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Department of Nutrition, University of California, Davis, CA 95616
2To whom correspondence should be addressed. E-mail: bllonnerdal{at}ucdavis.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • zinc transporter • ZIP6 • development • infant nutrition • metallothionein
Although severe zinc (Zn) deficiency is considered to be rare, mild or moderate Zn deficiency is believed to be widespread throughout the world (1). Because Zn requirements for fetal growth are high, pregnant women are at increased risk for Zn deficiency. It was estimated that 82% of pregnant women worldwide have a Zn intake lower than the U.S. Recommended Dietary Allowance, and this may approach 100% in developing countries (1). In humans, studies showed a correlation between maternal Zn status and neonatal and infant behavior (2,3), and Zn deficiency is associated with delayed motor (4,5) and cognitive development in children (6). This suggests that adequate Zn intake is important for optimal brain development. The hippocampus was shown to be critical for learning and memory in both humans and animals (7–9), and undergoes a period of maturation during the perinatal period (10,11). Studies showed that the hippocampus may be more sensitive to Zn deficiency than other parts of the brain (12,13). In addition, it was shown that maternal Zn deficiency during gestation (14) or lactation (15,16) can impair learning and memory later in adulthood. Thus, altered or inadequate Zn homeostasis in this brain region during development may account for the observations of cognitive impairment as a result of Zn deficiency.
Although dietary Zn deficiency results in decreased plasma Zn concentrations (17), researchers did not show any change in brain Zn concentration during Zn restriction in rodent models (12,17–20). However, Zn-deficient weanling rats (21) and chicks (22) increased brain Zn uptake after a 65Zn injection, illustrating that Zn uptake into the brain increases during Zn deficiency. Thus it is apparent that Zn deprivation affects Zn homeostasis in the brain (12); however, the mechanisms that control Zn homeostasis in the brain during Zn deficiency are currently unknown.
Metallothionein-I and -II (MT-I, MT-II)3 and members of the SLC30 and SLC39 transporter families likely maintain cellular Zn homeostasis. Metallothionein-I and -II are Zn-regulated, heavy-metal binding proteins (23), and MT-I expression is downregulated in the brain during Zn deficiency (24,25). MT-III is a member of the metallothionein family with an amino acid sequence similar to that of MT-I and MT-II (26), and its expression is restricted to the brain (27). It was shown to have growth inhibitory properties (26), is highly expressed in regions containing vesicular Zn (28), and its expression is less sensitive to Zn deficiency than MT-I in vitro (29) and in the brain (25). Members of the SLC30 (ZnT transporters) and SLC39 (ZIP transporters) families were shown to transport Zn across the plasma or intracellular membranes (30,31). LIV-1 (SLC39A6 or ZIP6) was shown to transport Zn in transfected cells (32); it is required for proper embryonic development in zebra fish (33), and its mRNA is detectable throughout the brain, including the hippocampus (32). ZnT-1 (SLC30A1) promotes Zn efflux out of cells (34,35), and its expression is positively regulated by Zn (36,37). In addition, ZnT-1 is upregulated in vivo during transient forebrain ischemia in gerbils (38), presumably to protect against excess Zn influx. ZnT-3 protein expression is restricted to the brain and is believed to transport Zn into synaptic vesicles (39). Thus, these transporters may represent mediators of Zn homeostasis in the brain that are potentially regulated by Zn deficiency.
Rats born or suckled from Zn-deficient dams have adverse behavioral outcomes in adulthood, suggesting that the developing brain is sensitive to Zn intake. However, there is currently little information available about the regulation of brain Zn transporters during Zn deficiency. Because many studies suggest that brain Zn is homeostatically maintained and brain Zn uptake increases during Zn deficiency, we hypothesized that Zn uptake into the brain is increased and is associated with increased LIV-1 expression and decreased ZnT-1 expression in the neonatal brain during Zn deficiency. Our objectives were therefore to examine the effects of low maternal Zn intake on brain Zn uptake and zinc transporter expression and localization in the young neonate using the rat as a model. We chose to use rat pups at postnatal d 11 because that time represents a sensitive developmental period when the pup is no longer a newborn yet still exclusively nursed. We believe this corresponds to a vulnerable time point with regard to Zn homeostasis in the first part of life in humans.
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MATERIALS AND METHODS |
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Rats.
