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Department of Nutrition, University of California, Davis, CA 95616
1To whom correspondence should be addressed. E-mail: bllonnerdal{at}ucdavis.edu.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • zinc • vitamin A • zinc transport • mammary gland • lactation • rats
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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); however, a lack of sensitive indicators of zinc nutriture precludes accurate assessment of zinc status. During lactation in humans and rodents, milk zinc concentration is maintained over a wide range of dietary Zn intake, and decreases only after plasma Zn concentration is reduced (2
,3
). Many intervention studies attempting to improve zinc nutriture have been aimed at lactating women; however, most of these studies have failed to show an effect of increased maternal zinc intake on milk zinc concentration despite improved serum zinc concentrations (4
,5
). The failure of maternal zinc supplementation to alter milk zinc concentration suggests that mammary gland zinc transport is tightly regulated.
Inadequate vitamin A intake is prevalent in nonindustrialized countries, and effects of vitamin A deficiency on zinc metabolism have been documented. Severe vitamin A deficiency decreased intestinal zinc absorption and altered tissue mineral concentrations, whereas vitamin A supplementation increased liver metallothionein (MT) concentration in rats (1
,6
–8
); however, the mechanisms responsible for these effects of dietary vitamin A on zinc metabolism are unclear. Furthermore, marginal zinc and vitamin A deficiency often coexist in many populations and may result in distinct effects on zinc metabolism, thus interfering with homeostatic zinc regulation and potentially confounding intervention studies.
Recently, several proteins have been described that participate in zinc trafficking across membranes; some of these have been identified in mammals (9
). Five mammalian genes involved in zinc transport have been identified and their protein products are referred to as ZnT-1, -2, -3, -4 and -5. ZnT-1–ZnT-4 are structurally similar; they have six transmembrane domains and a histidine-rich domain that is believed to play a key role in zinc binding. ZnT-1 has been proposed to export zinc from cells, is localized to the plasma membrane and is expressed ubiquitously (10
). ZnT-2 facilitates the vesicular localization of zinc into endosomal vesicles in small intestine, kidney and testes (11
), although its physiologic importance is unknown. ZnT-3 is abundant in the hippocampus and cortex (12
), responsible for the accumulation of zinc in synaptic vesicles and has been proposed to serve a neuromodulatory role. ZnT-4 is expressed in many tissues (13
), although the mechanism of ZnT-4–mediated transport has not been determined. A point mutation in ZnT-4 that results in a premature termination codon is believed to be responsible for the murine lethal milk phenotype (lm).2
Milk produced by lm/lm females contains insufficient zinc to support the needs of suckling mice (14
); however, a direct relationship between this mutation and low zinc concentration in milk has yet to be confirmed through the use of an in vivo model. ZnT-5 is unique in that it has 15 transmembrane domains and is highly expressed in pancreatic ß-cells associated with secretory granules (15
). Additionally, other genes encoding putative zinc transporters in humans (hZIP) have been identified as a result of gene sequence homology with known zinc transporters found in plants and yeast (16
). However, the role these transporters play in regulating zinc homeostasis remains to be determined. Intracellularly, zinc trafficking is controlled primarily by MT (17
), a high affinity intracellular zinc binding ligand that is regulated directly by zinc, and changes in MT reduction-oxidation activity (18
) or intracellular levels of MT (17
) are believed to alter the concentration of "labile" zinc within the cell.
