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.
Saved in:
| Title: | 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. |
|---|---|
| Authors: | Yu-Syuan Luo1 (AUTHOR), Cichocki, Joseph A.1 (AUTHOR), Nan-Hung Hsieh1 (AUTHOR), Lewis, Lauren1 (AUTHOR), Wright, Fred A.2 (AUTHOR), Threadgill, David W.3 (AUTHOR), Chiu, Weihsueh A.1 (AUTHOR) Wchiu@cvm.tamu.edu, Rusyn, Ivan1 (AUTHOR) Irusyn@cvm.tamu.edu |
| Source: | Environmental Health Perspectives. Jun2019, Vol. 127 Issue 6, p067011-1-067011-10. 10p. 1 Chart, 7 Graphs. |
| Abstract: | 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 (1,000mg/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 [Acot1 (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-1)/Hepatitis A virus cellular receptor 1 (Havcr1)] 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 (Acot1, 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. [ABSTRACT FROM AUTHOR] |
| Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | GreenFILE |
| FullText | Links: – Type: pdflink Text: Availability: 0 |
|---|---|
| Header | DbId: 8gh DbLabel: GreenFILE An: 139551497 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
| IllustrationInfo | |
| Items | – Name: Title Label: Title Group: Ti Data: 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. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Yu-Syuan+Luo%22">Yu-Syuan Luo</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Cichocki%2C+Joseph+A%2E%22">Cichocki, Joseph A.</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nan-Hung+Hsieh%22">Nan-Hung Hsieh</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Lewis%2C+Lauren%22">Lewis, Lauren</searchLink><relatesTo>1</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Wright%2C+Fred+A%2E%22">Wright, Fred A.</searchLink><relatesTo>2</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Threadgill%2C+David+W%2E%22">Threadgill, David W.</searchLink><relatesTo>3</relatesTo> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Chiu%2C+Weihsueh+A%2E%22">Chiu, Weihsueh A.</searchLink><relatesTo>1</relatesTo> (AUTHOR)<i> Wchiu@cvm.tamu.edu</i><br /><searchLink fieldCode="AR" term="%22Rusyn%2C+Ivan%22">Rusyn, Ivan</searchLink><relatesTo>1</relatesTo> (AUTHOR)<i> Irusyn@cvm.tamu.edu</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Environmental+Health+Perspectives%22">Environmental Health Perspectives</searchLink>. Jun2019, Vol. 127 Issue 6, p067011-1-067011-10. 10p. 1 Chart, 7 Graphs. – Name: Abstract Label: Abstract Group: Ab Data: 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 (1,000mg/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 [Acot1 (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-1)/Hepatitis A virus cellular receptor 1 (Havcr1)] 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 (Acot1, 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. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Environmental Health Perspectives is the property of National Institute of Environmental Health Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
| PLink | https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=8gh&AN=139551497 |
| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1289/EHP5105 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 10 StartPage: 067011-1 Titles: – TitleFull: 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. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Yu-Syuan Luo – PersonEntity: Name: NameFull: Cichocki, Joseph A. – PersonEntity: Name: NameFull: Nan-Hung Hsieh – PersonEntity: Name: NameFull: Lewis, Lauren – PersonEntity: Name: NameFull: Wright, Fred A. – PersonEntity: Name: NameFull: Threadgill, David W. – PersonEntity: Name: NameFull: Chiu, Weihsueh A. – PersonEntity: Name: NameFull: Rusyn, Ivan IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 06 Text: Jun2019 Type: published Y: 2019 Identifiers: – Type: issn-print Value: 00916765 Numbering: – Type: volume Value: 127 – Type: issue Value: 6 Titles: – TitleFull: Environmental Health Perspectives Type: main |
| ResultId | 1 |
