Zinc in the Fetus and Neonate

Introduction

In a remarkably short time, the general perception of zinc has progressed from that of a rather obscure essential trace mineral of doubtful significance for human health to that of a micronutrient of exceptional biologic and public health importance. This is most evident in relation to early development, both prenatal and postnatal. Space allotted to an overview of trace minerals other than iron and zinc in previous editions of this book is therefore devoted entirely to zinc in this edition, and the reader is referred to other texts for information on other trace minerals. The principal focus of this chapter is on the complex biology of zinc, which underlies its clinical importance.

Biochemistry and Biology of Zinc

The abundance of zinc in the human body (approximately 2 g in the adult female and 2.5 g in the adult male) is second only to that of iron among those trace elements for which a nutritional requirement has been established in humans. In contrast to iron and iodine, however, zinc is distributed relatively evenly throughout the body, being found as a component of thousands of zinc metalloproteins or zinc-binding proteins and also of nucleic acids. This wide distribution of the element, along with the tight homeostatic control within tissues over a wide range of dietary intakes, makes assessment of zinc status particularly challenging. With an atomic weight of 65.39, zinc is near several first-row transition elements of biologic importance, yet its biochemical properties are very different from those of other elements of similar atomic weight. One of the properties of the zinc atom that has proved to be of outstanding value in biology is its ability to participate in strong but readily exchangeable ligand binding. Coupled with this feature is the notable flexibility of the coordination geometry of this metal. These two properties are responsible for its unique ability to interact with a wide range of organic ligands and thus to be incorporated into myriad biologic systems. The principal amino acids supplying ligands that bind with zinc are histidine, glutamic acid, aspartic acid, and cysteine. Structural zinc sites have four protein ligands, with cysteine being preferred. Zinc affects tertiary and quaternary protein structure, and the resulting scaffolding of these zinc coordination spheres is important for the function and reactivity of the metal atom.

Zinc can participate in oxidation-reduction (redox) reactions, specifically through the combined biochemistry of zinc, metallothionein, and glutathione. In contrast to iron and copper, however, the zinc atom has no oxidant properties; it exists virtually entirely in the divalent state, an attribute that simplifies the safe transport of Zn ²⁺ , both extracellularly and intracellularly, and its incorporation into biologic systems.

The biologic roles of zinc are now recognized in protein structure and function, including those for enzymes, transcription factors, hormonal receptor sites, and biologic membranes. Zinc has numerous central roles in DNA and RNA metabolism, and it is involved in signal transduction, gene expression, and apoptosis.

First to be appreciated were the catalytic properties of zinc, a function of its biochemistry outlined earlier. The number of zinc metalloenzymes with known three-dimensional structures exceeds 200. Although zinc also has a structural role in numerous enzymes, its primary importance is as an active component of the catalytic site. Zinc metalloenzymes have been identified in each of the six major enzyme classifications. Several of the key enzymes involved in nucleic acid metabolism, cellular proliferation, differentiation, and growth are either zinc metalloenzymes or zinc-dependent enzymes. A major advance in the understanding of the biology of zinc was the identification of proteins that contain a zinc finger motif . Structurally, the zinc finger motif is a recurring pattern of amino acids with conserved cysteine and histidine residues at the base to which zinc binds in a tetrahedral arrangement. Subsequently, hundreds of zinc finger motifs were identified. More than 1000 genes in the human genome encode members of three protein families with zinc finger domains alone: C2H2 zinc fingers, RING fingers, and LIM domains. The number of genes containing zinc finger domains exceeds 3% of all identified human genes. Although all zinc fingers are quite similar, they differ in their precise conformation. Steroid hormone receptors, for example, have several such domains that are involved in the structure itself, and one each for binding to DNA and RNA polymerases. Among the identified zinc transcription factors are several involved in early intrauterine development.

The numerous transcription factor proteins with the zinc finger motif gives this metal a broad role in gene expression. This role has perhaps been best characterized by the self-regulation of this metal of its own metabolism and that of metallothionein, with which zinc is so closely associated. Gene expression in this context is considered later, in the discussion of zinc metabolism.

Zinc is an important regulator of apoptosis. This micronutrient has cytoprotective functions that suppress major pathways leading to apoptosis and also directly influences apoptotic regulators, especially the caspase family of enzymes. In airway epithelial cells, zinc is colocalized with the precursor forms of caspase 3, mitochondria, and microtubules. A decline in intracellular zinc concentration may trigger pathways leading to caspase activation. An early and direct effect of zinc deficiency, not only on proliferation and differentiation but also in inducing apoptosis, has been demonstrated in growth plate chondrocytes of the chick.

There is evidence of a direct signaling function of zinc at all levels of signal transduction. Zinc can modulate cellular signal recognition, second-messenger metabolism, and protein kinase and protein phosphatase activities. In the brain, zinc is sequestered in the presynaptic vesicles of zinc-containing neurons, from which zinc is released into the cleft and is then recycled into the presynaptic terminal. Synaptically released zinc functions as a conventional synaptic neurotransmitter or neuromodulator but, analogous to calcium, also functions as a transmembrane neural signal. The best-established physiologic role of this vesicular zinc is the tonic modulation of brain excitability. Vesicular-rich regions such as the hippocampus are responsive to dietary zinc deprivation, which causes brain dysfunction, including learning impairment and susceptibility to epileptic seizures. Normal neuronal function is dependent on normal zinc homeostasis in the brain.

The biology of zinc is closely linked with that of metallothionein, a unique small intracellular protein of less than 7 kDa that is strongly conserved across species. Of the 61 to 68 amino acids in the protein, more than one-third are cysteine. Metallothionein occurs in all tissues, including those of the conceptus, and is especially abundant in liver and also in pancreas, intestine, and kidney. The metallothioneins have a high affinity for zinc and are critical for maintaining cytoplasmic zinc pools to protect against cytotoxicity. Zinc is the major physiologic inducer of metallothionein. Its synthesis is also stimulated by cytokines, especially the interleukins (IL)-1 and IL-6, tumor necrosis factor-α, and stress hormones (glucocorticoids and catecholamines), supporting a key role for zinc in the inflammatory response as well as in zinc metabolism. Zinc binds directly and reversibly to the zinc finger domains of metal response element–binding transcription factor 1 (MTF-1), which functions as a cellular zinc sensor. As a result of this binding, MTF-1 assumes a DNA-binding conformation and translocates to the nucleus, where it binds to metal-response elements of the metallothionein gene, thereby initiating transcription. MTF-1 provides zinc responsiveness to many genes and acts as a master regulatory transcription factor for microRNA genes. involved in gene expression, including of zinc transporters. Null mutation of the MTF-1 gene is lethal in embryonic mice.

Factors that increase the induction of maternal hepatic metallothionein during early pregnancy may divert zinc from the conceptus to the maternal liver, potentially resulting in a conceptus that is deficient in zinc. Curtailment of fetal zinc uptake can occur with maternal ingestion of alcohol, a mechanism that may be important in the origin of fetal alcohol syndrome. Close similarities have been recognized between the teratogenicity of maternal zinc deficiency and alcohol administration to mice in early gestation, and this effect can be diminished by parenteral administration of zinc. Cytokines cause a similar disturbance of maternal zinc metabolism and also are teratogenic in rodents.

Physiology of Zinc