Zinc deficiency and development

Harold H Sandstead, MD
The University of Texas Medical Branch
Galveston, TX USA 77555-1109
e-mail: hsandste@UTMB.edu

In 1961 Prasad, Halsted and Nadimi (1) reported a syndrome of iron deficiency anemia, stunting, hypogonadism, and hepatosplenomegaly in Iranian farmers.They speculated that zinc deficiency was the cause of the stunting and delayed development. This was counter to the existing paradigm that held human zinc deficiency was highly unlikely because zinc is ubiquitous. Subsequent research in Egypt (2-6), Iran (7-10) confirmed their hypothesis, and with data from experiments in animals (11, 12) provided the basis for the hypothesis that maternal zinc deficiency contributes to the high prevalence of teratology in the region (13).

Research over the past 40 years has shown the essentiality of zinc for development and that zinc deficiency is relatively common (14), affecting all social groups (15). The prevalence of zinc deficiency is greatest among the poor. Primary deficiency from dietary inadequacy is the common form (16, 17); while conditioned deficiency can complicate many illnesses (18). Zinc deficiency affects many systems because of zinc’s essential roles in many aspects of metabolism (19, 20) including the activity of more than 300 enzymes, the structure of many proteins, and control of genetic expression. Zinc status affects basic processes of cell division, growth,. differentiation, development, performance and aging through its requirement for synthesis and repair of DNA (21-25), RNA (26-28) and protein (29-34), and for many other aspects of metabolism indicated by the references (35-42). Clinical signs of zinc deficiency include acrodermatitis (43-47), low immunity (48-52), diarrhea (53-56), poor healing (57-63), stunting (6, 8, 64-67), hypogonadism (6, 8, 64, 68), fetal growth failure (69, 70), teratology (71), abortion (72), other abnormalities of pregnancy (73), liver failure in alcoholic cirrhosis (42, 74), and neuropsychological abnormalities (75). The essentiality of zinc for differentiation, development and performance Is exemplified by abnormalities that occur in zinc deficient preimplantation embryos (76) and the teratology caused by zinc deficiency in early gestation (11, 12). In rats zinc deficiency after in the third of gestation and during lactation (in rats) causes morphological abnormalities in neurons (77-79), residual functional deficits in neuropsychological performance (80-89), and according to preliminary observations the premature death of neurons (90). The essentiality of zinc for differentiation is also illustrated by effects of zinc deprivation on the developing testis (91). Low zinc nutriture prevents spermatogenesis. Finally, possibly related to its role in differentiation, zinc is protective against certain nitrosamine carcinogens (92), and recent findings suggest zinc deficiency, by itself, increases tumor formation in esophagus (93). The investigation of these phenomena in humans and the application of the knowledge to human health are tasks for the 21st century.

Mild zinc deficiency is more common than severe deficiency, but less well understood. In some respects this area of research is a new frontier. Mild deficiency is not obvious, but because of zinc’s essential functions, is a potential cause of morbidity. As is usual in science, our work has been influenced by that of others (9, 94-97).

The common causes of zinc deficiency are low dietary intakes and low bioavailability. Red meat is the best common source of bioavailable zinc (98,99). Therefore individuals who do not consume this food on a regular basis are at risk of zinc deficiency, just as they are of iron deficiency (100, 101). In addition similar factors affect the bioavailabilty of zinc (7, 102-111) and iron (112-114). Therefore it seemed likely that dietary zinc and iron deficiencies might be associated.

To see if this hypothesis was true my colleagues and I studied young women (115). The rate of disappearance of injected 67Zn tracer from their blood was increased when serum ferritin was between about 5-20 ng/mL (R2 = 0.777, p = 0.0003). When the MCV was decreased the rate of zinc disappearance slowed. Low serum ferritin was associated with low consumption of red meat.

Because of our concern that mild zinc deficiency might impair child development and performance my colleagues and I also studied 740 apparently healthy, low income, 6-9 y children from three cities, Shanghai, Chongqing and Qingdao, PRC (116). The children participated in a 10 week double-blind randomized controlled trial of 16 mg zinc alone, micronutrients alone, and 16 mg zinc with micronutrients. The micronutrient mixture was based on US NRC/NAS guidelines. The treatments were administered 6 days per week when the child attended school. Major outcomes were change in knee height (117), and change in neuropsychological performance, measured by a computerized battery of tasks. The growth response was highly significant by ANOVA. Zinc with micronutrients, and micronutrients alone induced the most growth. Zinc alone caused little change compared to growth of children who were not participants in the intervention trial. Changes in neuropsychological performance were highly significant by ANOVA for some measures. Zinc with micronutrients had the greatest effect on performance while micronutrients alone had the least effect.

We (Sandstead HH, Penland JG, Egger N, Alcock NW, Carroll R, Prasad AS; Zavaleta A, Dayal HH, Rocco C and Plotkin RA) followed-up the above study with a study of 375 apparently healthy, low income, 6-8 y Mexican-American children from Brownsville, TX. We finished data collection on May 31. The study was a 8-10 week double-blind randomized controlled trial of placebo, micronutrients alone, 24 mg iron with micronutrients, and 24 mg zinc with micronutrients. Treatments were administered 5 day per week when the child attended school. Major outcomes were change in knee height, neuropsychological performance and cell mediated immunity (on a subgroup of 54). Preliminary data analysis found that repletion with zinc and micronutrients caused in vitro PHA stimulated lymphocytes to increase release of IL-2 and decrease release of IL-10 (paired t-tests, p< 0.0001); lymphocytes from children given micronutrients only showed no change in in vitro response to PHA. These findings imply that zinc improved thymus function. Other analysis found that changes in lean body mass measured by bioelectrical impedance, knee height and weight were greatest in children who were treated with zinc plus micronutrients, while changes in those treated with micronutrients or iron plus micronutrients were similar. Changes in height, triceps skin fold, and arm circumference were apparently similar in the three groups that received nutrients.

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