Reference Values for Serum Zinc Concentration and Prevalence of Zinc Deficiency in Adult Iranian Subjects

Zinc, as an essential trace element for health, plays various biological roles in human body functions. Serum zinc reference values are essential for assessing zinc-associated abnormalities and the prevalence of zinc deficiency. This study aims at determining age- and sex-specific reference values for serum zinc concentrations in adult Iranian subjects. Serum zinc concentration was measured by flame atomic absorption spectrometry in 4,698 adult subjects, aged 20?C94?years, randomly selected from the population of the Tehran, Lipid, and Glucose Study. After application of exclusion criteria, reference values for serum zinc were determined in 2,632 apparently healthy subjects according to guidelines of the International Federation of Clinical Chemistry (nonparametric method). Dietary zinc was assessed in 2,906 individuals, of which 1,685 were healthy subjects, using a validated semiquantitative food frequency questionnaire. Reference values for serum zinc concentrations ranged between 9.6 and 31.6, 8.9 and 29.9, and 9.3 and 30.8???mol/L in men, women, and the total population, respectively. Prevalence of serum zinc deficiency was 3.0 and 2.4?% in men and women, respectively (p?=?0.267); in men, but not in women, the prevalence increased significantly with age (p for trend <0.001). Of the total participants, 10.3?% (6.5 men and 3.8?% women, p?<?0.01) had lower zinc intake compared to dietary reference intakes. The zinc density of the population was 6.3?mg/1,000?kcal. In conclusion, this study presents reference values for serum zinc concentration in adult Iranian subjects for both sexes and different age groups. Prevalence of serum zinc deficiency and dietary zinc inadequacy seems to be lower in Iranians, compared to some other populations.     

Clioquinol Synergistically Augments Rescue by Zinc Supplementation in a Mouse Model of Acrodermatitis Enteropathica

Background

Zinc deficiency due to poor nutrition or genetic mutations in zinc transporters is a global health problem and approaches to providing effective dietary zinc supplementation while avoiding potential toxic side effects are needed.

Methods/Principal Findings

Conditional knockout of the intestinal zinc transporter Zip4 (Slc39a4) in mice creates a model of the lethal human genetic disease acrodermatitis enteropathica (AE). This knockout leads to acute zinc deficiency resulting in rapid weight loss, disrupted intestine integrity and eventually lethality, and therefore provides a model system in which to examine novel approaches to zinc supplementation. We examined the efficacy of dietary clioquinol (CQ), a well characterized zinc chelator/ionophore, in rescuing the Zip4 ^{intest KO} phenotype. By 8 days after initiation of the knockout neither dietary CQ nor zinc supplementation in the drinking water was found to be effective at improving this phenotype. In contrast, dietary CQ in conjunction with zinc supplementation was highly effective. Dietary CQ with zinc supplementation rapidly restored intestine stem cell division and differentiation of secretory and the absorptive cells. These changes were accompanied by rapid growth and dramatically increased longevity in the majority of mice, as well as the apparent restoration of the homeostasis of several essential metals in the liver.

Conclusions

These studies suggest that oral CQ (or other 8-hydroxyquinolines) coupled with zinc supplementation could provide a facile approach toward treating zinc deficiency in humans by stimulating stem cell proliferation and differentiation of intestinal epithelial cells.     

Dietary Zinc Deficiency Effects Dorso-lateral and Ventral Prostate of Wistar Rats: Histological,Biochemical and Trace Element Study

Zinc deficiency has become a global problem affecting the developed and developing countries due to inhibitors in the diet which prevents its absorption or due to a very low concentration of bioavailable zinc in the diet. Being present in high concentration in the prostate and having diverse biological function, we investigated the effects of dietary zinc deficiency for 2 and 4 weeks on dorso-lateral and ventral prostate. Sixty prepubertal rats were divided into three groups: zinc control (ZC), pair fed (PF) and zinc deficient (ZD) and fed on 100 μg/g (zinc control and pair fed groups) and 1 μg/g (zinc deficient) diet. Zinc deficiency was associated with degenerative changes in dorso-lateral and ventral prostate as made evident by karyolysis, karyorhexis, cytoplasmolysis, loss of cellularisation, decreased intraluminar secretion and degeneration of fibromuscular stroma. In response, protein carbonyl, nitric oxide, acid phosphatase, 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase increased, exhibiting variable level of significance. Total protein and total zinc concentration in dorso-lateral and ventral prostate as well as in serum decreased (P?P?相似文献   

Zinc and Zinc Transporters in Macrophages and Their Roles in Efferocytosis in COPD