This study complied with the Guide for the Use and Care of Laboratory Rats and was administered under the auspices of Animal Resource Services of the University of California, Davis, which is accredited by the American Association for the Accreditation of Laboratory Animal Care. Virgin Sprague-Dawley rats (n = 44; 
250 g) were obtained from a commercial source (Charles River). The rats were maintained in stainless steel hanging cages in a temperature-controlled facility with a 12-h dark:light cycle and allowed to consume purified, deionized water ad libitum. After consumption of standard nonpurified diet (Ralston Purina) for a 7-d acclimation period, rats (n = 14–16/diet) were randomly assigned to 1 of the 3 experimental diets. Rats were fed diets for 70 d preconception through postnatal day (PN) 10. Throughout the experiment, food intake was recorded every other day and animal weight was recorded weekly. On PN 2, litters were culled to 8 pups/litter. On PN 11, pups were randomly selected for brain Zn uptake assay, gene expression, protein expression, or mineral analysis.
Measurement of brain 65Zn retention.
On PN 11, pups were separated from dams and injected i.p. with 1 µCi 65Zn (specific activity = 2.94 mCi/mg Zn) diluted in 100 µL of PBS. Pups were decapitated 3 or 8 h postinjection, brains were removed and placed in preweighed vials, and brain 65Zn retention was measured in a 
-scintillation counter (Beckman, Gamma 8500). Data were normalized by multiplying brain Zn retention by the ratio of each pup’s weight to the mean control pup weight (26.3 g) to account for the individual variability in pup weight and differences in pup weight due to diet. Data are expressed as becquerel (Bq)/g brain (wet weight).
Immunohistochemistry. On PN 11, control pups (n = 2) were deeply anesthetized by i.p. injection of 100 µL of ketamine (50 g/L) and perfused intracardially with PBS, followed by 4% phosphate buffered paraformaldehyde, pH 7.4. Pups were decapitated and heads were incubated in 4% phosphate buffered paraformaldehyde for an additional 24 h at 4°C, Brains were dissected and immersion-fixed in 4% phosphate buffered paraformaldehyde at 4°C for 7 additional days. Brains were serially dehydrated with ethanol, embedded in paraffin, and sectioned (5 µm). Sections corresponding to Plate 35 of Paxinos and Watson (42) were selected for immunostaining. LIV-1–expressing cells were visualized after incubation with affinity-purified LIV-1 antibody raised against a synthetic mouse LIV-1 peptide (peptide sequence VSEPRKSFMYSRNTNDN, 75 mg/L dilution, a generous gift from Dr. Liping Huang), detected with 3,3' diaminobenzidine tetrahydrochloride (DAB) and counterstained with hematoxylin. Slides were stained without primary antibody as a negative control. Slides were viewed under light microscopy (Olympus BX51) using either a 40X (choroid plexus) or 63X (cortex, hippocampus, endothelial cells) objective lens, and images were captured with a digital camera (Olympus Qcolor3).
Measurement of mRNA expression by semiquantitative RT-PCR. On PN 11, pups were decapitated and brains were immediately minced, placed in 5–10 mL of RNAse inhibitor solution (RNAlater, Ambion), and stored at –20°C until RNA extraction. After the removal of RNase inhibitor solution, total brain RNA was isolated by acid guanidinium thiocyanate-phenol-chloroform extraction using the method of Chomczynski and Sacchi (43) (TriZol, Invitrogen) and stored at –80°C until mRNA isolation. Messenger RNA isolation, cDNA synthesis, and PCR were performed as described previously (44), using the following primers: LIV-1, 5'-TGACGACCTCATTCACCACCACCA-3', 5'-CTGGCATCATTGTGCAGCATCTCG-3'; ZnT-1, 5'-CCCACTGCTCAAGGAGTCCGCTCT-3', 5'-CTATCACCACAGCGGGGACACTGC-3'; ZnT-3, 5'-ACCGCGTGTCTCAGTCAGGCCTCT-3', 5'-TGATGGGGTCGGCCACCTTGTACTT-3'; MT-1, 5'-CCAGATCTCGGAATGGACCCCAAC-3', 5'-GTGCACTTGTCCGAGGCACCTTTG-3'; MT-3, 5'-TGCCCCTGTCCTACTGGTGGTTCC-3', 5'-CGCCTTTGCAAACACAGTCCTTGG-3'. Zn transporters (LIV-1, ZnT-1 and ZnT-3) and metallothionein (MT-I and MT-III) primers were designed using the Primer3 program (45), and ß-actin primers were purchased (Classic QuantumRNA ß-actin Internal Standards, Ambion). PCR was performed in duplicate for each rat, and the mean result of the duplicates was used as a single value for statistical comparisons.
