Interstrain differences in the liver effects of trichloroethylene in a multistrain panel of inbred mice.

Trichloroethylene (TCE) is a widely used industrial chemical and a common environmental contaminant. It is a well-known carcinogen in rodents and a probable carcinogen in humans. Studies utilizing panels of mouse inbred strains afford a unique opportunity to understand both metabolic and genetic basis for differences in responses to TCE. We tested the hypothesis that strain- and liver-specific toxic effects of TCE are genetically controlled and that the mechanisms of toxicity and susceptibility can be uncovered by exploring responses to TCE using a diverse panel of inbred mouse strains. TCE (2100 mg/kg) or corn oil vehicle was administered by gavage to 6- to 8-week-old male mice of 15 mouse strains. Serum and liver were collected at 2, 8, and 24 h postdosing and were analyzed for TCE metabolites, hepatocellular injury, and gene expression of liver. TCE metabolism, as evident from the levels of individual oxidative and conjugative metabolites, varied considerably between strains. TCE treatment-specific effect on the liver transcriptome was strongly dependent on genetic background. Peroxisome proliferator-activated receptor-mediated molecular networks, consisting of the metabolism genes known to be induced by TCE, represent some of the most pronounced molecular effects of TCE treatment in mouse liver that are dependent on genetic background. Conversely, cell death, liver necrosis, and immune-mediated response pathways, which are altered by TCE treatment in liver, are largely genetic background independent. These studies provide better understanding of the mechanisms of TCE-induced toxicity anchored on metabolism and genotype-phenotype correlations that may define susceptibility or resistance.

[1]  A. Schecter,et al.  Levels of methyleugenol in a subset of adults in the general U.S. population as determined by high resolution mass spectrometry. , 2000, Environmental Health Perspectives.

[2]  J. Corton.  Evaluation of the Role of Peroxisome Proliferator-Activated Receptor α (PPARα in Mouse Liver Tumor Induction by Trichloroethylene and Metabolites , 2008 .

[3]  D. Putt,et al.  Renal toxicity of perchloroethylene and S-(1,2,2-trichlorovinyl)glutathione in rats and mice: sex- and species-dependent differences. , 2002, Toxicology and applied pharmacology.

[4]  I. Rusyn,et al.  Pharmacokinetic analysis of trichloroethylene metabolism in male B6C3F1 mice: Formation and disposition of trichloroacetic acid, dichloroacetic acid, S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine. , 2009, Toxicology and applied pharmacology.

[5]  S. Wing,et al.  Environmental injustice in North Carolina's hog industry. , 2000, Environmental health perspectives.

[6]  C. Scott,et al.  Modes of action of trichloroethylene for kidney tumorigenesis. , 2000, Environmental health perspectives.

[7]  F. Gonzalez,et al.  The acyl-CoA thioesterase I is regulated by PPARalpha and HNF4alpha via a distal response element in the promoter. , 2007, Journal of lipid research.

[8]  Ivan Rusyn,et al.  Genome‐level analysis of genetic regulation of liver gene expression networks , 2007, Hepatology.

[9]  Robert W. Williams,et al.  Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function , 2005, Nature Genetics.

[10]  I. Rusyn,et al.  Epigenetic effects of the continuous exposure to peroxisome proliferator WY-14,643 in mouse liver are dependent upon peroxisome proliferator activated receptor alpha. , 2007, Mutation research.

[11]  Ivan Rusyn,et al.  Population-based discovery of toxicogenomics biomarkers for hepatotoxicity using a laboratory strain diversity panel. , 2009, Toxicological sciences : an official journal of the Society of Toxicology.

[12]  J. Fisher,et al.  Metabolism of trichloroethylene. , 2000, Environmental health perspectives.

[13]  J. S. Marron,et al.  Distance-Weighted Discrimination , 2007 .

[14]  C. Padungtod,et al.  Generalized eruption accompanied by hepatitis in two Thai metal cleaners exposed to trichloroethylene. , 2004, Industrial Health.

[15]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[16]  J. Suttles,et al.  The Fatty Acid-binding Protein, aP2, Coordinates Macrophage Cholesterol Trafficking and Inflammatory Activity , 2005, Journal of Biological Chemistry.

