US EPA

3536428 

Journal Article 

Project 2: Genomic And Genetic Analysis Of Liver And Kidney Toxicity Of Trichloro 

Swenberg, JA 

2014 

RePORTER Database National Institutes of Health 

English 

Our previous research has established that the genetic makeup of the host plays a key role in metabolism and its biological effects of trichloroethylene (TCE) in mouse liver. Genetic polymorphisms have a profound effect on differences between individuals who may have developed disease after exposure to environmental agents, yet these factors are not being fully considered in risk assessment. Indeed, the need to account for differences among humans in cancer susceptibility other than from possible early-life susceptibility is becoming ever more evident to both the scientific community and the regulatory agencies. A hypothesis thatapparent species- and organ-specific metabolism and toxicity of TCE are genetically controlled and that the mechanisms of susceptibility can be successfully elucidated using a panel of inbred mice will be addressed here. First, we will elucidate genetic determinants of inter-individual differences in TCE metabolism by collecting time course, dose-response, and repeat dose data on TCE metabolites in blood and tissues from a large panel of genetically diverse inbred mouse strains. The data will be used to investigate the genetic causes of variation in the metabolism of TCE, a step crucial for understanding the potential for TCE-inducedadverse health effects in a heterogeneous human population. Second, we will build population-wide pharmacokinetic models for TCE metabolism, which will account for inter-individual variability in metabolism from the genetics point of view by using the time-course and dose-response data obtained on the genetically-diverse animals. Third, we will determine the effects of inter-individual genetic variability on strain-specific responses to TCE through dose-response modeling of gene expression and metabolomicdata. Collectively, this project is timely in proposing a paradigm that will not only offer valuable insights into the molecular basis for genetically-determined variability in response to TCE, and develop PBPK and statistical models, but also will provide necessary science-based underpinnings and tools for the new paradigms being incorporated into the risk assessment and decision-making on TCE and related chlorinated solvents, as well as other environmental agents. 

Accounting; Address; Adverse effects; Animal Model; Animals; Biological; Biological Markers; Chemicals; Communities; Complex; Data Analyses; Decision Making; Development; Disease; Ecology; environmental agent; Environmental Pollution; Exposure to; Gene Expression; Genetic; genetic analysis; Genetic Determinism; Genetic Polymorphism; Genetic Predisposition to Disease; genetic resource; Genomics; Genotype; Human Biology; human disease; improved; Inbred Mouse; Inbred Strains Mice; Individual; Individual Differences; innovation; insight; Institution; Kinetics; Knowledge; Malignant Neoplasms; Metabolism; metabolomics; Modeling; Molecular; mouse model; multidisciplinary; National Institute of Environmental Health Sciences; National Research Council (U.S.); Organ Specificity; Outcome; Pathway interactions; pharmacokinetic model; Phenotype; Physiological; Population; Predisposition; programs; Reaction Time; Research; research study; Research Support; response; Risk Assessment; Science; Sex Characteristics; Signal Pathway; Solvents; species difference; Statistical Models; success; Superfund; Techniques; Testing; time use; Tissues; Toxic effect; Toxicogenetics; Toxicology; Transcript; Translational Research; Trichloroethylene; Variant; Variation (Genetics)