Measurement of protein expression by immunoblotting. On PN 11, rat pups were quickly decapitated, and whole brains or hippocampi were immediately dissected and frozen in liquid nitrogen and stored at –80°C. Brains were homogenized in ice-cold buffer (10 mmol/L HEPES, pH 7.4, 0.32 mol/L sucrose, 2 mmol/L EDTA) containing protease inhibitors [0.2 mmol/L 4-(2-aminoethyl)-benzenesulfonyl fluoride, 0.1 mmol/L EDTA, 13 µmol/L bestatin, 1.4 µmol/L M E-64, 0.1 µmol/L leupeptin, 0.03 µmol/L aprotinin, Sigma] with 12 strokes of a Dounce homogenizer. The homogenates were centrifuged at 1000 x g for 15 min at 4°C. The protein concentration of the postnuclear supernatant was measured by the Bradford assay.
Equal amounts of protein (30 µg) were resolved by SDS-PAGE under reducing conditions. Protein was transferred to nitrocellulose for 90 min at 350 mA. Blots were blocked overnight at 4°C with 5% nonfat milk in PBS-T (PBS/0.1% Tween-20) and washed in PBS-T. Blots were incubated with primary antiserum (rabbit anti-ZnT-1, 1:1,000, in PBS-T), affinity-purified antibody (rabbit anti-LIV-1, 15 mg/L in PBS-T) or monoclonal antibody (mouse anti-ß-actin, 1:5000, in PBS-T) for 1 h, washed in PBS-T, incubated with donkey-anti-rabbit IgG conjugated to horseradish peroxidase (1:20,000 in PBS-T) or donkey anti-mouse IgG conjugated to horseradish peroxidase (1:5000 in PBS-T), and washed extensively with PBS-T. Blots were visualized with enhanced chemiluminescence (Super Femto Detection Reagent, Pierce Endogen) and quantified using the Chemi-doc Gel Quantification System (Bio-Rad).
Mineral analysis. On PN 11, rat pups were anesthetized by CO2 inhalation, and blood was collected into heparinized vials by heart puncture. Pups were decapitated and brains were dissected. Plasma was separated by centrifugation at 1500 x g for 15 min at 4°C and stored at –20°C until analysis. Pup brains (n = 9) and plasma (n = 5) were digested at room temperature for 5 d with 0.1 mol/L ultra-pure nitric acid and wet-ashed using a modification of Clegg et al. (41). Zn was analyzed by flame atomic absorption spectrophotometry.
Statistical analysis. Prism GraphPad was used to conduct statistical analysis and graphing (46). Statistical comparisons were made using one-way ANOVA and Tukey-Kramer post hoc tests. Data are expressed as means ± SD, and significant effect of diet was determined at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Little information is available regarding the regulation of brain Zn uptake mechanisms. ZIP2 and ZIP4 are not expressed in the brain (49–51), and we were unable to detect ZIP1 or ZIP3 protein in rat brain homogenate by immunoblotting (Chowanadisai, Kelleher, and Lönnerdal, unpublished observations), eliminating these 4 Zn transporters from the regulatory process. LIV-1 was shown to localize to the plasma membrane in Chinese-hamster ovary cells, and overexpression of the gene in these cells leads to increased Zn uptake (32). Similarly, we determined using immunostaining that LIV-1 is localized to the plasma membrane in neurons, suggesting that it plays a role in Zn uptake into neurons. In addition, we determined that LIV-1 is localized to the apical membrane of the choroid plexus. Because Zn given by intracerebroventricular injections is taken up by the brain (52), it is possible that Zn transport into the brain from the cerebrospinal fluid is also mediated by LIV-1. Furthermore, its expression is upregulated in Zn-deficient pups, suggesting that LIV-1 plays a role in regulating brain Zn homeostasis. Although the effects of Zn deficiency on LIV-1 expression have not been reported previously, similar to our observations, other members of the SLC39 zinc transporter family are regulated by Zn either at the level of transcription, cellular localization, or both (53,54). LIV-1 was shown to associate with ubiquitin and contains many putative sites for degradation signaling (32), which may be a site of Zn regulation as has been shown for zinc transporters in yeast (55). In addition to increased Zn uptake via LIV-1 during Zn deficiency, reductions in Zn export my play a role in maintaining brain Zn levels. ZnT-1 is a Zn transporter localized to the plasma membrane that presumably exports Zn out of the cell (34). Similar to our observations of reduced brain ZnT-1 expression (Figs. 4, 5) in Zn-deficient neonatal rats, ZnT-1 mRNA expression also decreased in the mouse visceral yolk sac and rat intestine during Zn deficiency (37,56). These results suggest that reduced ZnT-1 expression during Zn deficiency leads to greater retention of Zn within the brain due to reduced Zn efflux.