[17]  Graziano Pesole,et al.  Pscan: finding over-represented transcription factor binding site motifs in sequences from co-regulated or co-expressed genes , 2009, Nucleic Acids Res..

[18]  I. Rusyn,et al.  Mechanisms of peroxisome proliferator-induced DNA hypomethylation in rat liver. , 2008, Mutation research.

[19]  Masayuki Yamamoto,et al.  A Combinatorial Code for Gene Expression Generated by Transcription Factor Bach2 and MAZR (MAZ-Related Factor) through the BTB/POZ Domain , 2000, Molecular and Cellular Biology.

[20]  W. Dekant,et al.  Metabolism of trichloroethene--in vivo and in vitro evidence for activation by glutathione conjugation. , 1990, Chemico-biological interactions.

[21]  Ivan Rusyn,et al.  Toxicogenetics: population-based testing of drug and chemical safety in mouse models. , 2010, Pharmacogenomics.

[22]  F. Gonzalez,et al.  Sex-dependent regulation of hepatic peroxisome proliferation in mice by trichloroethylene via peroxisome proliferator-activated receptor α (PPARα) , 2000 .

[23]  B. Thrall,et al.  Contribution of dichloroacetate and trichloroacetate to liver tumor induction in mice by trichloroethylene. , 2002, Toxicology and applied pharmacology.

[24]  C. Bult,et al.  Aging in inbred strains of mice: study design and interim report on median lifespans and circulating IGF1 levels , 2009, Aging cell.

[25]  Richard S Paules,et al.  Use of transcriptomics in understanding mechanisms of drug-induced toxicity. , 2010, Pharmacogenomics.

[26]  W. Yap,et al.  Human variability and susceptibility to trichloroethylene. , 2000, Environmental health perspectives.

[27]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[28]  H J Clewell,et al.  Evaluating noncancer effects of trichloroethylene: dosimetry, mode of action, and risk assessment. , 2000, Environmental health perspectives.

[29]  D. Putt,et al.  Metabolism and Tissue Distribution of Orally Administered Trichloroethylene in Male and Female Rats: Identification of Glutathione- and Cytochrome P-450-Derived Metabolites in Liver, Kidney, Blood, and Urine , 2006, Journal of toxicology and environmental health. Part A.

[30]  I. Jolliffe.  Principal Component Analysis , 2002 .

[31]  F. Gonzalez,et al.  Sex-dependent regulation of hepatic peroxisome proliferation in mice by trichloroethylene via peroxisome proliferator-activated receptor alpha (PPARalpha). , 2000, Carcinogenesis.

[32]  E. K. Maloney,et al.  trans-Activation of PPARalpha and PPARgamma by structurally diverse environmental chemicals. , 1999, Toxicology and applied pharmacology.

[33]  I. Rusyn,et al.  Replication and narrowing of gene expression quantitative trait loci using inbred mice , 2009, Mammalian Genome.

[34]  Cheng Li,et al.  Adjusting batch effects in microarray expression data using empirical Bayes methods. , 2007, Biostatistics.

[35]  D. Stevens,et al.  Kinetics of chloral hydrate and its metabolites in male human volunteers. , 2008, Toxicology.

[36]  Eleazar Eskin,et al.  A sequence-based variation map of 8.27 million SNPs in inbred mouse strains , 2007, Nature.

[37]  J. Fisher,et al.  Analysis of dichloroacetic acid in rat blood and tissues by hydrophilic interaction liquid chromatography with tandem mass spectrometry. , 2005, Rapid communications in mass spectrometry : RCM.

[38]  Y. Nishiwaki,et al.  Trichloroethylene liver toxicity in mouse and rat: microarray analysis reveals species differences in gene expression , 2009, Archives of Toxicology.

[39]  J. Fisher,et al.  Identification of S-(1,2-dichlorovinyl)glutathione in the blood of human volunteers exposed to trichloroethylene. , 1999, Journal of toxicology and environmental health. Part A.

[40]  J. Peters,et al.  Modulation of cytochrome P-450 gene expression in endotoxemic mice is tissue specific and peroxisome proliferator-activated receptor-alpha dependent. , 1999, The Journal of pharmacology and experimental therapeutics.

