Improving linkage of hepatic toxicity and pathology endpoints with toxicogenomics Public Deposited

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  • March 21, 2019
Creator
  • Powell, Christine Louise
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • The science of toxicology is directed toward understanding the mechanisms by which environmental agents cause adverse health effects in humans. Traditional methodologies to assess toxicity have relied on observable adverse effects which have proven to be useful diagnostic indicators; however, frequently they do not provide mechanistic insight necessary to unravel the complex biological networks responsible for the development of disease. Toxicogenomics, a sub-discipline of toxicology which examines the global genomic response of organisms to a toxic insult, when applied in parallel with classical toxicological endpoints can advance the field by providing molecular markers of exposure and response, and defining disease processes. Thus, we hypothesize that molecular signatures defining disease mechanisms and early effects of exposure can be phenotypically anchored to biomarkers of oxidative stress and DNA damage. In Aim 1, a molecular signature of incipient toxicity for an acute sub-toxic dose of acetaminophen was phenotypically anchored to oxidative stress markers based on its mechanism of hepatotoxicity. The detection of early changes in a biologic process at doses and times with no apparent clinical signs of toxicity provides an improved basis to develop predictive markers of effect. In Aim 2, molecular signatures were identified that temporally modeled disease pathology and oxidative stress for a choline-deficient model of rodent hepatocellular carcinoma (HCC). Measures of oxidative DNA damage established a temporal linkage between fibrosis and accumulation of DNA lesions, processes that may contribute to hepatocyte transformation. Moreover, comparison of rat and human HCC expression profiles, regardless of etiology, demonstrated that advanced stages of liver disease converge onto a common and indistinguishable phenotype. In Aim 3, gene expression profiling combined with measures of oxidative stress established that dietary fatty acids can have a profound yet differential effect on oxidative stress in the liver mediated by their ability to activate PPAR[alpha]. Many environmental exposures exhibit human toxicity and disease through oxidative-stress signaling pathways. Thus, dietary fatty acids can markedly influence sensitivity or resistance to disease. In summary, toxicogenomics moves the field of toxicology beyond traditional approaches by linking the critical molecular events caused by exposure to environmental factors with disease.
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  • In Copyright
Advisor
  • Rusyn, Ivan
Degree granting institution
  • University of North Carolina at Chapel Hill
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  • Open access
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