In this study, we focused on several zinc transporters that we believed might participate in the regulation of mammary gland zinc homeostasis. We used a rat model to identify mammary gland zinc transporters and determined their localization by immunostaining. Furthermore, due to the assumption that marginal intake of zinc and vitamin A is much more prevalent than severe zinc or vitamin A deficiency and the documented interactions of zinc and vitamin A, we examined effects of marginal zinc and vitamin A intake on zinc transporter gene expression and protein levels, and intracellular zinc partitioning was assessed by changes in MT protein levels.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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This study was approved by Animal Research Services at the University of California, Davis, which is accredited by the American Association for the Accreditation of Laboratory Animal Care. Virgin Sprague-Dawley rats (n = 24; 
250 g) were obtained commercially (Simonsen, Gilroy, CA) and maintained in stainless steel hanging cages. Rats (n = 6/diet) were randomly assigned to consume 1 of 4 experimental diets ad libitum. Purified experimental diets (AIN-93G) differed only in vitamin A and zinc levels with groups receiving one of the following: 1) a diet low in zinc (ZD, 10 mg Zn/kg); 2) a diet low in vitamin A [AD, 0.4 retinol equivalents (RE)/g]; 3) a diet low in zinc and vitamin A (DD, 10 mg Zn/kg, 0.4 RE/g); or 4) a control diet (C, 25 mg Zn/kg, 4 RE/g) (19
). Rats were fed diets for 70 d before mating, throughout gestation and 10 d into lactation. On postnatal d 2, litters were culled to 10 pups. On postnatal d 10, dams were removed from pups for 4 h, anesthetized (intraperitoneal, 1.6 mg xylazine/kg and 33 mg ketamine/kg), and milk was manually expressed after oxytocin injection (subcutaneous, 10 IU/dam). Blood was removed via cardiac puncture and collected into heparinized vials and dams were killed by asphyxiation with CO2.
Tissues.
Plasma was separated immediately and frozen at -80°C until analysis. Mammary glands were dissected and immediately homogenized in TRIzol (Life Technologies, Rockville, MD) for RNA extraction, snap-frozen in liquid nitrogen for determination of zinc concentration and zinc transporter protein level or fixed in cacodylic acid/formaldehyde buffer for immunostaining.
Immunostaining.
Fixed tissues from control rats were embedded in frozen tissue mounting medium (Fisher Scientific, Pittsburgh, PA), sectioned (4 µm) and mounted on positively charged microscope slides. Frozen sections were dried at room temperature and localization of ZnT-1, ZnT-2 and ZnT-4 was determined using rabbit polyclonal antiserum (1:1000), detected with 3,3' diaminobenzidine tetrahydrochloride (DAB) and counterstained with hematoxylin.
Zinc and retinol analysis.
Plasma was digested at room temperature with 0.1 mol/L trace mineral–free nitric acid (Fisher Scientific). Mammary glands were minced and rinsed three times in fresh isotonic saline at room temperature for 10 min each to remove sequestered milk. Whole milk and blot-dried, minced mammary gland were digested with concentrated nitric acid and wet-ashed using a modification of Clegg et al. (20
). Zinc was analyzed by flame atomic absorption spectroscopy (Model Smith-Heifjie 4000, Thermo Jarrell Ash, Franklin, MA). Plasma and mammary gland retinol was extracted and analyzed by HPLC as described previously (19
).
Identification of zinc transporter transcripts by polymerase chain reaction (PCR).
Total mammary gland RNA was extracted in TRIzol following manufacturer’s instructions. mRNA was isolated from total RNA (MicroFast Track Kit, Invitrogen, Carlsbad, CA) and 2 µg was used for reverse transcription (RT) with oligo (dT) primers (cDNA cycle Kit, Invitrogen). PCR was performed from an aliquot of the RT reaction using gene-specific primers (Advantage cDNA PCR Kit, Clontech, Palo Alto CA). PCR primers and cycling conditions were as follows: ZnT-1: 5'CCTTCATGTTCATGGTGCTG, 3'GTGTTGGTCTCCTCCTGGTC; 94°C for 1 min, followed by 30 cycles at 94°C for 45 s, 58°C for 50 s, 68°C for 2.5 min, and a final extension at 68°C for 3 min; ZnT-2: 5'CATTGCCCAGAATGTTGATG, 3'GTCCCAATGGTGTAGTGGACC; 94°C for 1 min, followed by 25 cycles at 94°C for 30 s, 68°C for 3 min, and a final extension at 68°C for 3 min; ZnT-4: 5'TCCTGGAAGGTGTACCAAGA, 3'CACAGCTGTCAAGGACTCCA; 30 cycles at 94°C for 30 s, 68°C for 3 min, and a final extension at 68°C for 3 min. PCR transcripts were separated on a 2% agarose gel and identified by staining in SYPR Gold (1:10,000 dilution in Tris-Acetate-EDTA buffer, Sigma, St. Louis, MO) for 30 min at room temperature, protected from light (Molecular Probes, Eugene, OR) and visualized using the Chemi-doc Gel Quantification System (Bio-Rad, Hercules, CA).
