INTER-INDIVIDUAL DIFFERENCES IN TRICHLOROETHYLENE TOXICOKINETICS AND TOXICODYNAMICS IN GENETICALLY-DIVERSE MICE Public Deposited

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  • March 21, 2019
Creator
  • Venkatratnam, Abhishek
    • Affiliation: Gillings School of Global Public Health, Department of Environmental Sciences and Engineering
Abstract
  • One of the many challenging issues in toxicology is addressing human variability in chemical risk assessment. Among several intrinsic and extrinsic factors that contribute towards inter-individual differences in toxic responses, genetic differences are well known to drive variability in xenobiotic metabolism and adverse effects. Traditional toxicity studies in rodents often rely on single genotype-based models that fail to capture diverse responses similar to those observed in humans. Recent advances in mouse genetics have led to the development of large panels of recombinant lines collectively known as population-based mouse models. Although their utility in biomedical research has been sufficiently demonstrated, their application in toxicity studies needs to be investigated. My doctoral dissertation focuses on investigating inter-individual differences in toxicokinetics (TK) and toxicodynamics (TD) in population-based mouse models with trichloroethylene (TCE) as case study toxicant. The central hypothesis of my dissertation is that genetic differences in the mouse population will drive inter-individual differences in TCE metabolism and related effects. Aim 1 demonstrated sufficient statistical power and precision in the mouse population to identify genetic loci driving variability in TCE metabolism and TD. Next, extent of quantitative variability in some toxicokinetic parameters were comparable to those observed in humans suggesting the appropriateness of such model in addressing human variability in adverse outcomes. Aim 2 characterized transcriptional responses that were strongly influenced by genetic background, dose, or a combination of genetic background and dose to better understand individual- versus population-level responses. Aim 3 assessed the utility of different population-based models in capturing diverse responses in a standard 90-day oral toxicity study that is often conducted for safety assessments. Collectively, this doctoral dissertation serves as a comprehensive guide in incorporating population-based mouse models in toxicity studies.
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Advisor
  • Rusyn, Ivan
  • Wade, Terry
  • Chiu, Weihsueh
  • Gold, Avram
  • Bodnar, Wanda
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2018
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