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American Journal of Clinical Nutrition, Vol. 88, No. 4, 1067-1073, October 2008
© 2008 American Society for Nutrition

ORIGINAL RESEARCH COMMUNICATION

Zinc deficiency in Mexican American children: influence of zinc and other micronutrients on T cells, cytokines, and antiinflammatory plasma proteins1,2,3

Harold H Sandstead1, Ananda S Prasad1, James G Penland1, Frances WJ Beck1, Joseph Kaplan1, Norman G Egger1, Nancy W Alcock1, Richard M Carroll1, VMS Ramanujam1, Hari H Dayal1, Carmen D Rocco1, Ruth Ann Plotkin1 and Antonio N Zavaleta1

1 From the University of Texas Medical Branch, Galveston, TX (HHS, NGE, NWA, RMC, VMSR, HHD, CDR, and RAP); the Grand Forks Human Nutrition Research Center, Grand Forks, ND (JGP); the Division of Hematology-Oncology and Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, MI (ASP and FWJB); Department of Pediatrics, Immunology Division, Children's Hospital, Detroit, MI (JK), and the University of Texas, Brownsville, TX (ANZ)

2 Supported by the USDA Agricultural Research Service (cooperative agreement 58-1235-2-151) with the University of Texas Medical Branch for research by JC Smith Jr (representing USDA) and HHS (representing the University of Texas Medical Branch) and by grants from the Gerber Foundation and the USDA (97-35200-4577 to HHS) and the NIH (1R01 AI50698-01A to ASP) and Labcatal, France (to ASP). Treatments were generously supplied by the General Nutrition Products Company.

3 Reprints not available. Address correspondence to HH Sandstead, Division of Human Nutrition, Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX 77555-1109. E-mail: hsandste{at}utmb.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background:The Third National Health and Nutrition Examination Survey suggested some Mexican American children are at risk of zinc deficiency.

Objective:We measured the effects of zinc and micronutrients or of micronutrients alone on indexes of cell-mediated immunity and antiinflammatory plasma proteins.

Design:Subjects (n = 54) aged 6-7 y were randomly assigned and treated in double-blind fashion in equal numbers with 20 mg Zn (as sulfate) and micronutrients or with micronutrients alone 5 d/wk for 10 wk.

Results:Before treatment the mean ± SD plasma zinc was 14.9 ± 1.7 µmol/dL and the range was within the reference; hair zinc was 1.78 ± 0.52 µmol/g and 41.6% were ≤1.68 µmol/g; serum ferritin was 25.7 ± 18.6 µg/L and 50.0% were ≤20 µg/L. The zinc and micronutrients treatment increased the lymphocyte ratios of CD4+ to CD8+ and of CD4+CD45RA+ to CD4+CD45RO+, increased the ex vivo generation of interleukin-2 (IL-2) and interferon-{gamma} (IFN-{gamma}), decreased the generation of interleukin-10 (IL-10), and increased plasma interleukin-1 receptor antagonist (sIL-1ra) and soluble tumor necrosis factor receptor 1 (sTNF-R1). Micronutrients alone increased the ratio of CD4+ to CD8+ but not of CD4+CD45RA+ to CD4+CD45RO+, increased IFN-{gamma} but had no effect on IL-2 or IL-10, and increased sIL-1ra but not sTNF-R1. Efficacy of zinc and micronutrients was greater than micronutrients alone for all indexes except the ratio of CD4+ to CD8+, which was affected similarly.