Preparation of cDNA probes and determination of mRNA relative abundance by Northern Blotting.
PCR transcripts were separated by gel electrophoresis through a 2% low melt agarose gel, excised, isolated, purified (Geneclean Kit, BIO101, Vista, CA) and sequenced to confirm identity. Verified transcripts were ligated separately into a TOPO cloning vector and transfected into Escherichia coli (TOPO Cloning Kit, Invitrogen). Positive clones were selected for on kanamycin (50 mg/L) containing Luria-Bertani (LB) plates and amplified in kanamycin-containing LB broth at 37°C for 10 h with shaking. Plasmid DNA was isolated using Qiagen Midi Kit (Qiagen, Valencia, CA) and digested with EcoR1 (Amersham Pharmacia Biotech). Restriction digests were separated and purified as described above. Glyceraldyde phosphatedehydrogenase (GAPDH) cDNA (a generous gift from Katti Jessen, University of California, Davis) was used as a normalization control. cDNA probes were labeled with 32P (cDNA Labeling Kit, Amersham Pharmacia Biotech) and desalted (S-200 MicroSpin Columns, Amersham Pharmacia Biotech). Equal amounts of mRNA from individual mammary glands (10 µg) were denatured in 3-morpholinopropoanesulfonic acid (MOPS) sample buffer containing ethidium bromide (Sigma) and electrophoresed through a 0.8% agarose gel containing MOPS-EDTA buffer (Sigma). mRNA was transferred to nylon membranes (Hybond, Amersham Pharmacia Biotech), cross-linked at 80°C under vacuum, prehybridized in Rapid-hyb (Amersham Pharmacia Biotech) for 1 h at 68°C and hybridized at 68°C for 2 h. Following hybridization, blots were stringently washed in 2X saline-sodium citrate buffer (SSC)/0.1% SDS at room temperature for 20 min, twice in 1X SSC/0.1% SDS at 68°C for 15 min and once in 0.5X SSC/0.1%SDS at 68°C for 15 min. Radiolabeled membranes were exposed overnight at -80°C in an autoradiography cassette with 2 enhancing screens (Fisher). Relative amounts of mRNA were quantified by densitometry using the Chemi-doc Gel Quantification System (Bio-Rad).
Preparation of mammary gland membrane and soluble protein fractions.
Mammary gland protein was isolated following a modification of McMahon and Cousins (9
). Mammary gland (500 mg) was homogenized for 20 s in 10 mL Hepes-EDTA buffer (20 mmol/L Hepes, pH 7.4/1 mmol/L EDTA/250 mmol/L sucrose/protease inhibitor mixture containing 4-(2-aminoethyl)benzenesulfonyl fluoride, trans-epoxysuccinyl-L-leucyl-amido(4-guanidino)butane, bestatin, leupeptin, aprotinin, and sodium EDTA (Sigma) with an ice-cold polytron homogenizer. The homogenate was centrifuged for 5 min at 300 x g followed by 30 min at 21,000 x g at 4°C. The supernatant (soluble protein) was removed and the crude membrane fraction (pellet) was resuspended in 0.5 mL homogenization buffer and stored at -80°C. Protein concentration was determined by the Lowry assay (21
).
Production of antibodies to ZnT-1, ZnT-2 and ZnT-4.
