Cindy D. Davis

Low Dietary Zinc Alters Indices of Copper Function and Status in Postmenopausal Women

OBJECTIVES To better define the relationship between dietary zinc and copper for humans so that sound recommendations for intakes of these elements can be made. METHODS A study was conducted to ascertain the effect of moderately excessive and deficient intakes of zinc on copper metabolism and use in humans fed low and luxuriant amounts of copper. Twenty-one postmenopausal women housed in a metabolic unit completed the study as designed. After a 10-d equilibration period in which they were fed a diet providing 31.5 micromol (2 mg) Cu and 91.8 micromol (9 mg) Zn/8.4 MJ (2000 kcal), the women were divided into two groups. One group was fed a diet containing 15.7 micromol (1 mg) Cu/8.4 MJ (2000 kcal), and the other group was fed a diet containing 47.2 micromol (3 mg) Cu/8.4 MJ (2000 kcal). After equilibration, both groups were fed the basal diet providing 45.9 micromol (3 mg) Zn/8.4 MJ (2000 kcal) for 90 d; this was followed by another 10-d equilibration period before dietary zinc was increased to 811 micromol (53 mg)/8.4 MJ (2000 kcal) for 90 d. RESULTS The women were in positive copper balance only when the diet provided 47.2 micromol (3 mg) Cu and 811 micromol (53 mg) Zn/d. Immunoreactive ceruloplasmin concentrations and platelet cytochrome-c oxidase activity on a platelet number basis were significantly lower and the ratio between enzymatic and immunoreactive ceruloplasmin was significantly higher during low dietary than during high dietary zinc intake. Serum cholesterol was higher in subjects fed 15.7 micromol (1 mg) Cu/d than in those fed 47.2 micromol (3 mg) Cu/d. Total and low-density lipoprotein cholesterol concentrations decreased with zinc supplementation. Whole-blood glutathione concentration and erythrocyte glutathione peroxidase activity were lower during high than during low dietary zinc intake. CONCLUSIONS The findings indicate that an inadequate intake of zinc (45.9 micromol/d; 3 mg/d) was more effective than a moderately high intake of zinc (811 micromol/d; 53 mg/d) in inducing changes associated with a decreased copper status in postmenopausal women. Furthermore, the findings indicate that copper status indicators might be useful in evaluating changes in zinc status in humans, and an intake of 15.7 micromol (1 mg)/d of copper may be inadequate for postmenopausal women.

Inadequate dietary copper increases tumorigenesis in the Min mouse

Multiple intestinal neoplasia (Min) mice are a good model for the investigation of the effects of dietary alterations on genetic susceptibility for intestinal cancer. In the current study, nursing dams and their pups were placed on an AIN-93G diet containing either 1 or 6 ppm copper. The pups were maintained on the same concentration of dietary copper after weanling until they were 13-weeks-old. Animals fed copper deficient diets had a significantly (P<0.0003) higher small intestine tumor incidence and a significantly (P<0.04) higher small intestine tumor burden than animals fed adequate dietary copper. Therefore, inadequate dietary copper can increase the spontaneous tumorigenesis that occurs in the Min mouse.

Manganese Absorption and Retention in Rats Is Affected by the Type of Dietary Fat