Conclusions:Before treatment, concentrations of hair zinc in 41.6% of subjects and serum ferritin in 50% were consistent with the presence of zinc deficiency. The greater efficacy of the zinc and micronutrients treatment compared with micronutrients alone supports this interpretation.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
The essentiality of zinc for life was discovered in the 19th century (1) and further defined in the early 20th century (2). Prasad et al (3, 4), Sandstead et al (5), and Halsted et al (6) first characterized human dietary zinc deficiency in the 1960s. Today, the worldwide prevalence of dietary zinc deficiency is believed to be ≥20.5% (7). The prevalence of zinc deficiency among US children is unknown, although evidence of the condition among Mexican American children was reported in the 1970s (8, 9). The Third National Health and Nutrition Examination Survey reported median dietary zinc of Mexican American boys and girls, 6–11 y of age, of 9.27 and 8.07 mg daily, respectively (10). Consistent with an increased risk of dietary zinc deficiency in this population, commonly consumed ethnic foods, such as maize tortilla, an unfermented flat bread, and frijoles, a refried bean-paste, suppressed intestinal absorption of zinc from animal flesh (oyster) (11).

The genesis of this project involved the above reports, clinical knowledge of coauthors (CDR and RAP) about Mexican American children in Brownsville, TX, past evidence of low growth among Mexican American children in Brownsville (12, 13), research findings in 740 Chinese school children 6-9 y of age that included a 10-wk double-blind randomized controlled trial of zinc treatment (14), and results of a pilot survey of 99 children that confirmed the possibility of zinc deficiency among young Mexican American schoolchildren in Brownsville, TX (15). Our decision to conduct this substudy was based on the well-known essentiality of zinc for immunity (16).


   SUBJECTS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
This report describes results of a substudy of 54 subjects that is part of a larger study involving 359 Mexican American children 6–9 y of age, which was reviewed and approved by the Institutional Review Board of the University of Texas Medical Branch and the Board of Directors of the Brownsville Independent School District (BISD). Procedures were in accordance with the ethical standards of the institutional review committees on human experimentation of the respective institutions and the 1983 revision of the Helsinki Declaration of 1975. Parents were informed of the study in both English and Spanish through oral presentation and printed documents. Parents consented by signature, and the children (subjects) were not compelled to participate.

The 36 boys and 18 girls, aged 6–7 y, were from 4 elementary schools in low-income districts of Brownsville. The number of subjects was based on the capacity of the analytic laboratory. They were divided into 2 groups of similar composition and assigned randomly and in a double-blind fashion to one of the treatments: 20 mg Zn (as zinc sulfate) and micronutrients or micronutrients alone (Table 1Go). The statistician assigned the treatments without specific knowledge of the subjects and held the code until completion of the trial. Classroom teachers administered the treatments with a morning snack 5 d/wk for 10 wk and recorded compliance. Throughout the study the subjects were offered breakfast and lunch 5 d/wk that was prepared according to guidelines from the US Department of Agriculture. The composition of the micronutrients treatment was similar to that administered to Chinese children (14).


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  		TABLE 1. Micronutrient preparation1

 
Specimens of blood for zinc and serum ferritin were collected from consenting subjects before and after treatment, between 0800 and 1130, after an overnight fast, by technicians from the Brownsville Community Health Center (BCHC). The specimens were stored in a cool container and transported to the BCHC at the end of the morning. Serum and heparinized plasma were stored in trace metal-free plastic tubes, first at –20 °C and later at –70 °C. Specimens of hair (1 cm) were collected with the use of stainless steel scissors from the lower occipital scalp of consenting subjects and stored in paper envelopes.

Specimens from specific subjects before and after treatment were analyzed together; plasma zinc was measured by atomic absorption spectroscopy (AAS; Perkin-Elmer 5100 PC; Perkin-Elmer, Waltham, MA) (17), and hair zinc was measured by AAS after appropriate washing and digestion (18, 19). These methods were evaluated by 23 separate AAS analyses of a plasma standard on different days that found a mean ± SD zinc concentration of 1.44 ± 0.07 mg/L (CV: 4.86%), compared with a certified value of 1.48 mg/L, and by AAS analysis of 10 samples of Bovine Liver Powder Reference Material 1577a (National Bureau of Standards, Gaithersburg, MD), of different weights, after digestion in hydrogen peroxide, and found a concentration of 129.9 ± 3.2 µg/g (CV: 2.46%), compared with the certified value of 123 ± 8 µg/g. Serum ferritin was measured immunologically (sensitivity: 0.23 ng/mL; CV: 6.5% over range of 10–202 ng/mL) (20).