Peptides, predicted from the published mRNA sequences of ZnT-1 (GTRPOVHSGKE, LifeTechnologies) ZnT-2 (GKFNFHTMTIQIESYSEDMKSCQECQGPSE, Genemed Synthesis, South San Francisco, CA) and ZnT-4 (QLIPGSSSKWEEVQSKA, Genemed Synthesis,) were synthesized with an additional cysteine residue for conjugation to keyhole limpet hemocyanin (KLH) at the C-terminal end. Sequences were verified by amino acid analysis and mass spectroscopy. KLH-conjugated peptides were injected into New Zealand White rabbits (1 mg peptide/rabbit) for polyclonal antibody production. Antibody specificity was verified by peptide competition analysis. Briefly, membrane protein (20 µg) from mammary gland at d 10 lactation was resolved and transferred as described below. After blocking, blots were incubated with primary antibody (1:10,000) ± 1 g/L peptide for 1 h. After incubation with secondary antibody, blots were visualized as described below.
Western blotting/Slot blotting.
Equal amounts of mammary gland protein (20 µg) were resolved through 10% polyacrylamide SDS-PAGE gels under reducing conditions (ZnT-1, ZnT-2, ZnT-4) and transferred to nitrocellulose for 1 h at 300 mA or vacuum-applied to nitrocellulose (MT). Blots were blocked overnight at 4°C with 50 g/L nonfat milk in PBS/0.1% Tween-20 (PBS-T) and washed 3 times in PBS-T. Blots were incubated with zinc transporter antibody (1:10,000), or a mouse monoclonal antibody to MT (1:2,000, Dako, Carpinteria, CA) for 1 h and washed 3 times in PBS-T. Blots were incubated with donkey-anti-rabbit immunoglobulin (Ig) G conjugated to horseradish peroxidase (ZnT-1, ZnT-2, ZnT-4, Amersham Pharmacia Biotech) in 50 g/L nonfat milk or sheep-anti-mouse IgG conjugated to horseradish peroxidase (MT, Dako). Blots were visualized with chemiluminescence (Super Signal Femto, Pierce) and quantified using the Chemi-doc Gel Quantification System (Bio-Rad).
Statistical analysis.
Results are presented as mean ± SD for the number of samples reported. Statistical analysis was performed using Prism Graphpad version 3.02 (San Diego, CA). Tests for interaction were made using two-way ANOVA and post-tested using the Bonferroni test. Significant effect of diet was determined by one-way ANOVA and post-tested using the Tukey test. Significance of difference was demonstrated at P < 0.05.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Specificity of antibodies generated against ZnT-1, ZnT-2 and ZnT-4 peptides was confirmed by the disappearance of specific immunoreactive bands after peptide coincubation (Fig. 1
). Two immunoreactive bands were identified for ZnT-1 at 80 and 49 kDa which responded similarly to peptide coincubation. One immunoreactive band for ZnT-2 (46 kDa) and ZnT-4 (42 kDa) was identified.
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Expression of ZnT-1, ZnT-2 and ZnT-4 was identified by RT-PCR performed on mRNA isolated from the mammary gland of control rats at d 10 of lactation. Immunostaining of mammary gland from control rats at d 10 of lactation was used to determine the general location of these zinc transporters. ZnT-1 was localized to the serosal membrane in multiple cell types of the mammary gland. ZnT-2 and ZnT-4 were localized intracellularly and primarily in the mammary epithelial cells lining the alveoli lumen (Fig. 2
). Although we were unable to determine the specific subcellular localization of ZnT-2 and ZnT-4, ZnT-2 was detected primarily distal of the nucleus, whereas ZnT-4 was detected throughout the entire mammary epithelial cell.
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Although there were no effects of diet on plasma, mammary gland or milk Zn concentration, there was a significant interaction between zinc and vitamin A on plasma Zn concentration such that in rats fed adequate dietary Zn, plasma Zn concentration was dependent upon dietary vitamin A (Table 1
). There was a significant effect of zinc intake on plasma retinol (ROH) and a significant effect of vitamin A intake on mammary gland ROH. Additionally, mammary gland ROH concentration was dependent upon vitamin A intake in rats fed marginal Zn.
