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Research Newsletter-Fall/Winter 2009


Yang Song, Ph.D.
LPI Graduate Fellow

Before starting my doctoral studies at Oregon State University, I received a bachelor of medicine degree from a medical school in China, majoring in Preventive Medicine. I interned for two years in Beijing General Railway Hospital and also worked in the China Disease Control and Prevention (China's CDC) for one year. These experiences made me think that the best way to improve human health is to develop strategies to prevent diseases. Moreover, chronic diseases like cancer and cardiovascular diseases cannot be completely treated, whereas dietary intervention strategies can effectively decrease disease incidence. Fascinated by the potent effects of various foods and nutrients in disease prevention, I decided to pursue a Ph.D. degree in the field of nutrition. Five years ago, I left Beijing and came to Oregon State University to become a graduate student in the Linus Pauling Institute.

My general research interest is nutrition and cancer; specifically, the foods or nutrients that can be used as chemoprevention agents. How do eating habits influence the risk of cancer? What micronutrients in the diet could effectively prevent cancer? How do these micronutrients work? Could they be provided as supplements to prevent cancer? These are the questions that I wanted to answer.

My research in Dr. Emily Ho's laboratory is focused on one essential micronutrient, zinc, which is present in virtually all cells. Like other essential minerals, including iron and copper, zinc is bound to many different proteins and is required for numerous cell and physiological functions, such as growth and development, immune response, wound healing, neurological function, and reproduction. Since zinc itself does not have redox (reduction-oxidation) activity, it serves as a good cofactor for a large group of proteins. The primary functions of zinc in biological systems can be categorized as catalytic, structural, and regulatory. For instance, zinc is required for the formation and stabilization of protein structure and is essential for the activity of more than 300 enzymes. Recent research suggests that zinc also serves as a regulator of activities of numerous redox-sensitive signaling molecules and transcription factors by modulating intracellular redox status.

Human zinc deficiency

Human zinc deficiency was first described in Iran in the early 1960s by Prasad and colleagues. They observed that zinc-deficient patients displayed symptoms of "severe growth retardation, anemia, hypogonadism, hepatosplenomegaly, rough and dry skin, mental lethargy and geophagia." Human zinc deficiency is clinically categorized as either marginal or severe, based on the severity of the symptoms. Marginal zinc deficiency is one of the most prevalent mineral deficiencies in the U.S. and is usually caused by inadequate zinc intake. Marginally zinc-deficient patients display numerous non-specific symptoms, such as growth retardation, skin changes, vulnerability to infection, and delayed wound healing. On the other hand, severe zinc deficiency is rare in developed countries. It's usually caused by inborn defects of zinc absorption or secondary factors, including liver disease, chronic renal disease, sickle-cell disease, or high intakes of unleavened flour. The affected patients suffer from severe dysfunctions of the central nervous, immune, reproductive, epidermal, and skeletal systems.

According to the International Zinc Nutrition Consultative Group, approximately two billion people worldwide are at risk for zinc deficiency. Although the true prevalence of zinc deficiency is difficult to evaluate due to the lack of sensitive and specific biomarkers, the actual prevalence has been confirmed by several zinc supplementation trials in healthy infants, toddlers, and preschool children. These trials observed improved neurophysiologic performance, positive growth response, and significantly reduced mortality and morbidity in the zinc-supplemented populations. The prevalence of zinc deficiency is much higher in developing countries than in developed countries because of the limited source of zincabundant foods, such as red meat and seafood. However, the prevalence of marginal zinc deficiency in developed countries may still be high. Data from National Health and Nutrition Examination Survey (NHANES 2001-2002) supported the same conclusion, finding that approximately 12% of the population does not consume the Estimated Average Requirement for zinc and could be at risk for marginal zinc deficiency. Moreover, the prevalence of zinc deficiency is even higher in certain populations, such as children, women, and elderly people, because of the high need for zinc or reduced zinc absorption.

Zinc deficiency and cancer

The connection between zinc deficiency and cancer has been suggested by several large epidemiological studies. These observational cohort studies found that low zinc status is associated with increased cancer incidence. Zinc deficiency impairs DNA integrity and, thus, increases the cell susceptibility to abnormal growth.

DNA damage can be caused by numerous endogenous and exogenous agents, such as ionizing radiation, ultraviolet light, reactive oxygen species, ethidium bromide, and food-borne carcinogens (polycyclic aromatic hydrocarbons and heterocyclic amines). In addition, deficiencies of micronutrients like vitamin C, vitamin E, iron, and zinc may damage DNA through breaks or oxidative modifications. Accumulation of DNA mutations is an essential event in cancer initiation, promotion, and progression. DNA damage initiates cells and may cause the progression to cancer. During the promotion stage, initiated cells start to grow and differentiate rapidly and accumulate DNA mutations, resulting in changes in cell behavior. During the progression stage, cancer cells grow aggressively, resulting in the appearance of a small tumor.

Previous in vitro studies in our lab have shown that zinc depletion in cells increased DNA damage. However, the effects of zinc deficiency on DNA integrity in cells in the body are still unclear. Thus, one focus of my research has been to explore the effects of zinc depletion on DNA integrity in vivo and to understand the mechanisms of these effects.

Our studies confirm that dietary zinc depletion impairs DNA integrity in vivo. We found that both marginal and severe zinc deficiencies are capable of increasing DNA strand breaks in the peripheral blood cells of rats, but this damage was reversible and could be reduced to normal levels by zinc repletion. We also observed similar effects in human subjects with marginal zinc depletion and repletion, indicating that zinc is also essential for maintaining DNA integrity in humans.

At least two mechanisms are likely involved in the effect of zinc deficiency on DNA damage (see the figure below). First, zinc deficiency compromises the functions of the zinc-containing antioxidant enzyme, copper-zinc superoxide dismutase, and increases oxidative stress. Increased oxidative stress causes oxidative DNA damage directly. Second, zinc deficiency impairs DNA repair functions by interfering with the activities and expression of DNA repair proteins. Altogether, zinc-deficient cells take a double hit—DNA damage is increased and the ability to repair that damage is compromised.

Possible mechanism by which zinc deficiency causes DNA damage

Zinc and prostate cancer

Zinc has a very special connection with prostate cancer. The prostate has the highest concentration of zinc of any soft tissue in the body. Zinc concentrations in malignant prostate tissue are only about 10-25% of those in healthy prostates, suggesting that high zinc concentrations may be required for the maintenance of prostate health. However, the specific functions of zinc in the prostate and the mechanisms by which zinc maintains prostate health are still unclear.

We found that marginal zinc deficiency alone did not increase oxidative DNA damage in the prostates of rats. However, a combination of both marginal zinc deficiency and high intensity chronic exercise, which produces oxidative stress, markedly increased oxidative DNA damage in the prostate. Our study suggests that marginal zinc deficiency sensitizes the prostate to exogenous oxidative stress. Moreover, marginal zinc depletion decreases zinc concentrations and affects DNA integrity only in the dorsolateral—not ventral—lobes of the prostate. About 70% of human prostate cancers are found in the human prostate area equivalent to the rat dorsolateral lobe. These data suggest that the prostate dorsolateral lobe—the area of the prostate most susceptible to cancer—is more sensitive to marginal zinc deficiency than the ventral lobe. Overall, our findings demonstrate the importance of maintaining good zinc status for good health in physically active people.

Last updated November 2009