Global S&T Development Trend Analysis Platform of Resources and Environment
DOI | 10.1289/EHP788 |
Characterization of Variability in Toxicokinetics and Toxicodynamics of Tetrachloroethylene Using the Collaborative Cross Mouse Population | |
Cichocki, Joseph A.1; Furuya, Shinji1; Venkatratnam, Abhishek1; McDonald, Thomas J.2; Knap, Anthony H.3; Wade, Terry3; Sweet, Stephen3; Chiu, Weihsueh A.1; Threadgill, David W.4; Rusyn, Ivan1 | |
2017-05-01 | |
发表期刊 | ENVIRONMENTAL HEALTH PERSPECTIVES |
ISSN | 0091-6765 |
EISSN | 1552-9924 |
出版年 | 2017 |
卷号 | 125期号:5 |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | BACKGROUND: Evaluation of interindividual variability is a challenging step in risk assessment. For most environmental pollutants, including perchloroethylene (PERC), experimental data are lacking, resulting in default assumptions being used to account for variability in toxicokinetics and toxicodynamics. OBJECTIVE: We quantitatively examined the relationship between PERC toxicokinetics and toxicodynamics at the population level to test whether individuals with increased oxidative metabolism are be more sensitive to hepatotoxicity following PERC exposure. METHODS: Male mice from 45 strains of the Collaborative Cross (CC) were orally administered a single dose of PERC (1,000 mg/kg) or vehicle (Alkamuls-EL620) and euthanized at various time points (n = 1/strain/time). Concentrationtime profiles were generated for PERC and its primary oxidative metabolite trichloroacetate (TCA) in multiple tissues. Toxicodynamic phenotyping was also performed. RESULTS: Significant variability among strains was observed in toxicokinetics of PERC and TCA in every tissue examined. Based on area under the curve (AUC), the range of liver TCA levels spanned nearly an order of magnitude (similar to 8-fold). Expression of liver cytochrome P4502E1 did not correlate with TCA levels. Toxicodynamic phenotyping revealed an effect of PERC on bodyweight loss, induction of peroxisome proliferator activated receptor-alpha (PPAR alpha)-regulated genes, and dysregulation of hepatic lipid homeostasis. Clustering was observed among a) liver levels of PERC, TCA, and triglycerides; b) TCA levels in liver and kidney; and c) TCA levels in serum, brain, fat, and lung. CONCLUSIONS: Using the CC mouse population model, we have demonstrated a complex and highly variable relationship between PERC and TCA toxicokinetics and toxicodynamics at the population level. https://doi.org/10.1289/EHP788. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000413786500007 |
WOS关键词 | TRICHLOROETHYLENE METABOLISM ; ENVIRONMENTAL CHEMICALS ; PERCHLOROETHYLENE ; MICE ; TOXICITY ; EXPOSURE ; RATS ; PHARMACOKINETICS ; CARCINOGENICITY ; HEPATOTOXICITY |
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/22569 |
专题 | 资源环境科学 |
作者单位 | 1.Texas A&M Univ, Dept Vet Integrat Biosci, College Stn, TX USA; 2.Texas A&M Univ, Dept Environm & Occupat Hlth, College Stn, TX USA; 3.Texas A&M Univ, Geochem & Environm Res Grp, College Stn, TX USA; 4.Texas A&M Univ, Dept Mol & Cellular Med, College Stn, TX USA |
推荐引用方式 GB/T 7714 | Cichocki, Joseph A.,Furuya, Shinji,Venkatratnam, Abhishek,et al. Characterization of Variability in Toxicokinetics and Toxicodynamics of Tetrachloroethylene Using the Collaborative Cross Mouse Population[J]. ENVIRONMENTAL HEALTH PERSPECTIVES,2017,125(5). |
APA | Cichocki, Joseph A..,Furuya, Shinji.,Venkatratnam, Abhishek.,McDonald, Thomas J..,Knap, Anthony H..,...&Rusyn, Ivan.(2017).Characterization of Variability in Toxicokinetics and Toxicodynamics of Tetrachloroethylene Using the Collaborative Cross Mouse Population.ENVIRONMENTAL HEALTH PERSPECTIVES,125(5). |
MLA | Cichocki, Joseph A.,et al."Characterization of Variability in Toxicokinetics and Toxicodynamics of Tetrachloroethylene Using the Collaborative Cross Mouse Population".ENVIRONMENTAL HEALTH PERSPECTIVES 125.5(2017). |
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