Graduate Thesis Or Dissertation
 

The function of zinc in the maintenance of DNA integrity in vivo

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https://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/r207tr821

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  • Approximately 12% of Americans do not consume the amount of zinc equal to the Estimated Average Requirement for zinc and could be at risk for marginal zinc deficiency. Zinc is an essential component of proteins in the defense against oxidative stress and DNA damage repair. Specifically in the prostate, zinc concentrations are inversely associated with prostate malignancy. Zinc deficiency may predispose cells to the development of cancer by increasing oxidative stress and DNA damage. Studies have shown that severe zinc-depletion increased DNA damage in testes. However, the effects of marginal zinc deficiency, which is more prevalent in human population and physiologically relevant, are understudied. This study aimed to specify the mechanisms by which zinc status affects DNA integrity and the prostate maintains zinc level in vivo. We examined the effects of zinc deficiency on DNA damage and oxidative stress in rat models and in human studies. In rats, severe zinc-depletion caused an increase in DNA damage in peripheral blood cells that decreased following zinc-repletion. DNA repair functions were impaired as indicated by compromised p53 DNA binding and differential activation of DNA repair proteins. Importantly, marginal zinc-depletion (MZD) also increased DNA damage and oxidative stress, and impaired DNA repair functions. However, these effects were not observed in the prostate. Only in combination with an exogenous stress (exercise), MZD increased DNA damage in the prostate, indicating that MZD may sensitize the prostate to exogenous DNA damaging agents. Similar to the rat study, marginal dietary zinc depletion (6wk) in healthy males increased DNA strand breaks in peripheral blood cells, alterations which were ameliorated by zinc repletion (4wk). Oxidative stress and antioxidants were not altered during zinc depletion/repletion periods. The increases in DNA damage were associated with impaired zinc homeostasis. MZD decreased zinc concentration as well as ZnT2 expression in the prostate dorsolateral lobe, indicating disregulation of zinc transporter and zinc homeostasis. Taken together, these studies suggest a key function of zinc in maintaining DNA integrity. Thus, the maintenance of adequate dietary zinc may have an important impact on protecting tissues, such as the prostate, from DNA damage and decreasing cancer risk.
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