Our previous studies have shown that nutritional zinc restriction exacerbates airway inflammation accompanied by an increase in caspase-3 activation and an accumulation of apoptotic epithelial cells in the bronchioles of the mice. Normally, apoptotic cells are rapidly cleared by macrophage efferocytosis, limiting any secondary necrosis and inflammation. We therefore hypothesized that zinc deficiency is not only pro-apoptotic but also impairs macrophage efferocytosis. Impaired efferocytic clearance of apoptotic epithelial cells by alveolar macrophages occurs in chronic obstructive pulmonary disease (COPD), cigarette-smoking and other lung inflammatory diseases. We now show that zinc is a factor in impaired macrophage efferocytosis in COPD. Concentrations of zinc were significantly reduced in the supernatant of bronchoalveolar lavage fluid of patients with COPD who were current smokers, compared to healthy controls, smokers or COPD patients not actively smoking. Lavage zinc was positively correlated with AM efferocytosis and there was decreased efferocytosis in macrophages depleted of Zn in vitro by treatment with the membrane-permeable zinc chelator TPEN. Organ and cell Zn homeostasis are mediated by two families of membrane ZIP and ZnT proteins. Macrophages of mice null for ZIP1 had significantly lower intracellular zinc and efferocytosis capability, suggesting ZIP1 may play an important role. We investigated further using the human THP-1 derived macrophage cell line, with and without zinc chelation by TPEN to mimic zinc deficiency. There was no change in ZIP1 mRNA levels by TPEN but a significant 3-fold increase in expression of another influx transporter ZIP2, consistent with a role for ZIP2 in maintaining macrophage Zn levels. Both ZIP1 and ZIP2 proteins were localized to the plasma membrane and cytoplasm in normal human lung alveolar macrophages. We propose that zinc homeostasis in macrophages involves the coordinated action of ZIP1 and ZIP2 transporters responding differently to zinc deficiency signals and that these play important roles in macrophage efferocytosis.     

Zip1, Zip2, and Zip8 mRNA Expressions Were Associated with Growth Hormone Level During the Growth Hormone Provocation Test in Children with Short Stature

Short stature of children is affected by multiple factors. One of them is growth hormone (GH) deficiency. Growth hormone therapy can increase the final height of children with growth hormone deficiency. Zinc is found to induce dimerization and to enhance the bioactivity of human GH. Two gene families have been identified involved in zinc homeostasis. Previous studies in our laboratory have shown that Zip1, Zip2, Zip6, and ZnT1 mRNA were associated with zinc level in established human breast cancer in nude mice model; Zip8 was significantly lower in zinc-deficient Wistar rats in kidney. In this study, five zinc transporters: Zip1, Zip2, Zip6, Zip8, and ZnT1 were chosen. We aimed to investigate the mRNA expression of zinc transporters and to explore the relationship between zinc transporters and growth hormone in short stature children. Growth hormone provocation test is used to confirm the diagnosis of growth hormone deficiency. Six short children for the test were enrolled. At the same time, 15 sex- and age-matched normal children were enrolled as control. The expression levels of zinc transporters in peripheral blood mononuclear cells were determined by quantitative real-time PCR. Zip1 and Zip2 mRNA expression positively correlated with growth hormone level (r?=?0.5133, P?=?0.0371; r?=?0.6719, P?=?0.0032); Zip8 mRNA expression negatively correlated with growth hormone level (r?=??0.5264, P?=?0.0285) during the test in short stature children. The average expression level of Zip2 was significantly higher and Zip6, Zip8 mRNA levels were significantly lower in short stature children than in health controls at 0 min (P?<?0.05, P?<?0.05).     

Zinc depletion regulates the processing and secretion of IL-1β

Sterile inflammation contributes to many common and serious human diseases. The pro-inflammatory cytokine interleukin-1β (IL-1β) drives sterile inflammatory responses and is thus a very attractive therapeutic target. Activation of IL-1β in sterile diseases commonly requires an intracellular multi-protein complex called the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome. A number of disease-associated danger molecules are known to activate the NLRP3 inflammasome. We show here that depletion of zinc from macrophages, a paradigm for zinc deficiency, also activates the NLRP3 inflammasome and induces IL-1β secretion. Our data suggest that zinc depletion damages the integrity of lysosomes and that this event is important for NLRP3 activation. These data provide new mechanistic insight to how zinc deficiency contributes to inflammation and further unravel the mechanisms of NLRP3 inflammasome activation.     

