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Characterization of Variability in Toxicokinetics and Toxicodynamics of Tetrachloroethylene Using the Collaborative Cross Mouse Population.

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Title: Characterization of Variability in Toxicokinetics and Toxicodynamics of Tetrachloroethylene Using the Collaborative Cross Mouse Population.
Authors: 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 irusyn@cvm.tamu.edu
Source: Environmental Health Perspectives. May2017, Vol. 125 Issue 5, p1-12. 12p. 1 Diagram, 7 Graphs.
Subject Terms: *Animal experimentation, *Gas chromatography, *Mass spectrometry, *Solvents, *Toxicity testing, Body weight, Dynamics, Hepatotoxicology, Mice, Polymerase chain reaction, Probability theory, T-test (Statistics), Western immunoblotting, Phenotypes, Reverse transcriptase polymerase chain reaction, Data analysis software, Descriptive statistics
Abstract: 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. OBJECTIVES: 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). Concentration-time 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 (~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 (PPARa)-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. [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.)
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  Data: Characterization of Variability in Toxicokinetics and Toxicodynamics of Tetrachloroethylene Using the Collaborative Cross Mouse Population.
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  Data: <searchLink fieldCode="AR" term="%22Cichocki%2C+Joseph+A%2E%22">Cichocki, Joseph A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Furuya%2C+Shinji%22">Furuya, Shinji</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Venkatratnam%2C+Abhishek%22">Venkatratnam, Abhishek</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22McDonald%2C+Thomas+J%2E%22">McDonald, Thomas J.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Knap%2C+Anthony+H%2E%22">Knap, Anthony H.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Wade%2C+Terry%22">Wade, Terry</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Sweet%2C+Stephen%22">Sweet, Stephen</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Chiu%2C+Weihsueh+A%2E%22">Chiu, Weihsueh A.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Threadgill%2C+David+W%2E%22">Threadgill, David W.</searchLink><relatesTo>4</relatesTo><br /><searchLink fieldCode="AR" term="%22Rusyn%2C+Ivan%22">Rusyn, Ivan</searchLink><relatesTo>1</relatesTo><i> irusyn@cvm.tamu.edu</i>
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  Data: <searchLink fieldCode="JN" term="%22Environmental+Health+Perspectives%22">Environmental Health Perspectives</searchLink>. May2017, Vol. 125 Issue 5, p1-12. 12p. 1 Diagram, 7 Graphs.
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  Label: Abstract
  Group: Ab
  Data: 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. OBJECTIVES: 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). Concentration-time 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 (~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 (PPARa)-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. [ABSTRACT FROM AUTHOR]
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  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.)
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        Value: 10.1289/EHP788
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        Text: English
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