Although brain Zn levels were maintained, MT-I expression in the brain was reduced during Zn deficiency similar to what we reported previously in the mammary gland (57), suggesting that alterations in brain Zn pools occur to mediate Zn homeostatic mechanisms. Although we observed a decrease in MT-I expression in Zn-deficient pups, we did not observe any change in ZnT-3 or MT-III expression. Both ZnT-1 and MT-I are positively regulated by Zn through increased nuclear translocation and DNA binding of metal transcription factor-1 (MTF-1) to metal response elements (MREs) in their promoter regions (37,58). MT-III mRNA expression in mouse brain is affected to a lesser degree by dietary Zn deficiency than MT-1 (25), and scanning of the MT-II promoter region using the Transcription Element Search System (59) revealed that although 2 potential MREs are present within 1000 bp of the mouse MT-III transcription start site, 5 MREs are present within 200 bp of the mouse MT-I start site, suggesting that MT-I and MT-III are regulated to a different extent by Zn. In addition, no MREs were detected within 1000 bp of the ZnT-3 transcription start site, which suggests that MTF-I may not regulate ZnT-3 transcription at all. Furthermore, it is physiologically reasonable that ZnT-3 and MT-III expression is regulated differently from MT-I and ZnT-1 because they have physiologic roles involving synaptic Zn that are independent of Zn homeostasis. ZnT-3 is required for the sequestration of synaptic Zn (60), a Zn pool that is hypothesized to modulate neurotransmission via interactions with N-methyl D-aspartate (NMDA) and -aminobutyric acid receptors (61,62). MT-III is highly expressed in regions containing vesicular Zn and may participate in the binding of synaptic Zn (28) because it is highly expressed in regions containing vesicular Zn. Thus, it is conceivable that ZnT-3 and MT-III have physiologic roles involving synaptic Zn regulation instead of brain Zn homeostatic roles; thus, they are regulated to a different extent by Zn and may be less affected by Zn deficiency than LIV-1, ZnT-1 and MT-I.
If the brain responds to Zn deficiency by altering Zn transporter expression to maintain adequate brain Zn concentration, one question concerns whether this response is adequate to maintain optimal brain development. Kirksey et al. (2,3) observed that maternal serum Zn concentrations are correlated with the development of behavior observed in y 1 of life. In animal studies, Zn deficiency during the prenatal and postnatal periods is associated with impaired maturation and differentiation of cerebellar neurons (63–65) and impaired learning and memory (14–16,66). These behavioral processes are mediated via the hippocampus. We determined that LIV-1 and ZnT-1 protein expression increased and decreased, respectively, in the hippocampus, a region that was suggested to be more sensitive to Zn deficiency (12), suggesting that the hippocampus is able to regulate Zn homeostasis through these mechanisms. Neurotrophins, neural adhesion molecules, and NMDA receptors are brain proteins important for learning and memory. Preliminary studies showed that Zn-deficient pups have lower nerve growth factor and brain-derived neurotrophic factor concentrations and reduced NMDA receptor and polysialic acid-neural cell adhesion molecule expression in their brains (Chowanadisai, Kelleher, and Lönnerdal, unpublished observations), suggesting that it is likely that brain development is compromised during Zn deficiency despite efforts to maintain Zn levels, perhaps as a consequence of Zn depletion in specific brain Zn pools.
The association between maternal Zn status and neonatal cognitive outcome in humans and animals suggests that adequate Zn intake during pregnancy and lactation is necessary to ensure proper brain development. The results of this study showed that even a mild maternal Zn deficiency resulted in increased Zn influx into the brain potentially via increased LIV-1 expression. Additionally, Zn export and sequestration were reduced potentially via reductions in ZnT-1 and MT-I expression, respectively, thereby maintaining neonatal brain Zn concentration. In a recent intervention study in Bangladeshi infants by Black et al. (67), 6 mo of weekly Zn supplementation had a beneficial effect on orientation-engagement at 12 mo of age. This suggests that exploratory behavior is reduced in these infants without Zn supplementation and highlights the need for further studies of Zn deficiency and brain development.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: MRE, metal response element; MT, metallothionein; MTF, metal transcription factor; MZD, marginally zinc deficient; NMDA, N-methyl D-aspartate; PN, postnatal day; ZD, moderately zinc deficient; ZnT, zinc transporter.
Manuscript received 19 November 2004. Initial review completed 30 December 2004. Revision accepted 31 January 2005.
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