For measurement of the other outcomes, specimens of heparinized whole blood were collected in the afternoon before treatment and during the last 3 wk of treatment. The specimens were sent at ambient temperature by overnight air express to the laboratory of ASP in Detroit, MI. In 6 specimens, a portion of the blood was clotted and insufficient cells could be isolated for all of the ex vivo assays for that subject.

Identification of T cell subsets was performed on 100 µL whole blood admixed with 100 µL phosphate-buffered saline (PBS) as previously described (21). The cells were stained for 45 min at 4 °C with combinations of fluorescein isothiocyanate (FITC)–or red dye-1 (RD1)–labeled mouse monoclonal antihuman antibodies (CalTag Laboratories, Burlingame, CA), washed once with PBS, and then treated with fluorescence-activated cell sorting lysing solution (BD Biosciences, San Jose, CA) to remove erythrocytes. The remaining cells were then fixed with 3.7% formaldehyde for 1 min, washed twice with PBS, and then resuspended in 0.5 mL PBS for analysis by flow cytometry. The following combinations of fluorochrome-labeled monoclonal antihuman antibodies were used to identify specific cell populations: CD4-FITC/CD8-RD1 (CD4+ compared with CD8+ lymphocytes); CD4-FITC/CD45RA-RD1 (naive CD4 T cells) and CD4-FITC/CD45RO-RD1 (mature CD4 T cells). Results were analyzed by CELL QUEST software (version 3.2; BD Biosciences).

Ex vivo generation of interleukin-2 (IL-2), interferon gamma (IFN-{gamma}), and interleukin-10 (IL-10) was performed with the use of mononuclear cells isolated from heparinized whole blood by discontinuous density gradient with the use of Histopaque 1077 (Sigma-Aldrich, St Louis, MO); the cells were washed once with sterile saline and then resuspended in RPMI-1640 incubation media (21). The mononuclear cells (106/mL) were stimulated with phytohemagglutinin-P (10 µg/mL for 48 h) to generate IL-2 and IFN-{gamma}, or with concanavalin-A (25 µg/mL for 24 h) to generate IL-10. Although IL-10 can be generated from phytohemagglutinin-stimulated cells, concanavalin-A was used because of its slightly greater ability to stimulate the generation of T helper 2 (Th2) cytokines (22). Supernatant fluids were harvested and stored at –20 °C until concentrations of the cytokines were measured with the use of Quantikine enzyme-linked immunoabsorbent assays (R&D Systems Inc, Minneapolis, MN). Plasma samples were measured for soluble interleukin-1 receptor antagonist (sIL-1ra/IL-1 F3) and soluble tumor necrosis factor receptor 1 (sTNF-R1), 2 plasma factors thought to modify the in vivo effects of sIL-1 and TNF family members, respectively (23). Concentrations of the plasma sIL-1ra and sTNF-R1 were measured with the use of Quantikine enzyme-linked immunoabsorbent assays obtained from R&D Systems Inc.

The data were evaluated with the use of STATVIEW 5.0.1 (SAS Institute, Cary, NC). Normality was determined by the Kolmogorov-Smirnov test, and nonlinear data were log transformed. Statistical methods included paired t tests and the analysis of covariance (ANCOVA). Subject's concentrations of plasma zinc before and after treatment, hair zinc before treatment, and serum ferritin before treatment were considered potential covariates in the ANCOVA.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Effects of treatments on concentrations of plasma and hair zinc and serum ferritin are shown in Table 2Go. All plasma zinc concentrations were within the reference range. Plasma zinc concentrations increased significantly and similarly after both treatments. Before treatment, plasma and hair zinc concentrations correlated inversely (n = 48, r = 0.302, P < 0.04). Before treatment, the hair zinc concentrations of 41.6% of subjects were ≤1.68 µmol/g. Treatment with zinc and micronutrients was associated with a decrease in hair zinc concentration, a finding interpreted in another study as consistent with increased hair growth (24). Before treatment, the 25th percentile for serum ferritin was 15 µg/L, and the 50th percentile for serum ferritin concentrations was 21 µg/L. After treatment, no significant change was observed in the serum ferritin concentration.


