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,2
* Western Human Nutrition Research Center, Agriculture Research Service, U.S. Department of Agriculture;
Department of Food and Nutrition, Seoul National University, Seoul, South Korea;
** Department of Medical Pathology, University of California Davis Medical Center;
The School of Public Health, Seoul National University, Seoul, South Korea;
Division of Nutritional Genomics, Children’s Hospital Oakland Research Institute, Oakland, CA; and
Department of Nutrition and Rowe Program in Genetics, University of California at Davis, Davis, CA 95616
2To whom correspondence should be addressed. E-mail: lhuang{at}whnrc.usda.gov.
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ABSTRACT |
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KEY WORDS: • zinc transporter • zinc supplementation • quantitative RT-PCR • microarray • humans
Zinc is an essential trace metal for humans (1). It plays important roles in growth and development, skin and bone metabolism, neuropsychiatric performance, immune functions, and hormonal excretions (2–5). Zinc deficiency causes retarded growth, hair loss, skin lesions, emotional disorders, intercurrent infections, and delayed puberty in adolescents (6). Severe zinc deficiency can be present in people with malnutrition, extensive burns, chronic debilitating disorders, chronic renal diseases, and genetic disorders, such as acrodermatitis enteropathica (6–8). Mild zinc deficiency has been reported in children and pregnant women (2,9–15). It was shown that mild zinc deficiency affects growth and neuropsychologic performance in children (16) and may cause retarded fetal growth or shortened pregnancy in pregnant women (17). Although the symptoms of severe zinc deficiency are obvious, assessment of marginal zinc deficiency is difficult due to the lack of clinical signs and reliable laboratory indicators.
Because of the importance of zinc in maintaining physiologic functions in humans, a reliable assay for the assessment of zinc deficiency has been sought by scientists and clinicians involved in trace metal metabolism research. Different approaches have been used to develop an assay to detect zinc deficiency. Previous studies indicated that human serum zinc levels are under tight homeostatic control. Thus, they would not reflect changes in zinc intakes (18). Assessing changes in enzymatic activities of several zinc-containing enzymes including alkaline phosphatase, 5'-nucleotidase, and superoxide dismutase under zinc depletion conditions was inconclusive (19–21). Fluctuations in metallothionein (MT)3 expression in blood cells in response to variations in zinc supplementation were demonstrated. The MT transcripts are upregulated by zinc and other heavy metals through the binding of metal ions to metal-responsive transcription factor-1, which in turn is able to bind to the metal regulatory elements in the promoters of the MT genes (22). Grider et al. (23) measured MT concentrations in RBC of young men and found that the MT levels did fluctuate in response to changes in dietary zinc intakes. Allan et al. (24) reported that the MT-2A mRNA level in human lymphocytes decreased in response to zinc depletion in the diet. However, MT expression levels also change in response to changes in other heavy metals, such as copper, manganese, cadmium, and cobalt in diet. Therefore, the changes in the MT expression levels would not necessarily reflect changes in the zinc intake levels (25).
Zinc absorption in humans occurs at the small intestinal mucosa (26). After zinc is absorbed into absorptive enterocytes and transferred into blood, it binds to albumin and later accumulates in liver for redistribution to other organs (27). Several zinc transport proteins that appear to be specifically involved in cellular zinc homeostasis via influx, efflux, or vesicular sequestration were described in mice and humans (28–37). These specialized zinc transporters, some of which are tissue specific, maintain intracellular zinc concentrations in a narrow physiologic range. The tight homeostatic control of cellular zinc may be achieved by a feedback mechanism by which zinc transporter expression levels change accordingly to avoid cellular zinc toxicity or deficiency when dietary zinc intakes fluctuate (38,39). Two families of zinc transporters have been identified (40,41). The ZNT family decreases cytoplasmic zinc concentrations by secretion, sequestration, or efflux, whereas the ZIP family increases cytoplasmic zinc by influx or release of stored zinc (40,41). Therefore, it is likely that the expression of the ZNT genes would be upregulated, whereas the ZIP genes downregulated when dietary zinc intakes increase. The responsiveness of these zinc transporters to various zinc levels may make them good candidates as cellular indicators of zinc status.