Oral Zinc Supplementation May Improve Cognitive Function in Schoolchildren

Zinc is an important micronutrient for humans, and zinc deficiency among schoolchildren is deleterious to growth and development, immune competence, and cognitive function. However, the effect of zinc supplementation on cognitive function remains poorly understood. The purpose of our study was to evaluate the effect of oral zinc supplementation (5 mg Zn/day for 3 months) on the Full Scale Intelligence Quotient (FSIQ), Verbal Intelligence Quotient (VIQ), and Performance Intelligence Quotient (PIQ) using a Wechsler Intelligence Scale for Children (WISC-III). We studied 36 schoolchildren aged 6 to 9 years (7.8?±?1.1) using a nonprobability sampling method. The baseline serum zinc concentrations increased significantly after zinc supplementation (p?<?0.0001), with no difference between sexes. Tests were administered under basal conditions before and after zinc supplementation, and there was no difference in FSIQ according to gender or age. The results demonstrated that zinc improved the VIQ only in the Information Subtest (p?=?0.009), although the supplementation effects were more significant in relation to the PIQ, as these scores improved for the Picture Completion, Picture Arrangement, Block Design, and Object Assembly Subtests (p?=?0.0001, for all subtests). In conclusion, zinc supplementation improved specific cognitive abilities, thereby positively influencing the academic performance of schoolchildren, even those without marginal zinc deficiency.     

The interplay between iron and zinc metabolism in Aspergillus fumigatus

Zinc plays a critical role in a diverse array of biochemical processes. However, excess of zinc is deleterious to cells. Therefore, cells require finely tuned homeostatic mechanisms to balance uptake and storage of zinc. Here we show that iron starvation affects zinc metabolism by downregulating expression of the plasma membrane zinc importer encoding zrfB and upregulating the putative vacuolar zinc transporter-encoding zrcA in Aspergillus fumigatus. Nevertheless, the zinc content of iron-starved mycelia exceeded that of iron replete mycelia, possibly due to unspecific metal uptake induced by iron starvation. In agreement with increased zinc excess and zinc toxicity during iron starvation, deficiency in siderophore-mediated high-affinity iron uptake caused hypersensitivity to zinc. Moreover, an increase of zinc uptake by conditional overexpression of zrfB was more toxic under iron depleted compared to iron replete conditions. This deregulated zinc uptake under iron starvation caused a decrease in heme production and an increase in protoporphyrin IX accumulation. Furthermore, zinc excess impaired production of the extracellular siderophore triacetylfusarinine C but not the intracellular siderophore ferricrocin. Taken together, these data demonstrate a fine tuned coordination of zinc and iron metabolism in A. fumigatus.     

Leaching with Penicillium simplicissimum: Influence of Metals and Buffers on Proton Extrusion and Citric Acid Production

In the presence of insoluble metal oxides (industrial filter dust, zinc oxide, synthetic mixture of metal oxides), Penicillium simplicissimum developed the ability to excrete considerable amounts of citric acid (>100 mM). Parallel with the increase of citric acid concentration in the culture broth, zinc was solubilized from zinc oxide. The adsorption of filter dust onto the mycelium (the pellets formed were less than 1 mm in diameter) was required for not only the citric acid excretion but also the leaching of zinc. When the filter dust was replaced with a synthetic mixture of metal oxides or with zinc oxide in combination with trace elements, levels of adsorption and citric acid production were observed to be similar to those in experiments where industrial filter dust was used. The two most important properties of the filter dust were its heavy-metal content and its buffering capacity. These properties were simulated by adding heavy metals in soluble form (as chlorides, sulfates, or nitrates) or soluble buffers to the medium. Both heavy metals and buffers were not able to induce a citric acid efflux. As with citric acid production by Aspergillus niger, the addition of manganese lowered citric acid excretion (by 40% with metal oxide-induced citric acid efflux and by 100% with urea-induced citric acid efflux). Copper antagonized the effect of manganese. The mechanism for the bulk of citric acid excretion by P. simplicissimum, however, seemed to be different from that described for citric acid accumulation by A. niger. Because of the inefficiency of metals in solubilized form and of soluble buffers to induce a strong citric acid efflux, adsorption of an insoluble metal compound (zinc oxide) turned out to be essential. Surface phenomena possibly involving the plasma membrane H⁺-ATPase are thought to participate in the induction of citric acid excretion by P. simplicissimum in the presence of industrial filter dust.     