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There were effects of diet on zinc transporter mRNA expression (Figs. 3A and B
) and protein level (Figs. 4A and B
) in the mammary gland. One ZnT-1 transcript (2.6 kb) was identified in the mammary gland of lactating rats and there was no effect of diet on mRNA expression. Two immunoreactive bands were identified as ZnT-1 protein. Both bands responded similarly to dietary treatment. The effect of diet was more pronounced for the larger 80 kDa band; therefore, it was used for subsequent analysis. ZnT-1 was lower in rats fed the marginal Zn or vitamin A diets (P < 0.0001) compared with control rats and there was an interaction between zinc and vitamin A intake on ZnT-1 protein level (P = 0.04).
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4.5 and 2.3 kb) were identified in the mammary gland. Both bands responded similarly to dietary treatment and we chose the larger 4.5 kb for subsequent analysis. Rats fed the marginal Zn and vitamin A diet had higher ZnT-2 mRNA expression than rats fed other diets, and there was an interaction between Zn and vitamin A intake on ZnT-2 mRNA levels. There was no effect on ZnT-2 protein level.
Two ZnT-4 transcripts (5.4 and 1.9 kb) were identified in the mammary gland. Both bands responded similarly to dietary treatment and we chose the larger 5.4 kb for subsequent analysis. Rats fed the marginal Zn or vitamin A diet had higher ZnT-4 mRNA expression and protein levels than controls and rats fed the diet marginal in zinc and vitamin A. There was an interaction between zinc and vitamin A intake on ZnT-4 mRNA expression (P < 0.0001).
There were also effects of zinc and vitamin A intakes on the amount of MT protein such that rats fed marginal Zn diets had lower (P = 0.0002) and rats fed marginal vitamin A diets had higher (P < 0.0001) MT protein levels in the mammary gland (immunoblot not shown). Additionally, there was an interaction between zinc and vitamin A intake on MT protein levels (P = 0.02) in the mammary gland.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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), or perhaps the presence of confounding inadequacies in micronutrients such as vitamin A. In this study, our model of chronic marginal zinc and vitamin A intake during lactation did not result in zinc or vitamin A deficiency as assessed by conventional indicators. Therefore, we believe our results may reflect zinc nutriture in many human populations and document sensitive physiologic alterations that maintain zinc homeostasis in the mammary gland as well as an interaction between zinc and vitamin A during lactation before overt zinc or vitamin A deficiency.
Previously, we documented the uptake of zinc into human mammary epithelial cells in culture to be time and concentration dependent, illustrating a saturable (i.e., transporter-regulated) and a nonsaturable component to mammary gland zinc uptake (23
). The mechanisms responsible for zinc transport in the mammary gland have not previously been determined; however, we propose that ZnT-1, ZnT-2 and ZnT-4 work in coordination to maintain milk zinc concentration (Fig. 5
). In this study, we have shown that regulation of milk zinc concentration is transcriptionally and post-transcriptionally controlled through alterations in ZnT-1, ZnT-2 and ZnT-4 levels in the mammary gland, which may reflect subtle changes in cellular MT levels but not total zinc or retinol concentrations. During marginally low zinc intake, ZnT-1 mRNA expression remained constant. These results are in accordance with observations made by McMahon and Cousins (9
) who found that even during severe zinc deficiency, with reduced plasma zinc concentration, ZnT-1 mRNA expression in tissues was not affected. However, a diet marginally low in zinc reduced ZnT-1 protein level in the mammary gland, thus allowing the mammary gland to reduce serosal zinc export through this ubiquitous transporter during low zinc intake. Although the mechanism behind this decrease is unknown, Gitan et al. (24
) showed that increased cellular zinc in yeast increases the ubiquitination of ZRT1, a yeast zinc import protein, and results in its removal from the plasma membrane and subsequent degradation to protect the yeast from overaccumulation of zinc. Although it remains to be determined whether ZnT-1 is regulated post-translationally in a similar manner, rats fed a diet marginally low in zinc also had a lower level of mammary gland MT without alterations in total mammary gland zinc, potentially increasing the ratio of zinc to MT and increasing the concentration of "labile" zinc affecting sensitive signaling pathways.
