Harold H. Sandstead

Effects of repletion with zinc and other micronutrients on neuropsychologic performance and growth of Chinese children.

The knowledge that zinc is essential for growth and neuropsychologic performance and a report of zinc-responsive stunting in Chinese children prompted this project. This article summarizes findings from a 10-wk, double-blind, controlled trial of zinc repletion in 740 urban, 6-9-y-old first graders from low-income families in Chongqing, Qingdao, and Shanghai, Peoples Republic of China. Treatments were 20 mg Zn alone (Z), 20 mg Zn with micronutrients (ZM), and micronutrients alone (M). The M mixture was based on National Research Council guidelines. Nutrients that might interfere with zinc retention were excluded or given in lower amounts. Main outcomes were changes in neuropsychologic performance and knee height. Hemoglobin, serum ferritin, plasma and hair zinc, and whole blood and hair lead were also measured. Anemia was not common, and serum ferritin concentrations were usually within the range of normal. Mean baseline plasma zinc concentrations were marginal in children from Chongqing and Qingdao and normal in children from Shanghai. After treatment with ZM or M plasma zinc increased. Hair zinc tended to decrease after all treatments. Mean baseline whole blood lead concentrations were slightly below the limit considered excessive for children by the US Centers for Disease Control and Prevention. Neuropsychologic performance and growth were most improved after treatment with ZM. These findings were consistent with the presence of zinc and other micronutrient deficiencies.

Requirements and toxicity of essential trace elements, illustrated by zinc and copper.

Early signs of toxicity of essential trace elements are important. Some trace elements are available over-the-counter (OTC) and/or are present at industrial waste sites. Physicochemically similar trace elements compete for ligands, impairing functions, which is exemplified by the zinc-copper antagonism described long ago by Van Campen, Hill and Matrone, and Klevay. Intestinal absorption of copper is inhibited by zinc. Thus risk of copper deficiency is increased when the molar ratio of zinc to copper (Zn:Cu) is high. As shown by experiments, copper deficiency can occur in humans. Manifestations include decreased erythrocyte copper-zinc superoxide dismutase, increased low-density-lipoprotein cholesterol, decreased high-density-lipoprotein cholesterol, decreased glucose clearance, decreased methionine and leucine enkephalins, and abnormal cardiac function. Calculation of a preliminary reference dose for OTC zinc that assumed high bioavailability and uncertain copper intakes established 9 mg as a safe amount for 60-kg adults.

Causes of Iron and Zinc Deficiencies and Their Effects on Brain

Low consumption of foods rich in bioavailable iron (Fe) and zinc (Zn) such as meat, particularly red meat, and high consumption of foods rich in inhibitors of Fe and Zn absorption, such as phytate, certain dietary fibers and calcium, cause Fe and Zn deficiencies. Neuropsychologic impairment is one of several potential outcomes of these deficiencies.

Possible roles of zinc nutriture in the fetal origins of disease

Risk of diseases of metabolism such as atherosclerosis and adult onset diabetes mellitus is increased by fetal malnutrition. Deficiencies of micronutrients essential for methylation are believed to contribute to the phenomenon in part through epigenetic abnormalities. Zinc is one of the nutrients essential for the epigenome. Because the worldwide prevalence of zinc deficiency is at least 20%, fetal zinc deficiency is common. We suggest fetal zinc deficiency contributes to the pathogenesis of metabolic diseases in adults. In support of our thesis, research in experimental models and humans established the essentiality of zinc at all stages of intrauterine and infant life. Experiments in rodents and/or non-human primates found that fetal and/or suckling zinc deficiency impairs neuropsychological functions of progeny and that the effects persist in spite of nutritional rehabilitation. In addition, maternal zinc deficiency in mice is reported to impair immunity of progeny; effects persist in spite of nutritional rehabilitation into the next generation. We suspect that zinc deficiency is a far greater human health problem than is generally recognized.

Subclinical zinc deficiency impairs human brain function.

Experiments in other species showed zinc essential for brain growth and function. Six randomized controlled comparative treatment experiments in Chinese and Mexican-American low-income children, aged 6-9 years, middle-income US adolescents, middle-income US premenopausal women and middle income US men, found that subclinical zinc deficiency changes brain function. Simultaneous treatment with a broad mixture of other micronutrients and/or an adequate omnivorous diet appeared to enhance the efficacy of zinc.

Association between zinc pool sizes and iron stores in premenopausal women without anaemia

The simultaneous occurrence of Zn and Fe deficiencies in man has been known since the discovery of human Zn deficiency. However, it is not established that low Fe stores per se or Fe-deficiency anaemia infer low Zn status. Therefore our objective was to identify relationships between Zn and Fe status in premenopausal women without anaemia. We also examined the contribution of food frequencies and blood loss to Zn and Fe status. The subjects were thirty-three apparently healthy premenopausal women without anaemia, who were not taking dietary supplements containing Zn or Fe or oral contraceptives. Main outcomes were Zn kinetic parameters based on the three-compartment mammillary model and serum ferritin (SF) concentration; contributing factors were the frequency of consumption of specific foods and menorrhagia. Lower SF was significantly associated with smaller sizes of Zn pools. The breakpoint in the relationship between SF and the lesser peripheral Zn pool was found to be 21.0 microg SF/l. SF also correlated positively with frequency of beef consumption and negatively with bleeding through menstrual pads (BTMP). Similar to SF, the Zn pool sizes correlated positively with frequency of beef consumption, and negatively with BTMP. In summary, Zn pool sizes and Fe stores were highly correlated in premenopausal women. SF concentrations < 20 microg/l suggest an increased likelihood of low Zn status.

