental models provide a potential approach to fill this critical need in human health risk assessment. OBJECTIVES: In this study, we aimed to better characterize the contribution of glutathione (GSH) conjugation to kidney toxicity of PERC and the degree of associated interindividual toxicokinetic (TK) and toxicodynamic (TD) variability by using the Collaborative Cross (CC) mouse population. METHODS: Male mice from 45 strains were intragastrically dosed with PERC (1,000 mg/kg) or vehicle (5% Alkamuls EL-620 in saline), and time-course samples were collected for up to 24 h. Population variability in TK of S-(1,2,2-trichlorovinyl)GSH (TCVG), S-(1,2,2-trichlorovinyl)-L-cysteine (TCVC), and N-acetyl-S-(1,2,2-trichlorovinyl)-L-cysteine (NAcTCVC) was quantified in serum, liver, and kidney, and analyzed using a toxicokinetic model. Effects of PERC on kidney weight, fatty acid metabolism-associated genes [Acotl (Acyl-CoA thioesterase 1). Fabp1 (fatty acid-binding protein 1), and Ehhadh (enoyl-coenzyme A, hydratase/3-hydroxyacyl coenzyme A dehydrogenase)], and a marker of proximal tubular injury [KIM-1 (kidney injury molecule-])/Hepatitis A virus cellular receptor 1 (Haver1)) were evaluated. Finally, quantitative data on interstrain variability in both formation of GSH conjugation metabolites of PERC and its kidney effects was used to calculate adjustment factors for the interindividual variability in both TK and TD. RESULTS: Mice treated with PERC had significantly lower kidney weight, higher kidney-to-body weight (BW) ratio, and higher expression of fatty acid metabolism-associated genes (Acotl, Fabp1, and Ehhadh) and a marker of proximal tubular injury (KIM-1/Havcr1). Liver levels of TCVG were significantly correlated with KIM-1/Havcr1 in kidney, consistent with kidney injury being associated with GSH conjugation. We found that the default uncertainty factor for human variability may be marginally adequate to protect 95%, but not more, of the population for kidney toxicity mediated by PERC. DISCUSSION: Overall, this study demonstrates the utility of the CC mouse population in characterizing metabolism-toxicity interactions and quantifying interindividual variability. Further refinement of the characterization of interindividual variability can be accomplished by incorporating these data into in silico population models both for TK (such as a physiologically based pharmacokinetic model), as well as for toxicodynamic responses. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000474528700014 |
WOS关键词 | TISSUE-SPECIFIC TOXICITY ; FATTY LIVER-DISEASE ; TRICHLOROETHYLENE METABOLISM ; TRICHLOROACETIC-ACID ; REACTIVE METABOLITE ; PERCHLOROETHYLENE ; GLUTATHIONE ; VARIABILITY ; MECHANISMS ; S-(1,2,2-TRICHLOROVINYL)-L-CYSTEINE |
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/183717 |
专题 | 资源环境科学 |
作者单位 | 1.Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX 77843 USA; 2.North Carolina State Univ, Bioinformat Res Ctr, Raleigh, NC 27695 USA; 3.North Carolina State Univ, Dept Stat & Biol Sci, Raleigh, NC 27695 USA; 4.Texas A&M Univ, Dept Mol & Cellular Med, College Stn, TX 77843 USA |
推荐引用方式 GB/T 7714 | Luo, Yu-Syuan,Cichocki, Joseph A.,Hsieh, Nan-Hung,et al. Using Collaborative Cross Mouse Population to Fill Data Gaps in Risk Assessment: A Case Study of Population-Based Analysis of Toxicokinetics and Kidney Toxicodynamics of Tetrachloroethylene[J]. ENVIRONMENTAL HEALTH PERSPECTIVES,2019,127(6). |
APA | Luo, Yu-Syuan.,Cichocki, Joseph A..,Hsieh, Nan-Hung.,Lewis, Lauren.,Wright, Fred A..,...&Rusyn, Ivan.(2019).Using Collaborative Cross Mouse Population to Fill Data Gaps in Risk Assessment: A Case Study of Population-Based Analysis of Toxicokinetics and Kidney Toxicodynamics of Tetrachloroethylene.ENVIRONMENTAL HEALTH PERSPECTIVES,127(6). |
MLA | Luo, Yu-Syuan,et al."Using Collaborative Cross Mouse Population to Fill Data Gaps in Risk Assessment: A Case Study of Population-Based Analysis of Toxicokinetics and Kidney Toxicodynamics of Tetrachloroethylene".ENVIRONMENTAL HEALTH PERSPECTIVES 127.6(2019). |
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