The aim of this study was to identify potential cellular indicators of zinc status in vitro by using cultured peripheral blood cells and then to evaluate these newly identified indicators in blood samples collected from human subjects. Microarray technology was used as an initial screen for identifying genes whose expression was influenced by zinc. The microarray analysis results indicated that the ZNT1 expression level changed in response to various zinc levels in cultured lymphoblastoid cells. Following this finding, we examined the expression patterns of other zinc transporters in lymphoblastoid cells by quantitative RT-PCR analysis and identified 2 potential zinc indicators, ZIP1 and ZNT1. We then investigated their expression levels in peripheral white blood cells collected from the human subjects who had taken a zinc supplement for 27 d.
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SUBJECTS AND METHODS |
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Blood collection. Blood samples were collected from fasting subjects in syringes (5-mL syringe with EDTA) before and after zinc supplementation and were kept on ice until processing.
Total RNA preparation. Human lymphoblastoid cells were treated with 0, 30, 50, or 100 µmol/L ZnSO4 for 24 h in RPMI 1640 media containing 10% (v:v) Chelex-treated FBS, 100 x 103 U/L penicillin G, 0.1 g/L streptomycin, and 0.25 g/L Fungizone. After ZnSO4 treatment, cells were washed 2 times with 1X PBS, pH 7.4, followed by centrifugation at 180 x g for 5 min at 4°C. Total RNA was extracted using Trizol reagent following the manufacturer’s protocol (Invitrogen, Cat. #15596-018). Blood leukocyte RNA was extracted using QiaAmp RNA blood mini kit (Qiagen). Briefly, the erythrocytes were lysed by adding the hypotonic buffer supplied in the kit to the blood, and the intact leukocytes were collected by centrifugation at 400 x g for 10 min at 4°C. The collected leukocytes were then homogenized using QIAshredder spin columns (Qiagen) under highly denaturing conditions. Total RNAs were then purified from the homogenized lysate using QIAamp spin columns (Qiagen).
Microarray analysis.
The cDNA used in microarray analysis was synthesized from 10 µg of total RNA using the SuperScript Choice system (Invitrogen). The cDNA was then transcribed in vitro in the presence of biotin-labeled nucleotides using T7 RNA polymerase after phenol-chloroform extraction and ethanol precipitation. cRNA was purified using the RNeasy mini kit (Qiagen) and fragmented at 94°C for 30 min in a buffer containing 0.2 mol/L Tris-acetate (pH 8.1), 0.5 mol/L potassium acetate, and 0.15 mol/L magnesium acetate. Fragmented cRNA was hybridized overnight at 45°C to the human genome U133A GeneChips (Affymetrix) representing 
22,500 transcripts. Hybridization was then detected using a confocal laser scanner (Affymetrix). Duplicate experiments and microarray assays were conducted. The expression data were generated using Microarray Suite 5.0 (MAS 5.0) Affymetrix GeneChip Software. The differentially expressed genes between mock- and ZnSO4-treated samples were identified as an average fold change of 
1.5 or 
1.5 between control and treatment and the P-values for the changes were <0.05.
Quantitative PCR.
The cDNA used in quantitative PCR was synthesized from 3 µg of total RNA using the SuperScript First-Strand Synthesis for RT-PCR kit (Invitrogen). The cDNA was diluted 4-fold and 2 µL cDNA was added to a quantitative PCR using FAM-labeled TaqMan probes purchased from Applied Biosystems. The quantitative PCR reactions were performed on a PRISM ABI 7900HT Sequence Detection System (Applied Biosystems) in triplicate, and the expression of ß-actin (BACT) was used for normalization. Copy numbers for the zinc transporter genes were calculated using the standard curve method and normalized to the copy numbers of BACT. For other target genes that have no standard curves, changes in expression were calculated using relative quantification as follows: 
Ct = Ctq – Ctcb, where Ct is the cycle number at which amplification rises above the background threshold, Ct is the change in Ct between 2 test samples, q is the target gene, and cb is the calibrator gene. The calibrator used in this study was BACT because it was shown to be invariant under changing zinc concentrations from microarray assays, quantitative PCR analyses, and Northern blot analysis (unpublished data) (39,43,44). Gene expression was then calculated as 2–Ct (Applied Biosystems).
