Zinc (Zn) is an essential micronutrient required for over 300 different cellular processes, including DNA and protein synthesis, enzyme activity, and intracellular signaling. Cellular Zn homeostasis necessitates the compartmentalization of Zn into intracellular organelles, which is tightly regulated through the integration of Zn transporting mechanisms. The pancreas, prostate, and mammary gland are secretory tissues that have unusual Zn requirements and thus must tightly regulate Zn metabolism through integrating Zn import, sequestration, and export mechanisms. Recent findings indicate that these tissues utilize Zn for basic cellular processes but also require Zn for unique cellular needs. In addition, abundant Zn is transported into the secretory pathway and a large amount is subsequently secreted in a tightly regulated manner for unique biological processes. Expression of numerous members of the SLC30A (ZnT) and SLC39A (Zip) gene families has been documented in these tissues, yet there is limited understanding of their precise functional role in Zn metabolism or their regulation. Impairments in Zn secretion from the pancreas, prostate, and mammary gland are associated with disorders such as diabetes, infertility, and cancer, respectively. In this review, we will provide a brief summary of the specific role of Zn in each tissue and describe our current knowledge regarding how Zn metabolism is regulated. Finally, in each instance, we will reflect upon how this information shapes our current understanding of the role of Zn in these secretory tissues with respect to human health and disease.

Male infertility accounts for ~40% of cases of failure to conceive. Testes have a strict zinc (Zn) requirement and severe Zn deficiency compromises spermatogenesis, sperm viability, and motility, compromising fertility in men. Despite the high prevalence of marginal Zn deficiency in humans, less emphasis has been placed on understanding the consequences on male reproduction. Swiss Webster mice were used to visualize Zip protein expression during spermatogenesis using immunohistochemistry. Data suggest Zip5 imports Zn into Sertoli cells and spermatocytes, augmented by Zip10 (primary spermatocytes) and Zip8 (secondary spermatocytes). Zip6, 8, and 10 expression was retained in round spermatids, although Zip8 and Zip10 expression disappears during spermatid maturation. Zip1 and Zip6 expression was detected in mature, elongated spermatids. Zip14 was detected in undifferentiated spermatogonia and Leydig cells. Mice fed diets (n = 10/group) reduced in Zn concentration [marginal-Zn diet (MZD), 10 mg Zn/kg; low-Zn diet (ZD), 7 mg Zn/kg] for 30 d had >35% lower liver Zn concentrations than mice fed the control diet (C; 30 mg Zn/kg) (P < 0.05). Plasma Zn and testosterone concentrations and the testes Zn concentration and weight were not significantly lower than in controls. Plasma Zn was greater in the ZD group than in the C and MZD groups. Mice fed ZD had a reduced number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells (~50%; P < 0.05), compromised seminiferous tubule structure, and reduced Zip10 and Zip6 abundance (>50%; P < 0.5) compared with mice fed C. Our data provide compelling evidence that reduced Zn intake may be associated with infertility in men, perhaps independent of decreased levels of circulating Zn or testosterone, which warrants further investigation in human populations.

BackgroundThe mammary gland is responsible for the transfer of a tremendous amount of zinc (∼1–3 mg zinc/day) from maternal circulation into milk during lactation to support the growth and development of the offspring. When this process is compromised, severe zinc deficiency compromises neuronal development and immune function and increases infant morbidity and/or mortality. It remains unclear as to how the lactating mammary gland dynamically integrates zinc import from maternal circulation with the enormous amount of zinc that is secreted into milk.Methodology/Principal FindingsHerein we utilized X-ray fluorescence microscopy (XFM) which allowed for the visualization and quantification of the process of zinc transfer through the mammary gland of the lactating mouse. Our data illustrate that a large amount of zinc first accumulates in the mammary gland during lactation. Interestingly, this zinc is not cytosolic, but accumulated in large, discrete sub-cellular compartments. These zinc pools were then redistributed to small intracellular vesicles destined for secretion in a prolactin-responsive manner. Confocal microscopy identified mitochondria and the Golgi apparatus as the sub-cellular compartments which accumulate zinc; however, zinc pools in the Golgi apparatus, but not mitochondria are redistributed to vesicles destined for secretion during lactation.Conclusions/SignificanceOur data directly implicate the Golgi apparatus in providing a large, mobilizable zinc storage pool to assist in providing for the tremendous amount of zinc that is secreted into milk. Interestingly, our study also provides compelling evidence that mitochondrial zinc pools expand in the mammary gland during lactation which we speculate may play a role in regulating mammary gland function.

The mammary epithelial cell transitions from a, non-secreting to a terminally differentiated, secreting cell during lactation. Zinc (Zn) is a key modulator of phenotypic transition as it regulates over 300 biological functions including transcription, translation, energy transformation, intracellular signaling and apoptosis. In addition, Zn must be redirected from normal cellular functions into the secretory compartment, as many components of the secretory system are Zn-dependant and an extraordinary amount of Zn is secreted (1–3 mg Zn/d) into milk. Herein, we utilized a “systems biology” approach of genomic and proteomic profiling to explore mechanisms through which Zn is reallocated during phenotype transition in the lactating mammary gland from mice and cultured mammary cells. Nine Zn transporters play key roles in Zn redistribution within the network during lactation. Protein abundance of six Zip (Zip3, Zip5, Zip7, Zip8, Zip10, Zip11) and three ZnT (ZnT2, ZnT4, ZnT9) proteins was expanded > 2-fold during lactation, which was not necessarily reflected by changes in mRNA expression. Our data suggest that Zip5, Zip8 and Zip10 may be key to Zn acquisition from maternal circulation, while multiple Zip proteins reuptake Zn from milk. Confocal microscopy of cultured mammary cells identified the Golgi apparatus (modulated in part by ZnT5, Zip7 and Zip11) and the late endosomal compartment (modulated in part by ZnT2 and Zip3) as key intracellular compartments through which Zn is reallocated during lactation. These results provide an important framework for understanding the Zn transporting network through which mammary gland Zn pools are redistributed and secreted into milk.

Dietary analysis predicts that marginal Zn deficiency is common in women of reproductive age. The lack of reliable biomarkers limits the capacity to assess Zn status and consequently understand effects of maternal Zn deficiency. We determined effects of marginal maternal Zn deficiency on mammary gland function, milk secretion, and milk composition in mice. Mice (n = 12/diet) were fed marginal (ZD; 15 mg Zn/kg diet) or adequate (ZA; 30 mg Zn/kg diet) Zn diets for 30 d prior to conception through mid-lactation. Mice fed the ZD had a higher plasma Zn concentration (~20%; P < 0.05) but lower milk Zn concentration (~15%; P < 0.05) compared with mice fed the ZA. ZnT2 abundance was higher (P < 0.05) in mice fed the ZD compared with mice fed the ZA; no effect on ZnT4 abundance was detected. The Zn concentration of mammary gland mitochondria tended to be ~40% greater in mice fed ZD (P = 0.07); this was associated with apoptosis and lower milk secretion (~80%; P < 0.01). Total milk protein was ~25% higher (P < 0.05), although the abundance of the major milk proteins (caseins and whey acidic protein) was lower (P < 0.05) in mice fed the ZD. Proteomic analysis of milk proteins revealed an increase (P < 0.05) in four proteins in mice fed the ZD. These findings illustrate that marginal maternal Zn deficiency compromises mammary gland function and milk secretion and alters milk composition. This suggests that lactating women who consume inadequate Zn may not produce and/or secrete an adequate amount of high quality milk to provide optimal nutrition to their developing infant.