Inflammation markers predict zinc transporter gene expression in women with type 2 diabetes mellitus

The pathology of type 2 diabetes mellitus (DM) often is associated with underlying states of conditioned zinc deficiency and chronic inflammation. Zinc and omega-3 polyunsaturated fatty acids each exhibit anti-inflammatory effects and may be of therapeutic benefit in the disease. The present randomized, double-blind, placebo-controlled, 12-week trial was designed to investigate the effects of zinc (40 mg/day) and α-linolenic acid (ALA; 2 g/day flaxseed oil) supplementation on markers of inflammation [interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, C-reactive protein (CRP)] and zinc transporter and metallothionein gene expression in 48 postmenopausal women with type 2 DM. No significant effects of zinc or ALA supplementation were observed on inflammatory marker concentrations or fold change in zinc transporter and metallothionein gene expression. Significant increases in plasma zinc concentrations were observed over time in the groups supplemented with zinc alone or combined with ALA (P=.007 and P=.009, respectively). An impact of zinc treatment on zinc transporter gene expression was found; ZnT5 was positively correlated with Zip3 mRNA (P<.001) only in participants receiving zinc, while zinc supplementation abolished the relationship between ZnT5 and Zip10. IL-6 predicted the expression levels and CRP predicted the fold change of the ZnT5, ZnT7, Zip1, Zip7 and Zip10 mRNA cluster (P<.001 and P=.031, respectively). Fold change in the expression of metallothionein mRNA was predicted by TNF-α (P=.022). Associations among inflammatory cytokines and zinc transporter and metallothionein gene expression support an interrelationship between zinc homeostasis and inflammation in type 2 DM.     

A Role for Zinc in the Structural Integrity of the Cytoplasmic Ribosomes of Euglena gacilis

Zinc deficiency in dark-grown Euglena gracilis Klebs, Z strain Pringsheim, results in the disappearance of cytoplasmic ribosomes. In contrast, ribosomes in zinc-sufficient Euglena are conserved, do not undergo turnover, and can be demonstrated at any stage of growth. The zinc content of ribosomes from zinc-deficient Euglena just prior to ribosomal disappearance is 300 to 380 micrograms of zinc per gram rRNA as compared to 650 to 1280 micrograms of zinc per gram rRNA in ribosomes from zinc-sufficient cells. Ribosomal disappearance is believed to involve a generalized disintegration process related to the lower content of zinc in the ribosomes. Reappearance of ribosomes requires the addition of zinc. It is proposed that adequate zinc may be essential for normal tertiary and quaternary structure of the cytoplasmic ribosomes of Euglena.     

Dietary Fiber Intake Increases the Risk of Zinc Deficiency in Healthy and Diabetic Women

Phytic acid is a major determinant of zinc bioavailability. Little is known about phytic acid intakes or indices of zinc bioavailability in type 2 diabetes mellitus (DM), a condition that predisposes to zinc deficiency. The aim of this cross-sectional study was to measure and explore the relationships among phytic acid intake, zinc bioavailability, and molecular markers of zinc homeostasis in 20 women with DM compared to 20 healthy women. The phytate/zinc, (calcium)(phytate)/zinc, and (calcium + magnesium)(phytate)/zinc molar ratios were used to indicate zinc bioavailability. Plasma zinc concentrations and zinc transporter (ZnT1, ZnT8, and Zip1) gene expression in mononuclear cells were measured. Participants with DM consumed 1,194?±?824?mg/day (mean?±?SD) phytic acid, an amount similar to the intake of healthy women (1,316?±?708?mg/day). Bread products and breakfast cereals contributed more than 40?% of the phytic acid intake in each group. A positive relationship was observed in all participants between phytic acid and dietary fiber (r?=?0.6, P?<?0.001) and between dietary fiber and the (calcium)(phytate)/zinc ratio (r?=?0.5, P?<?0.001). Compared to the healthy group, the messenger RNA ratio of ZnT1 (zinc export) to Zip1 (zinc import) was lower in participants with DM, which may indicate perturbed zinc homeostasis in the disorder. The plasma zinc concentration was not predicted by age, body mass index, health status, zinc bioavailability, or zinc transporter expression. Healthy and diabetic women consume phytic acid in amounts that are likely to decrease the bioavailability of dietary zinc. Recommendations to consume greater amounts of dietary fiber, much of which is associated with phytate, increase the risk of zinc deficiency.     