Cloning of ZIP and ZNT gene fragments. The amplicons generated with the Assays-on-Demand primer sets for ACT1, ZIP1, ZIP3, ZNT1, ZNT4, ZNT5, ZNT6, and ZNT7 (Applied Biosystems) were inserted into the cloning vector pCR 2.1-TOPO following the manufacturer’s protocol (Invitrogen, Cat. #051302). The identity of all plasmids was confirmed by sequencing. Plasmids were then linearized by either an EcoRI or XhoI restriction enzyme digestion before making a series of 10-fold dilutions (103 to 108) for establishing standard curves for mRNA quantification.
Human subjects. A group of 15 young women (20–24 y) and 10 elderly women (64–75 y) were recruited for this study through word of mouth and flyers on the campus of Seoul National University and in the neighboring areas of Seoul, South Korea (Table 1). The general health of subjects was examined and those in good health were selected for the study. Exclusion criteria included a BMI < 17 or > 28 kg/m2, smoking, chronic use of alcohol, prescription drugs, oral contraception, vitamin or mineral supplements, a hemoglobin level < 105 g/L, and the presence of acute disease or chronic disease such as diabetes, gastrointestinal disorder, or hyperlipidemia, and a usual dietary zinc intake of <5 mg/d or >15 mg/d. Young women completed a 24-h recall and 2-d diet record and elderly women completed a 24-h recall before the study. The mean plasma zinc concentrations for the young and elderly women at the start of the study were 10.11 ± 2.09 and 12.4 ± 1.13 µmol/L, respectively, which were in the normal ranges for the Korean population (11.06 ± 2.44 µmol/L) (21).
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Study design. The women were given 22 mg supplementary zinc as zinc gluconate to take daily for 27 d while living at home. They consumed a self-selected diet during this period. The nutrient intakes during the zinc supplementation period for the subjects were calculated using a nutrient database developed by the Korean Nutrition Society (Table 2). The dietary zinc intake of the subjects was constant during the zinc supplementation period.
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RESULTS |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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39% higher than that of ZIP1, and both ZIP genes had higher expression than the ZNT genes except for ZNT7 in lymphoblastoid cells (Fig. 2).
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DISCUSSION |
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TOPABSTRACTSUBJECTS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The spectrum of mRNA expression in human lymphoblastoid cells was examined in this study with regard to the expression of zinc transporters that are known to be tissue- and cell type–specific (29,34). ZIP2, ZNT2, ZNT3, and ZIP4 were undetectable in lymphoblastoid cells cultured under either zinc-depleted or -repleted conditions. Among the zinc transporters expressed in lymphoblastoid cells, ZNT7 was the most abundantly expressed; however, its expression was not influenced by extracellular zinc. The function of the ZNT family is to decrease the cytoplasmic zinc concentration by sequestration, secretion, or efflux (40), and this is done in opposition to the ZIP family (41). Thus, it would be likely that the expression of the ZIP genes is downregulated by zinc and the ZNT genes upregulated. Indeed, in our quantitative RT-PCR study, the expression of ZIP1 in lymphoblastoid cells was downregulated in response to the excess extracellular zinc (Fig. 3). However, the change in ZIP1 expression in lymphoblastoid cells in the presence of physiologic zinc concentrations was very small. In contrast, the regulation of ZNT1 expression by zinc in lymphoblastoid cells was more sensitive to the changes in extracellular zinc concentrations (Figs. 2and 3).