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  		TABLE 2. Plasma and hair zinc and serum ferritin concentrations before and after treatment1

 
Effects of treatment on T cells, cytokines, and antiinflammatory plasma proteins are shown in Table 3Go. The zinc and micronutrients treatment significantly increased the ratio of CD4+ to CD8+ lymphocytes and the ratio of CD4+CD45RA+ to CD4+CD45RO+ lymphocytes, increased the ex vivo monocyte generation of IL-2 and IFN-{gamma}, decreased the generation of IL-10, and increased the concentrations of plasma sIL-1ra and sTNF-R1. In contrast, the treatment of micronutrients alone significantly increased the ratio of CD4+ to CD8+ lymphocytes but not the ratio of CD4+CD45RA+ to CD4+CD45RO+ lymphocytes, increased the ex vivo generation of IFN-{gamma} but not of IL-2 and IL-10, and increased plasma sIL-1ra but not sTNF-R1. The zinc and micronutrients treatment was significantly more efficacious than the micronutrients alone for all indexes, with the exception of the ratio of CD4+ to CD8+ lymphocytes, which responded similarly to both treatments.


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  		TABLE 3. Treatment effects on T cells, cytokines, and antiinflammatory plasma proteins1

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study was done in Brownsville, TX, population {approx}172,400, located on the north bank of the Rio Grande across from Matamoros, Mexico. In 2005 the median income in Brownsville was $24 207 per family of 4, the second lowest in the United States, and the poverty rate was 42.6% (25). Because low family income is a main risk factor for malnutrition, the BISD offers a free breakfast and lunch to all school children 5 d/wk.

This study provides evidence of zinc deficiency, and the significant changes in some outcomes after micronutrients treatment suggest, but do not prove (lacking are a placebo group and measurements of specific micronutrients) that other micronutrient deficiencies were also present in this group of US children. This was accomplished through a treatment design that measured the efficacy of zinc treatment in the context of also treating other micronutrient deficiencies. This approach is based on the fact that in nature micronutrient deficiencies seldom occur alone. This phenomenon is related to the nature of food as a source of micronutrients (26), and it is the basis for the dictum, "Consume a variety of foods from diverse food groups that provide adequate energy" (27). We had previously shown this treatment design effective in a study of Chinese children 6–9 y of age, which showed that zinc administered with other micronutrients for 10 wk was more efficacious than zinc alone or other micronutrients alone for growth and neuropsychological performance (14).

The micronutrients mixture (Table 1Go) is based on the 1989 recommended dietary allowance or estimated safe and adequate daily dietary intake for 6-y-olds (28). The folic acid content is restricted, based evidence that folic acid can impair zinc retention and metabolism (29–34). Iron is excluded to avoid interference with zinc absorption (35).

Consistent with the low sensitivity of plasma zinc for detection of mild zinc deficiency before treatment, plasma zinc concentrations were all within the reference range (Table 2Go). The finding of an inverse correlation between plasma zinc and hair zinc is consistent with our findings in premenopausal women (36). Consistent with zinc deficiency, before treatment 41.6% of subjects had hair zinc concentrations ≤ 1.68 µmol/g, a concentration associated with low growth of children (37). Given our finding in premenopausal women that a serum ferritin concentration of 20 µg/L is predictive of a low rapidly exchangeable tissue zinc (38), we suggest the finding of a 50th percentile for serum ferritin of 21 µg/L in these subjects is also consistent with zinc deficiency. Also in light of the high association between dietary zinc and iron deficiencies (39), the finding of a 25th percentile for serum ferritin of 15 µg/L is consistent with one quarter of the subjects having absent bone marrow iron, based on findings in Swedish women (40).