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) and a similar role for ZnT-4 in endosomal zinc transport was predicted (26
). The tendency for reductions in ZnT-2 mRNA expression and protein levels (P = 0.08), concomitant with increased ZnT-4 mRNA expression and protein levels, suggests coordinated regulation to maintain milk zinc concentration. We propose that contrary to ubiquitous ZnT-1–mediated serosal zinc export and in addition to compartmentalized ZnT-2-mediated zinc transport, vesicular ZnT-4 participates in the import of zinc into endocytotic or secretory vesicles, which ultimately release zinc into milk. This integrated control of zinc transport by ZnT-1, ZnT-2 and ZnT-4 in the mammary gland would explain why a mutation in ZnT-4, which is presumed to be responsible for the lethal milk mutation in mice, reduces milk zinc by 50% but does not eliminate milk zinc altogether. Our results in the mammary gland are in contrast to observations of others that reduced dietary zinc does not affect the expression of ZnT-4 mRNA in tissues such as small intestine, testes, liver, kidney or brain (27
), indicating a specialized role for ZnT-4 in the mammary gland.
A number of studies have described negative effects of zinc deficiency on vitamin A status (1
). In this study, we have for the first time documented specific effects of marginal vitamin A intake, in the absence of vitamin A deficiency, on zinc transport mechanisms in the mammary gland of lactating rats. During lactation, marginal vitamin A intake increased ZnT-4 mRNA expression and ZnT-4 protein levels. Although the mechanisms responsible for these effects are not understood, marginal vitamin A intake decreased total mammary gland retinol and increased MT levels without affecting mammary gland zinc concentration, suggesting that the effects on zinc transporters may be related to alterations in cellular retinol or zinc partitioning. There is evidence that vitamin A plays a role in MT regulation because Sauer et al. (28
) observed that pretreatment of rats with retinol increased the level of MT protein in the liver sevenfold; however, the mechanism by which retinol alters MT is not yet understood.
In this study, we have also for the first time documented an interaction between marginal zinc and vitamin A intake during lactation on zinc transporter mRNA expression in the mammary gland at the molecular level. However, the interaction between Zn and vitamin A intake on ZnT-2 and ZnT-4 mRNA levels was not translated into similar changes in protein levels. Interestingly, although zinc and vitamin A intake interacted to increase ZnT-2 mRNA expression, ZnT-2 protein levels had a tendency to be reduced (P = 0.06). Thus, a diet low in vitamin A and zinc resulted in reduced ZnT-1 but had no effect on ZnT-2 or ZnT-4 protein levels in the mammary gland, a different response from those in rats fed diets marginally low in Zn or vitamin A independently. The combination of lower ZnT-1-and ZnT-2-mediated zinc export in conjunction with higher ZnT-4–mediated zinc transport, potentially into intracellular secretory vesicles, appears to adequately sustain both cellular and milk zinc levels.
The results of this study indicate that diets marginal in zinc and vitamin A during lactation affect zinc transporter levels, and these changes occur in coordination to maintain adequate cellular and milk zinc concentrations. Additionally, although marginal zinc and vitamin A intakes independently appear to evoke similar homeostatic responses by the mammary gland to maintain milk zinc, these events may be regulated by different cellular mechanisms because MT was reduced by marginal Zn intake and increased by marginal vitamin A intake. Furthermore, a diet marginal in both zinc and vitamin A affected mammary gland zinc transporters differentially by decreasing ZnT-1 and not affecting ZnT-4 protein levels. These alterations are not mediated directly by reductions in total plasma zinc and retinol but most likely by subtle alterations in zinc- and retinol-responsive transcriptional, and post-transcriptional control mechanisms within the mammary gland itself. Together, these results suggest that marginal intake of vitamin A may alter intracellular retinol metabolism and cellular MT in the mammary gland, thus affecting the regulation of zinc transport in the mammary epithelial cell, and may therefore play a role in mediating zinc partitioning in the mammary gland and subsequent zinc transport into milk. However, the mechanisms responsible for the uptake of zinc into the mammary gland and the effects of other nutritional inadequacies on their regulation remain to be determined.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Manuscript received 14 May 2002. Initial review completed 10 June 2002. Revision accepted 14 August 2002.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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24. Gitan, R. S. & Eide, D. J. (2000) Zinc-regulated ubiquitin conjugation signals endocytosis in the yeast ZRT1 transporter. Biochem. J. 346:329-336.
