Abhishek Venkatratnam1,2, Shinji Furuya1, Oksana Kosyk2, Avram Gold2, Wanda Bodnar2, Kranti Konganti3, David W Threadgill3, Kevin M Gillespie4, David L Aylor4, Fred A Wright4, Weihsueh A Chiu1, Ivan Rusyn1. 1. Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, Texas 77843. 2. Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, North Carolina 27599. 3. Department of Molecular and Cellular Medicine, Texas A&M University, College Station, Texas 77843. 4. Bioinformatics Research Center and Departments of Statistics and Biological Sciences, North Carolina State University, Raleigh, North Carolina 27695.
Abstract
Background: Trichloroethylene (TCE) is a known carcinogen in humans and rodents. Previous studies of inter-strain variability in TCE metabolism were conducted in multi-strain panels of classical inbred mice with limited genetic diversity to identify gene-environment interactions associated with chemical exposure. Objectives: To evaluate inter-strain variability in TCE metabolism and identify genetic determinants that are associated with TCE metabolism and effects using Collaborative Cross (CC), a large panel of genetically diverse strains of mice. Methods: We administered a single oral dose of 0, 24, 80, 240, or 800 mg/kg of TCE to mice from 50 CC strains, and collected organs 24 h post-dosing. Levels of trichloroacetic acid (TCA), a major oxidative metabolite of TCE were measured in multiple tissues. Protein expression and activity levels of TCE-metabolizing enzymes were evaluated in the liver. Liver transcript levels of known genes perturbed by TCE exposure were also quantified. Genetic association mapping was performed on the acquired phenotypes. Results: TCA levels varied in a dose- and strain-dependent manner in liver, kidney, and serum. The variability in TCA levels among strains did not correlate with expression or activity of a number of enzymes known to be involved in TCE oxidation. Peroxisome proliferator-activated receptor alpha (PPARα)-responsive genes were found to be associated with strain-specific differences in TCE metabolism. Conclusions: This study shows that CC mouse population is a valuable tool to quantitatively evaluate inter-individual variability in chemical metabolism and to identify genes and pathways that may underpin population differences.
Background: Trichloroethylene (TCE) is a known carcinogen in humans and rodents. Previous studies of inter-strain variability in TCE metabolism were conducted in multi-strain panels of classical inbred mice with limited genetic diversity to identify gene-environment interactions associated with chemical exposure. Objectives: To evaluate inter-strain variability in TCE metabolism and identify genetic determinants that are associated with TCE metabolism and effects using Collaborative Cross (CC), a large panel of genetically diverse strains of mice. Methods: We administered a single oral dose of 0, 24, 80, 240, or 800 mg/kg of TCE to mice from 50 CC strains, and collected organs 24 h post-dosing. Levels of trichloroacetic acid (TCA), a major oxidative metabolite of TCE were measured in multiple tissues. Protein expression and activity levels of TCE-metabolizing enzymes were evaluated in the liver. Liver transcript levels of known genes perturbed by TCE exposure were also quantified. Genetic association mapping was performed on the acquired phenotypes. Results:TCA levels varied in a dose- and strain-dependent manner in liver, kidney, and serum. The variability in TCA levels among strains did not correlate with expression or activity of a number of enzymes known to be involved in TCE oxidation. Peroxisome proliferator-activated receptor alpha (PPARα)-responsive genes were found to be associated with strain-specific differences in TCE metabolism. Conclusions: This study shows that CC mouse population is a valuable tool to quantitatively evaluate inter-individual variability in chemical metabolism and to identify genes and pathways that may underpin population differences.
Authors: Blair U Bradford; Eric F Lock; Oksana Kosyk; Sungkyoon Kim; Takeki Uehara; David Harbourt; Michelle DeSimone; David W Threadgill; Volodymyr Tryndyak; Igor P Pogribny; Lisa Bleyle; Dennis R Koop; Ivan Rusyn Journal: Toxicol Sci Date: 2010-12-06 Impact factor: 4.849
Authors: Daniel M Gatti; Karen L Svenson; Andrey Shabalin; Long-Yang Wu; William Valdar; Petr Simecek; Neal Goodwin; Riyan Cheng; Daniel Pomp; Abraham Palmer; Elissa J Chesler; Karl W Broman; Gary A Churchill Journal: G3 (Bethesda) Date: 2014-09-18 Impact factor: 3.154
Authors: Martin T Ferris; David L Aylor; Daniel Bottomly; Alan C Whitmore; Lauri D Aicher; Timothy A Bell; Birgit Bradel-Tretheway; Janine T Bryan; Ryan J Buus; Lisa E Gralinski; Bart L Haagmans; Leonard McMillan; Darla R Miller; Elizabeth Rosenzweig; William Valdar; Jeremy Wang; Gary A Churchill; David W Threadgill; Shannon K McWeeney; Michael G Katze; Fernando Pardo-Manuel de Villena; Ralph S Baric; Mark T Heise Journal: PLoS Pathog Date: 2013-02-28 Impact factor: 6.823
Authors: Lauren Zeise; Frederic Y Bois; Weihsueh A Chiu; Dale Hattis; Ivan Rusyn; Kathryn Z Guyton Journal: Environ Health Perspect Date: 2012-10-19 Impact factor: 9.031
Authors: Abhishek Venkatratnam; John S House; Kranti Konganti; Connor McKenney; David W Threadgill; Weihsueh A Chiu; David L Aylor; Fred A Wright; Ivan Rusyn Journal: Mamm Genome Date: 2018-01-20 Impact factor: 2.957
Authors: Lauren J Donoghue; Alessandra Livraghi-Butrico; Kathryn M McFadden; Joseph M Thomas; Gang Chen; Barbara R Grubb; Wanda K O'Neal; Richard C Boucher; Samir N P Kelada Journal: Genetics Date: 2017-08-29 Impact factor: 4.562