Human Zinc Deficiency: Discovery to Initial Translation

Ananda S Prasad first suspected zinc deficiency in 1958 after he, at the request of James A Halsted, evaluated a patient with severe iron deficiency. In addition to iron deficiency, the patient appeared ∼10 y old and was severely stunted and prepubertal, though his chronological and bone age were much older. He also had hepatosplenomegaly and ate clay. The condition was not rare in that 11 cases were reported. In 1961 Prasad joined the Vanderbilt Nutrition Group led by William J. Darby at the US Naval Medical Research Unit-3, Cairo, Egypt. Prasad et al. studied 40 males similar to the index case. Contrasts with the index case included no clay eating and infection with schistosomiasis and hookworm. Zinc kinetics confirmed the zinc deficiency. Endocrine studies showed hypopituitarism. Treatment with zinc and an omnivorous diet was more efficacious for growth than no treatment, diet alone, or iron and diet. Later, Halsted et al. confirmed these findings in stunted Iranian farmers. The key role of diet in the illness became evident when Prasad found 16 severely stunted farmers from 2 oases who were not infected with schistosomiasis or hookworm. Later, Reinhold et al., in Halsteds group, reported that phytate and other indigestible zinc-binding ligands in unleavened bread prepared from high-extraction wheat flour suppress zinc absorption.

Polyatomics in zinc isotope ratio analysis of plasma samples by inductively coupled plasma-mass spectrometry and applicability of nonextracted samples for zinc kinetics

Inductively coupled plasma-mass spectrometry (ICP-MS) is a powerful tool for both quantitative multielement analyses of inorganic elements and measurement of isotope ratios (IRs). The main disadvantage of this technique is the existence of polyatomic isobaric interferences at some key masses. Zinc has been investigated for such potential interferences in serum or plasma. The Zn isotopes,66Zn and68Zn, have no apparent interferences, but32S16O2 and32S2 are isobaric with64Zn. The possible effects of S and other major components of blood plasma—Na, K, Cl, P, Ca—on Zn IRs were investigated using a series of mineral solutions which simulated human plasma with respect to these elements. The mixture of all mineral elements interfered only with64Zn (6.66 ng/mL) and70Zn (8.51 ng/mL). Interferences to66Zn,67Zn, and68Zn were minimal containing 0.90, 0.94, and 0.39 ng/mL, respectively. The copresence of Na or S shifted35Cl16O2 (atomic mass 67 coming from Cl solution) to35Cl2 which reduced the contribution to67Zn. The hypothesis that Zn IRs obtained from plasma at various intervals after the intravenous administration of enriched67Zn to humans would reflect those obtained after extraction of Zn was therefore tested. To compare the two pretreatment methods, “extraction” versus “nonextraction,” specimens were collected from 10 human subjects at intervals of 5 min to 24 h postinjection, and in 4 subjects from 5 min to 9 d postinjection. Two separate aliquots of plasma from each time-point were dried and digested with hydrogen peroxide, and the residue dissolved in nitric acid. One specimen was subjected to zinc extraction using ammonium diethyldithiocarbamate chelate followed by back extraction into nitric acid. The matching aliquot received no further pretreatment. The normalized IRs obtained from67Zn/66Zn and67Zn/68Zn in both the “extracted” and “nonextracted” samples agreed well(r2 = 0.976 andr2 = 0.985, respectively) compared to those from other ratios (r2 = 0.838 for67Zn/64Zn andr2 = 0.747 for67Zn/70Zn). Considering the minimum possibility of isobaric interferences in plasma samples,67Zn/68Zn obtained from “nonextracted” samples is sufficient for routine Zn kinetic analysis by ICP-MS.

Zinc: Growth, development, and function

A comprehensive review of zincs roles in growth, development, and function is beyond the scope of this symposium. Therefore, selected historical and contemporary illustrations are cited. J. Trace Elem. Exp. Med. 13:41–49, 2000.

Dietary phytate, zinc and hidden zinc deficiency

Epidemiological data suggest at least one in five humans are at risk of zinc deficiency. This is in large part because the phytate in cereals and legumes has not been removed during food preparation. Phytate, a potent indigestible ligand for zinc prevents its absorption. Without knowledge of the frequency of consumption of foods rich in phytate, and foods rich in bioavailable zinc, the recognition of zinc deficiency early in the illness may be difficult. Plasma zinc is insensitive to early zinc deficiency. Serum ferritin concentration≤20μg/L is a potential indirect biomarker. Early effects of zinc deficiency are chemical, functional and may be hidden. The clinical problem is illustrated by 2 studies that involved US Mexican-American children, and US premenopausal women. The children were consuming home diets that included traditional foods high in phytate. The premenopausal women were not eating red meat on a regular basis, and their consumption of phytate was mainly from bran breakfast cereals. In both studies the presence of zinc deficiency was proven by functional responses to controlled zinc treatment. In the children lean-mass, reasoning, and immunity were significantly affected. In the women memory, reasoning, and eye-hand coordination were significantly affected. A screening self-administered food frequency questionnaire for office might help caregivers identify patients at risk of zinc deficiency.