Uptake,distribution, and remobilization of iron and zinc among various tissues of wheat–<Emphasis Type="Italic">Aegilops</Emphasis> substitution lines at different growth stages

Biofortification of wheat for higher grain iron and zinc is the most feasible and cost-effective approach for alleviating micronutrient deficiency. The non-progenitor donor Aegilops species had 2–3 times higher grain iron and zinc content than the wheat cultivars, whereas the wheat–Aegilops substitution lines mostly of group 2 and 7 chromosomes had intermediate levels of grain micronutrients. The non-progenitor Aegilops species also had the highest iron content and intermediate-to-highest zinc content in straw, lower leaves, and flag leaves at the pre-anthesis, grain-filling, and maturity growth stages. The micronutrients accumulation status is followed by wheat–Aegilops substitution lines and is the least in wheat cultivars indicating that the donor Aegilops species and their substituted chromosomes possess genes for higher iron and zinc uptake and mobilization. The grain iron content was highly positively correlated with iron content in the plant tissues. Most of the lines had much higher iron and zinc content in all tissues during grain-filling period indicating higher iron and zinc uptake from soil during this stage. Although iron and zinc contents are nearly similar in grains, there was much less zinc content in the plant tissues of all the lines suggesting that the Triticeae species take up less zinc which is mobilized to grains more effectively than iron.     

Effects of High Zinc Levels on the Lipid Synthesis in Rat Hepatocytes

Zinc deficiency impairs the hepatic lipid metabolism. Previous studies were focused on the negative effects of zinc deficiency on the hepatic lipid metabolism. A few studies investigated the effects of high zinc levels on the lipid metabolism in hepatocytes. In this study, rat hepatocytes were cultured and treated with different and high concentrations of zinc to investigate the effects of high zinc levels on the lipid synthesis in hepatocytes in vitro. The levels of hepatocytes functional markers, including alkaline phosphatase, lactate dehydrogenase, and albumin, were significantly higher in the zinc treatment groups than in the control group (p?<?0.05, p?<?0.01). The mRNA and protein levels of sterol regulatory element-binding protein 1c (SREBP-1c) were significantly higher in the zinc treatment groups than in the control group (p?<?0.05, p?<?0.01). Furthermore, the mRNA expression levels of acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FAS) were significantly higher in the medium- and high-dose zinc treatment groups than in the control group (p?<?0.01). The mRNA levels of stearoyl-CoA desaturase-1 (SCD-1) were significantly higher in the high-dose group (p?<?0.01). These results indicate that high levels of zinc increase hepatocytes activity and SREBP-1c expression, which upregulate the expression of ACC1, FAS, and SCD-1, thereby improving the lipid metabolism in the hepatocytes.     

Zinc transporter Slc30a1 regulates melanocyte development by interacting with mt2 in zebrafish

The essential trace element zinc is involved in multiple biological processes including development and metabolism, while its role in melanocyte formation is still unclear. Slc30a1a and Slc30a1b are zinc exporters in zebrafish. Here, we found that melanocytes were increased in slc30a1a and slc30a1b double mutant zebrafish. SMART-seq data revealed that genes involved in the melanoma pathway and the gene mt2, which encodes zinc-binding protein, were significantly upregulated in the mutants. In addition, the expression of mt2 was specifically increased in mutant melanocytes, as detected by in situ hybridization, suggesting an essential role of this gene in the tissue. Mechanistically, we demonstrated that elevated zinc levels resulting from Slc30a1 deficiency promoted melanocyte proliferation and that mt2 played a protective role in the process of Slc30a1/zinc-mediated melanocyte hyperplasia. This study uncovered the critical function of Slc30a1-mediated zinc homeostasis in melanocyte development and suggests that accumulated zinc in melanocytes would be a risk for inducing melanoma and that mt2 is a potential target for controlling diseases related to abnormal melanocyte development.     

The putative Arabidopsis zinc transporter ZTP29 is involved in the response to salt stress

Salt stress leads to a stress response, called the unfolded protein response (UPR), in the endoplasmic reticulum (ER). UPR is also induced in a wide range of organisms by zinc deficiency. However, it is not clear whether regulation of zinc levels is involved in the initiation of the UPR in plant response to salt stress. In this study, a putative zinc transporter, ZTP29, was identified in Arabidopsis thaliana. ZTP29 localizes to the ER membrane and is expressed primarily in hypocotyl and cotyledon tissues, but its expression can be induced in root tissue by salt stress. T-DNA insertion into the ZTP29 gene led to NaCl hypersensitivity in seed germination and seedling growth, leaf etiolation, and widening of cells in the root elongation zone. In addition, in ztp29 mutant plants, salt stress-induced upregulation of the UPR pathway genes BiP2 and bZIP60 was inhibited. Furthermore, under conditions of salt stress, upregulation of BiP2 and bZIP60 was inhibited by treatment with high concentrations of zinc in both control and ztp29 plants. However, zinc chelation restored salt stress-induced BiP2 and bZIP60 upregulation in ztp29 mutant plants. These experimental results suggest that ZTP29 is involved in the response to salt stress, perhaps through regulation of zinc levels required to induce the UPR pathway.