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 C. E. O'Brien, N. F. Krebs, J. L. Westcott, and Fang Dong Relationships Among Plasma Zinc, Plasma Prolactin, Milk Transfer, and Milk Zinc in Lactating Women J Hum Lact, May 1, 2007; 23(2): 179 - 183. [Abstract] [PDF]
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 Y. Y. Yu, C. P. Kirschke, and L. Huang Immunohistochemical Analysis of ZnT1, 4, 5, 6, and 7 in the Mouse Gastrointestinal Tract J. Histochem. Cytochem., March 1, 2007; 55(3): 223 - 234. [Abstract] [Full Text] [PDF]
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 N. F Krebs and K M. Hambidge Complementary feeding: clinically relevant factors affecting timing and composition Am. J. Clinical Nutrition, February 1, 2007; 85(2): 639S - 645S. [Abstract] [Full Text] [PDF]
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 W. Chowanadisai, B. Lonnerdal, and S. L. Kelleher Identification of a Mutation in SLC30A2 (ZnT-2) in Women with Low Milk Zinc Concentration That Results in Transient Neonatal Zinc Deficiency J. Biol. Chem., December 22, 2006; 281(51): 39699 - 39707. [Abstract] [Full Text] [PDF]
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S. L. Kelleher and B. Lonnerdal Mammary gland copper transport is stimulated by prolactin through alterations in Ctr1 and Atp7A localization Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2006; 291(4): R1181 - R1191. [Abstract] [Full Text] [PDF]
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 K. A. Bauerly, S. L. Kelleher, and B. Lonnerdal Effects of copper supplementation on copper absorption, tissue distribution, and copper transporter expression in an infant rat model Am J Physiol Gastrointest Liver Physiol, May 1, 2005; 288(5): G1007 - G1014. [Abstract] [Full Text] [PDF]
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 S. L. Kelleher and B. Lonnerdal Zip3 plays a major role in zinc uptake into mammary epithelial cells and is regulated by prolactin Am J Physiol Cell Physiol, May 1, 2005; 288(5): C1042 - C1047. [Abstract] [Full Text] [PDF]
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S. L. Kelleher and B. Lonnerdal Low Vitamin A Intake Affects Milk Iron Level and Iron Transporters in Rat Mammary Gland and Liver J. Nutr., January 1, 2005; 135(1): 27 - 32. [Abstract] [Full Text] [PDF]
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W. Chowanadisai, S. L. Kelleher, and B. Lonnerdal Maternal Zinc Deficiency Raises Plasma Prolactin Levels in Lactating Rats J. Nutr., June 1, 2004; 134(6): 1314 - 1319. [Abstract] [Full Text] [PDF]
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M. Domellof, B. Lonnerdal, K. G Dewey, R. J Cohen, and O. Hernell Iron, zinc, and copper concentrations in breast milk are independent of maternal mineral status Am. J. Clinical Nutrition, January 1, 2004; 79(1): 111 - 115. [Abstract] [Full Text] [PDF]
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S. L Kelleher and B. Lonnerdal Zn Transporter Levels and Localization Change Throughout Lactation in Rat Mammary Gland and Are Regulated by Zn in Mammary Cells J. Nutr., November 1, 2003; 133(11): 3378 - 3385. [Abstract] [Full Text] [PDF]
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S. L. Kelleher and B. Lonnerdal Marginal Maternal Zn Intake in Rats Alters Mammary Gland Cu Transporter Levels and Milk Cu Concentration and Affects Neonatal Cu Metabolism J. Nutr., July 1, 2003; 133(7): 2141 - 2148. [Abstract] [Full Text] [PDF]
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C. P. Kirschke and L. Huang ZnT7, a Novel Mammalian Zinc Transporter, Accumulates Zinc in the Golgi Apparatus J. Biol. Chem., January 31, 2003; 278(6): 4096 - 4102. [Abstract] [Full Text] [PDF]
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