In vitro and in vivo models to assess kidney toxicity of environmental carcinogens Public Deposited

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  • March 22, 2019
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  • DeSimone, Michelle C.
    • Affiliation: School of Medicine, Curriculum in Toxicology
Abstract
  • The etiology of sporadic kidney cancer in humans is unclear. However, it is known that VHL tumor suppressor gene mutations are found in the majority of human renal tumors, even in the earliest stages, and play an important role in kidney cancer development. Evidence suggests that VHL may be a target for environmental carcinogens such as trichloroethylene (TCE), which is associated with a specific point mutation in the VHL gene. Co-exposures to elevated levels of TCE and inorganic arsenic through groundwater and dietary sources are frequently found in human populations and are thought to cause multiple organ toxicities. We hypothesize that there is a mechanistic link between environmental co-exposures to TCE- and arsenic-induced renal toxicity that can be elucidated using genetically engineered model systems. Here we have generated both an in vitro model system of the TCE-associated VHL mutation in embryonic stem cells, as well as a unique F3 mouse population derived from the cross between FVB/N-Abcb1a/1b-/-, a multi-drug resistant transporter knockout, and CAST/EiJ, a wild-derived strain from a different subspecies of Mus musculus. We have employed these systems to elucidate the genetic and environmental components critical for the development of renal cell carcinoma due to environmental co-exposures to TCE and arsenic.
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  • ... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Toxicology.
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  • Threadgill, David W.
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