Because the zinc transporter genes are directly involved in zinc metabolism, our first choice for a cellular zinc biomarker was among the ZIP and ZNT genes. On the basis of our microarray and quantitative RT-PCR results, ZIP1 and ZNT1 were chosen as candidate biomarkers of zinc status for further study in the human subjects recruited. We excluded the MT genes as candidate biomarkers of zinc status because the expression of MT is also inducible by other heavy metals. In the present study, we found no significant difference between the 2 age groups of Korean women for ZNT1 expression in peripheral leukocytes before or after zinc supplementation. The expression levels of ZIP1 before zinc supplementation did not differ between the 2 age groups. The expression levels of ZIP1 were suppressed post-zinc supplementation in both young and elderly groups. However, the reduction in the expression of ZIP1 was greater in the elderly group than in the young group. The inverse relationship between zinc supplementation and the ZIP1 expression was significant in both age groups (P < 0.01 for young and P < 0.05 for elderly groups). The degrees of reduction in the ZIP1 expression (17% in young women and 21% in elderly women) in response to the dietary zinc supplementation were consistent with those using cultured lymphoblastoid cells (19% reduction).
In our zinc supplementation study, the mean decrease in ZIP1 mRNA expression was 4% larger in the elderly women than in the young women. This finding suggests that elderly women may retain more zinc in their bodies after zinc supplementation. Studies in experimental animals and humans showed that aging caused an increase in intestinal zinc absorption and a decrease in endogenous zinc excretion during zinc supplementation, which may lead to a slightly higher zinc accumulation in elderly adults (56,57). Our study on the effect of dietary zinc supplementation on ZIP1 expression agrees with the previous findings.
Although many individuals had an increase in ZNT1 expression with zinc supplementation, we did not find a clear relation between ZNT1 expression and increased dietary zinc in blood samples collected from either age group. However, we observed that ZNT1 expression increased sharply for some individuals after zinc supplementation (data not shown). This may be explained by differences in the subjects’ differential white blood cell counts. Whitney et al. (58) demonstrated by cDNA microarray analysis that differences displayed by subgroups of blood cells, such as lymphocyte, neutrophil, and reticulocyte subcomponents, accounted for specific features of interindividual variation in gene expression patterns. Because zinc transporters are expressed in a tissue- and cell type–specific manner, the variation in the relative proportions of specific blood cell subsets in the peripheral blood could affect the sensitivity of detecting the changes in ZNT1 expression. The high variability of ZNT1 expression profiles in our subjects is likely due to the varying proportions of blood cell subtypes between individuals. Because our in vitro gene expression study indicated that ZNT1 is the most sensitive gene responding to the changes in zinc concentrations besides the MT genes in lymphoblastoid cells, ZNT1 may yet be a useful biomarker of zinc status if a cell-sorting protocol is applied before expression analysis (59,60). The approach we are investigating will lend itself to the rapid examination of gene expression in B lymphocytes from whole blood in a large-scale population study for marginal zinc deficiency if a fully automated system has been developed. The test, however, requires a large sample of blood (5 mL of whole blood for isolation of 4–8 x 105 B lymphocytes) and requires particularly careful handling soon after collection.
B lymphocytes proliferate in bone marrow and mature in peripheral lymphatic tissues, such as lymph notes and spleen. The fully matured B lymphocytes later enter the circulation with a life span ranging from a few days to 2 wk (61). The changes in the expression of zinc transporters (ZNT1 and ZIP1) in B lymphocytes would likely reflect the changes of zinc contents in bone marrow, peripheral lymph nodes, spleen, and blood. Therefore, detection of the changes in expression of ZNT1 and ZIP1 in the circulating B lymphocytes would be expected to reflect the combination of acute and chronic changes in zinc intakes.
In conclusion, this is the first attempt to explore differential gene expression of cellular zinc indicators identified in in vitro assays in blood samples collected from human subjects before and after zinc supplementation. We demonstrated that ZIP1 gene expression is downregulated post-zinc supplementation regardless of age in Korean women. This provided an important measure of changes in zinc intakes in humans. Although the changes in the ZIP1 mRNA expression levels by zinc supplementation are relatively small, the expression of ZIP1 should serve as a useful reference for further study of biomarkers of zinc status in humans.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: BACT, ß-actin; BAG1, BCL-2 associated athanogene; BLK, B lymphoid tyrosine kinase; ERCC1, excision repair cross-complementing rodent repair deficiency, complementation group1; FBS, fetal bovine serum; MT, metallothionein; ZIP, ZRT1 and IRT1-like protein; ZNT, zinc transporter.
Manuscript received 21 January 2004. Initial review completed 23 February 2004. Revision accepted 30 April 2004.
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