Zinc has a key role in host defense (41). Zinc is essential for the synthesis and activity of the peptide hormone thymulin that mediates maturation of T helper cells and is highly sensitive to zinc deficiency (42, 43). In this and previous experiments (21) zinc deficiency suppressed T helper 1 (Th1) function but had less effect on Th2 function. Zinc is also essential for gene expression (44), affecting IL-2, IL-1ra, and IFN-{gamma} in this study (45).

Shown in Table 3Go, both the zinc and micronutrients and the micronutrients alone treatments increased the ratio of CD4 to CD8 (paired t tests), whereas treatment effects (ANCOVA) were similar, indicating no additional effect of zinc over that of the micronutrients alone and the background zinc (body zinc). In contrast, the zinc and micronutrients treatment was more efficacious than the micronutrients alone for the increased proportion of naive CD4+CD45RA+ cells relative to the CD4+CD45RO+ mature cells. Ex vivo generation of the Th1 cytokine IL-2 was also facilitated after the zinc and micronutrients treatment but not with the micronutrients alone treatment, a finding consistent with the essentiality of zinc for gene expression of IL-2 (45). In contrast, both the zinc and micronutrients and the micronutrients alone treatments improved the ex vivo generation of IFN-{gamma}, suggesting both zinc and other micronutrients affected gene expression of IFN-{gamma}. Consistent with the balance between Th1 and Th2 functions (21), zinc and micronutrients significantly decreased the ex vivo generation of the Th2 cytokine IL-10, whereas the micronutrients alone had no effect.

The antiinflammatory cytokine IL-10 is produced by CD4+ Th2 cells, monocytes, B cells, and CD4+CD25+ regulatory T cells (23, 46). IL-10 not only inhibits TNF-{alpha}, IL-1, IL-6, and IL-8, but it also inhibits the Th1 cytokines IL-2 and IFN-{gamma} (23). Because the subjects of this study were not clinically ill, it seems likely that zinc deficiency per se changed the redox environment of metallothionein (47, 48), causing the release of picomolar concentrations of free zinc ions that facilitated the gene expression of IL-10. When zinc nutriture became adequate, this mechanism switched off and Th1 functions became dominant.

Zinc status also affects gene expression of the inflammatory cytokines TNF-{alpha}, IL-1β, and IL-8 (41, 49, 50). The mechanism involves zinc-mediated induction of the zinc finger protein A-20 (41, 51) that binds to TNF receptor-associated factor 1, 2, and 6, resulting in inhibition of the phosphorylation of inhibitor of NF-{kappa}B (I{kappa}B) and the translocation of nuclear factor-{kappa}B (NF-{kappa}B) to the nucleus. As a consequence, gene expression of TNF-{alpha}, IL-1β, and IL-8 is decreased (41, 49, 50). In addition, adequate zinc nutriture decreases the activity of cyclic nucleotide phosphodiesterase, resulting in increased cyclic nucleotide guanosine monophosphate (52) that activates protein kinase A, thus promoting the inhibition of Raf-1 (v-raf-1 murine leukemia viral oncogene homolog 1) resulting in decreased I{kappa}B kinase β activity and NF-{kappa}B activation.

Both the zinc and micronutrients and the micronutrients alone treatments increased sIL-1ra, although the zinc and micronutrients treatment was the most efficacious. sIL-1ra blocks the action of IL-1{alpha} and IL-1β by competitive inhibition of the IL-1 receptor (23). Monocyte-macrophage cells generate sIL-1ra. Generation of sIL-1ra and IL-1β are differentially regulated at their respective promoter sites (23). Prasad et al (49, 53, 54) and Bao et al (50) found that zinc treatment of subjects without other micronutrients decreased IL-1β production. However, in this study both zinc and micronutrients and micronutrients alone increased plasma sIL-1ra, a finding interpreted as consistent with the differential release of sIL-1ra and IL-1β (23).