There is evidence that manganese (Mn) metabolism may be altered by the form and amount of dietary fat. Also, iron (Fe) absorption is greater with saturated fats, as compared to polyunsaturated fatty acids (PUFAs). The absorption of Fe and Mn are interrelated in many aspects; therefore, the form of dietary fat may indirectly alter Mn absorption. The reported studies were conducted to determine whether saturated fat, as compared to unsaturated fat, affected Mn absorption, retention, and metabolism. In experiment I, adult rats were fed diets containing either 0.7 or 100.4 µg/g Mn with the fat source as high-linoleic safflower oil or stearic acid. After 2 wk of equilibration, the animals were fed a test meal of 54Mn followed by whole-body counting for 10 d. Manganese absorption was significantly (p<0.05) lower in the stearic acid group (0.9–4.8%) than in the safflower oil group (20–33.8%); however, the biological half-life was shorter in the safflower oil group. Retention of 54Mn and total Mn was always significantly (p<0.05) greater in the safflower oil group when dietary Mn was low, but it was the same when dietary Mn was high. In experiment II, weanling rats were fed 1.3, 39.3, or 174.6 µg Mn/g and either stearate, high-oleic safflower oil or high-linoleic safflower oil for 8 wk. Long-term feeding of the stearate and low Mn-containing diet resulted in a significant (p<0.0001) reduction in heart superoxide dismutase activity and kidney and liver Mn concentrations compared to the other diets. These data show that stearic acid inhibitits Mn absorption, but it may not inhibit Mn retention when dietary Mn is high.

Effect of dietary zinc and copper on ?-Amyloid precursor protein expression in the rat brain

The β-amyloid precursor protein (APP) is the source of the amyloid β-peptide that accumulates in the brain in Alzheimers disease. Recently, APP has been shown to bind zinc and copper, and this binding has been suggested to control APP conformation and stability. In vitro studies show that zinc ions cause β-amyloid protein to form plaques resembling the amyloid plaques found in the brains of patients with Alzheimers disease. This suggests a role for zinc and/or copper in the neuropathogenesis of Alzheimers disease. Male Sprague-Dawley rats (100 ± 10 g) were fed diets containing 5, 35, or 350 μg zinc/g diet, and 1.5, 3 or 6 μg copper/g diet for 6 weeks. Brain APP expression was determined by using Western blots. Proteins were separated on 8.5% SDS-PAGE, and the APP immunoreactive species were detected by using anti-Alzheimer precursor protein A4 clone 22C11. Alterations in dietary zinc and copper significantly (P < 0.05) affected ceruloplasmin, red blood cell and extracellular superoxide dismutase activities, and tissue mineral concentrations. Although brain zinc concentrations were 13% lower (P < 0.005) in animals fed low dietary zinc than in animals fed high dietary zinc, and brain copper concentrations were 11% lower (P < 0.0001) in animals fed low dietary copper than in animals fed high dietary copper, there were no significant differences in the expression of APP among the different dietary treatments. Therefore, it seems that dietary zinc and copper do not affect APP expression in the rat brain. J. Trace Elem. Exp. Med. 10:249–258, 1997.

EFFECT OF BILIARY LIGATION ON MANGANESE ACCUMULATION IN RAT BRAIN

Neurologic and radiologic disorders have been reported to occur in miners inhaling manganese (Mn)-laden dust and in humans receiving long-term parenteral nutrition. These abnormalities have been attributed to Mn intoxication because of elevated serum Mn concentrations. Because the liver, by way of the bile, is the major route of Mn excretion, it is possible that anything that decreases biliary excretion could increase accumulation of Mn in the brain. The purpose of this study was to determine whether biliary ligation would increase Mn accumulation in the brain of rats that were exposed to deficient or adequate amounts of dietary manganese. The first experiment had a 2 x 3 factorial design, two levels of Mn (0 or 45 μg/g diet) and three surgical treatments (control, sham, or bile-ligation). Animals were sacrificed 10 d after being fed54Mn. In experiment 2, animals that had a sham operation or bile-ligation were sacrificed at 8 time points after being injected intraportally with54Mn complexed to albumin. The biliaryligated animals had a significantly (p < 0.001) smaller percentage of the54Mn in their brains (when expressed as a percentage of whole animal54Mn) than the sham-operated animals. Mn deficiency had a similar effect. However, we did observe an increased accumulation of the radioisotope in the brain over time. Therefore, in short-term studies, biliary-ligated rats do not appear to be a good model for Mn accumulation in the brains of people with cholestatic liver disease.