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Research Interests
Selenium is the only essential nutrient that has been shown, in both animal models and human clinical trials, to reduce cancer risk. Yet, the mechanism(s) of these effects remain(s) unclear. Considerable research has shown that various selenium-compounds can affect carcinogenesis at several points in the progression of cancer strongly suggesting that there are several ways in which selenium-compounds can be anticarcinogenic. Dr. Uthus's primary research focus is to determine the effects of selenium and bioactive food components (such as folic acid) on epigenetic events. The importance of epigenetic events is that they represent a mechanism by which gene function is selectively activated or inactivated. Because epigenetic events are susceptible to change, they represent excellent targets to explain how dietary factors modify cancer risk and tumor behavior.
A second focus of his research is to determine, using animal models, the effects of selenium and bioactive food components on markers of oxidative stress and markers of cancer susceptibility. The focus is on the methionine sulfoxide reductase enzyme system which is vital for repair of proteins containing oxidized methionine residues. This system is basically comprised of two enzymes, MsrA and MsrB. MsrB requires selenium; without adequate dietary selenium, the enzyme does not function maximally. If not repaired, these oxidized methionine residues can lead to decreased or complete inactivation of protein function. The ultimate goal of this research is to determine whether selenium, through MsrB, affects cancer susceptibility.
The third area of his research involves the use of the long-living Ames dwarf mouse as a model to study the effects of altered methionine metabolism on aging and cancer. Ames dwarf mice (df/df) are deficient in growth hormone, prolactin, and thyroid-stimulating hormone. These mice live significantly longer and have a reduced rate of cancer compared to their normal siblings. In collaborative work, Dr. Uthus showed that the Ames dwarf mouse has a markedly altered methionine metabolism. The working hypothesis for this area of research is that the prolonged life and reduced cancer is the result of this altered methionine metabolism.
Work by Dr. Uthus is currently expanding to include nutritional programming. Improper maternal nutrition during pregnancy and lactation is known have subsequent health effects in newborns that can continue throughout their life (hence the term nutritional programming). For example, undernutrition of the mother can result in increased risk of obesity and related diseases (such as cardiovascular disease and diabetes) in later life of the offspring. Proposed work by Dr. Uthus will determine whether maternal nutritional status produces epigenetic changes that contribute to metabolic disorders in the offspring.
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Research Accomplishments
Dr. Uthus has had an active research interest in the study of how dietary trace minerals affect methionine/methyl metabolism. He showed that dietary selenium can affect redox states of sulfhydryl compounds including homocysteine and cysteine and has demonstrated that selenium deficiency decreases homocysteine concentrations. Dr. Uthus also has demonstrated that rats fed selenium-deficient diets had significantly hypomethylated liver and colon DNA compared with rats fed diets supplemented with selenite or selenomethionine. Rats fed selenium-deficient diets also had significantly increased carcinogen-induced aberrant crypt formation. Recently he showed that low selenium results in promoter region methylation (an epigenetic event) and hence reduces expression of the von Hippel Lindau tumor suppressor gene. Thus, alterations in DNA methylation may be a potential mechanism whereby dietary selenium affects tumorigenesis.
Work by Dr. Uthus and collaborators has shown that dietary selenium and folate interact to affect DNA methylation, DNA methyltransferase activity, and aberrant crypt formation in rats. Although deficiency of selenium and deficiency of folate have both been shown to cause global DNA hypomethylation and increased cancer susceptibility, the nutrients have different effects on one carbon metabolism. Whereas folate deficiency causes increased plasma homocysteine concentrations and decreased S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) ratios, selenium deficiency causes decreased plasma homocysteine concentrations and slightly increased SAM to SAH ratios in the liver. Increased plasma homocysteine concentrations have recently been hypothesized to be a risk factor for cancer and a new potential tumor marker.
Ames dwarf mice (df/df) are deficient in growth hormone, prolactin, and thyroid-stimulating hormone and, as stated, live significantly longer than their normal siblings. Previous work has reported that the dwarf mice exhibit enzyme activities and levels that combat oxidative stress more efficiently than those of normal mice. Recently, Dr. Uthus found that the Ames dwarf mouse has an altered methionine metabolism. For example, the specific activity of liver methionine adenosyltransferase (MAT) was significantly elevated as were cystathionine synthase, cystathionase, and glycine N-methyltransferase (GNMT). Even though the activities of MAT and GNMT were elevated, the concentration of liver SAM was decreased and SAH increased in the dwarf mice. These data indicate that dwarf mice, compared to wild type mice, have a markedly different metabolism of methionine. Altered methionine metabolism may partially explain earlier reports indicating less oxidative damage to proteins in dwarf mice. Taken together, the data suggest that methionine metabolism may play a role in oxidative defense in the dwarf mouse and should be studied as a potential mechanism of extended lifespan and lower incidence of cancer.
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