The zinc and micronutrients treatment was also the most efficacious for sTNF-R1, and the micronutrients alone treatment had no significant effect. Normally, the extracellular domain of both TNF-receptors, type 1 (p55) and type 2 (p75), are solubilized into the extracellular fluid as sTNF-R1, and the capacity to bind TNF-{alpha} is retained at affinity levels comparable to those of membrane-bound TNF receptors. High concentrations of soluble TNF receptors function as specific inhibitors of TNF activity. Apparently, TNF concentrations and soluble receptor concentrations correlate directly, suggesting that stimuli causing increased TNF also induce shedding of TNF receptors, although shedding of the soluble receptor may also be regulated independently (55). Zinc appears to induce sTNF-R1 shedding independently, because zinc inhibits the gene expression of TNF-{alpha} (41, 49, 50, 54).

Other research found zinc more efficacious than placebo for the treatment of common infantile diarrhea and pneumonia (56), prevention of infections in patients with sickle cell disease (57), and prevention of infections in the elderly (53). This study showed that zinc was especially efficacious when other unidentified micronutrient deficiencies were also treated, suggesting that zinc treatment of the above conditions would be enhanced by a similar approach.

Finally, the findings suggest that an increase in the micronutrients content of the breakfast and lunch program would be appropriate. More flesh foods, especially red meat, should be considered (39).


   ACKNOWLEDGMENTS
 
The children (subjects) and their parents made this study possible. The Board of the Brownsville Independent School District (BISD) gave permission for the study, provided services of the nursing department personnel led by Ms Ana Milam, and encouraged principals and staff of the respective schools to facilitate our work. The Board of the Community Preventive Maintenance Association (COPRIMA) provided services of their employees, including Mr Martin C Arambula who served as field coordinator, interviewed caregivers, translated the study forms from English to Spanish, and worked as the anthropometrist. Similarly, the Board of the Brownsville Community Health Center (BCHC) and the director provided the services of their employees. We thank Mr William Dorrow of the General Nutrition Products Co, Greenville, SC, for preparation of the treatments. We also thank Dr Wolfgang Maret for his helpful review of the manuscript.

The author's responsibilities were as follows—HHS, ASP, and JGP: planned this substudy and consulted with HHD about statistical and design issues; HHS: examined each subject for the main study; HHS and NGE: measured knee height; NGE: measured fat-free mass; JGP: was responsible for the neuropsychological studies; HHS: analyzed the data in consultation with JGP and HHD; HHS: analyzed data for this substudy with ASP and FWJB; HHS, ASP, FWJB, JGP, and NGE: interpreted the data; HHS: prepared the initial draft of this report that was edited and added to by ASP, FWJB, JGP, and NGE; JK: collaborated with the initial IL-2 assay; FWJB: measured lymphocyte subpopulations, cytokines, and antiinflammatory plasma proteins; RMC: analyzed serum ferritin; NWA: supervised analysis of plasma and hair zinc analysis; VMSR: personally repeated the zinc analysis to confirm the findings; CDR: introduced HHS to the director of the Brownsville Community Health Center and encouraged the cooperation of the Brownsville Independent School District (BISD), gave logistical advice, informed the board members of the BISD and Community Preventive Maintenance Association (COPRIMA) of the project, and participated in the informed consent process; RAP: participated in the pilot study, gave logistical advice, informed board members of the BISD and COPRIMA of the project, and participated in the informed consent process; ANZ: gave logistical advice, instructed MCA about anthropometric methods, informed board members of the BISD and COPRIMA about the project, participated in the informed consent process, and added important sociocultural information to the manuscript. None of the authors had a personal or financial conflict of interest.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 SUBJECTS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication May 22, 2008. Accepted for publication June 25, 2008.




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