[41]  S. Makris,et al.  Evidence of Autoimmune-Related Effects of Trichloroethylene Exposure from Studies in Mice and Humans , 2009, Environmental health perspectives.

[42]  Andrew I Su,et al.  Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics' , 2005, Nature Genetics.

[43]  Frank J. Gonzalez,et al.  The acyl-CoA thioesterase I is regulated by PPARα and HNF4α via a distal response element in the promoter Published, JLR Papers in Press, May 7, 2007. , 2007, Journal of Lipid Research.

[44]  David J. Waxman,et al.  trans-activation of PPARα and PPARγ by structurally diverse environmental chemicals , 1999 .

[45]  J. Christopher Corton,et al.  Role of the peroxisome proliferator-activated receptor α (PPARα) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver , 2004 .

[46]  Peter F. Johnson,et al.  Interleukin-6-Specific Activation of the C/EBPδ Gene in Hepatocytes Is Mediated by Stat3 and Sp1 , 1998, Molecular and Cellular Biology.

[47]  J. Suttles,et al.  The fatty acid-binding protein, aP2, coordinates macrophage cholesterol trafficking and inflammatory activity. Macrophage expression of aP2 impacts peroxisome proliferator-activated receptor gamma and IkappaB kinase activities. , 2005, The Journal of biological chemistry.

[48]  D. H. Ramdhan,et al.  Differential Response to Trichloroethylene-Induced Hepatosteatosis in Wild-Type and PPARα-Humanized Mice , 2010, Environmental health perspectives.

[49]  Doni Hikmat Ramdhan,et al.  Molecular mechanism of trichloroethylene-induced hepatotoxicity mediated by CYP2E1. , 2008, Toxicology and applied pharmacology.

[50]  P J Lioy,et al.  Seasonal influences on childhood lead exposure. , 2000, Environmental health perspectives.

[51]  J. Latendresse,et al.  Dissimilar Characteristics of N-Methyl-N-Nitrosourea-Initiated Foci and Tumors Promoted by Dichloroacetic Acid or Trichloroacetic Acid in the Liver of Female B6C3F1 Mice , 1997, Toxicologic pathology.

[52]  D. Thiele,et al.  Cirrhosis after repeated trichloroethylene and 1,1,1-trichloroethane exposure. , 1982, Gastroenterology.

[53]  Jintao Wang,et al.  Genetic correlates of gene expression in recombinant inbred strains , 2007, Neuroinformatics.

[54]  D. Koop.  Hydroxylation of p-nitrophenol by rabbit ethanol-inducible cytochrome P-450 isozyme 3a. , 1986, Molecular pharmacology.

[55]  X. Cui,et al.  Transformations for cDNA Microarray Data , 2003, Statistical applications in genetics and molecular biology.

[56]  J Christopher Corton,et al.  Role of the peroxisome proliferator-activated receptor alpha (PPARalpha) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver. , 2004, Toxicology.

[57]  Jerry L. Campbell,et al.  Plasma binding of trichloroacetic acid in mice, rats, and humans under cancer bioassay and environmental exposure conditions. , 2003, Drug metabolism and disposition: the biological fate of chemicals.

[58]  I. Rusyn,et al.  Liquid chromatography electrospray ionization tandem mass spectrometry analysis method for simultaneous detection of trichloroacetic acid, dichloroacetic acid, S-(1,2-dichlorovinyl)glutathione and S-(1,2-dichlorovinyl)-L-cysteine. , 2009, Toxicology.

[59]  R J Bull,et al.  Mode of action of liver tumor induction by trichloroethylene and its metabolites, trichloroacetate and dichloroacetate. , 2000, Environmental health perspectives.

[60]  Members of the Complex Trait Consortium,et al.  Standardizing global gene expression analysis between laboratories and across platforms , 2005 .

[61]  M. A. Pereira,et al.  Wy-14,643-induced hypomethylation of the c-myc gene in mouse liver. , 2001, Toxicological sciences : an official journal of the Society of Toxicology.

[62]  M. A. Pereira,et al.  Effect of trichloroethylene and its metabolites, dichloroacetic acid and trichloroacetic acid, on the methylation and expression of c-Jun and c-Myc protooncogenes in mouse liver: prevention by methionine. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.