Zinc: Future Directions
Zinc and Health: Workshop Summary
This NIH Workshop on Zinc and Health has served to synthesize
remarkable recent progress and our understanding of zinc in health and
disease. It is abundantly clear that zinc is of extraordinary and
diverse importance in human biology and nutrition. Despite encouraging
recent progress, zinc research is still in a relatively early stage of
its evolution. This workshop, however, has achieved a broad consensus
on priority research areas that will be most productive in accelerating
progress relevant to human health and disease.
In broad terms, these are:
I. Accelerated research directed to achieving a clearer understanding
of the chemistry, biology and pathobiology of zinc. Specific systems
meriting special focus include the gastrointestinal, immune and central
Research questions and directives to characterize the biological
role of zinc:
Research questions to characterize the role of zinc in the gastrointestinal
How shall the characterization, chemistry, and thermodynamics of transporters
for zinc be evaluated?
How are the activities of zinc finger proteins (of all classes) affected
by cellular zinc status?
Do zinc finger proteins form zinc-regulated gene control networks?
Determine the relationship of zinc to the structural and biochemical properties
of calcium channels.
Determine the neurobehavioral roles of the neuronal circuits that use synaptically-released
zinc as a trans-synaptic signal
Characterize the time course of zinc-induced neuronal injury after stroke,
trauma, and seizures
Identification of novel zinc binding motifs: enhance searching genomes
for new zinc metalloenzymes.
Development of specific inhibitors of biologically relevant zinc metalloenzymes
such as metalloproteinases (bone development, tumor invasion, etc.).
What is the function of metallothionein?
What impact does zinc dysregulation have upon zinc-modulated synaptic transmission
Examine the consequences (beneficial or otherwise) of zinc mediated inhibition
What role has the development of zinc finger proteins and zinc homeostatic
mechanisms played in eukaryotic evolution?
Identify zinc-dependent transcription factors and regulated genes, the
role of gene in hormone-receptor interactions, gene-dependent signal transduction
pathways, and identify gene-associated signals which affect cell cycle
When and where does apoptosis require zinc?
How does zinc act in concert with other apoptotic regulators e.g., Bc1-2?
Does increased apoptosis occur in human zinc deficiency and if so, in which
Are any of the clinical manifestations of zinc deficiency due to increased
Research questions and directives to characterize the role of zinc in
Does zinc maintain intestinal defense systems?
Relationship of zinc to intestinal fluid balance.
Define the linkages of intestinal zinc transporters to body zinc status.
Is there a brush border (apical) membrane zinc transporter for enterocytes?
Research questions or directives to characterize the role of zinc in
the central nervous system:
What is the mechanism of zinc activation and why does zinc only induce
How does zinc increase IFN-? production and what is the influence of zinc
on other immunostimulants?
Examine zinc as an inhibitor of site-specific reactions, and explore how
zinc's inhibitory effects might be useful for therapy.
II. Research questions or directives regarding the elucidation of the
details of zinc metabolism and mechanisms of zinc homeostasis at a molecular,
subcellular, cellular organ/system and whole body level.
What role do zinc-modulated synapses (synapses at which the boutons
release zinc) play in normal neurobehavioral control ?
Describe the pathophysiology of zinc-induced neuron death.
Support animal-model studies-emphasizing central (hypothalamic) control
of food intake and body weight regulation during zinc-related anorexia.
Is zinc the indicator of the presence of or cause of amyloid deposits or
lesions in the brain?
What is the life cycle of presynaptic vesicular zinc in the CNS ?
Characterize regulation of zinc transporters at zinc-modulated synapses
in the central nervous system.
What is the normal physiological function of the zinc ions that are co-released
with glutamate at cerebrocortical synapses ?
What is the function of metallothionein-3 in the central nervous system?
Evaluate the effects of zinc deficiency on signal transduction pathways
pertaining to anorexia and body weight regulations.
III. Research questions or directives for the clarification of the epidemiology
of human zinc deficiency and improved methods/strategies for the detection,
prevention and management of zinc deficiency in otherwise healthy humans
as well as in a wide range of disease states.
Evaluate mechanisms for zinc absorption and their regulation.
What are the effects on zinc absorption due to interactions with non-essential
elements and among dietary factors?
What are the signals that modulate the changes in urinary and endogenous
fecal excretion with changes in intake?
What tissues or cell types preferentially and by what mechanism retain
zinc with deficiency or gain zinc with toxicity? How is this preferential
retention altered with dietary factors, growth, reproduction and disease?
What are the effects of prior zinc status on zinc absorption?How does gene
deletion or over-expression affect zinc metabolism?
Characterization of dietary, physiologic and pathologic factors that perturb
Undertake the characterization of processes of absorption and excretion
in the gastrointestinal tract in response to range of dietary zinc and
Identification of the regulatory signals for adaptive responses.
Support studies linking observations of subcellular Zn transport with whole
How does zinc enter the cell, where is it stored, how is its concentration
controlled, and what is its hierarchy and method of distribution within
How and where is zinc uptake and distribution regulated?
How is zinc intake related to growth and how do requirements change with
Evaluate the physiologic and developmental regulation of zinc transporters.
Determine the relative metabolic importance of importers vs. exporters.
Evaluate how overlap of activity of other cation transporters is responsible
for mineral-mineral interactions involving zinc.
IV. Research questions or directives regarding the characterization
of the benefits/risks of zinc supplementation with emphasis on recognized
zinc responsive biological systems including oxidative stress and host
defense to infection.
What are the short term and long-term consequences of transitory zinc deficiency
during different developmental stages? Are there epigenetic consequences
of prenatal zinc deficiency?
What is the role of zinc in various diseases and how do zinc requirements
change depending on disease pathology, e.g. diabetes?
What is the role of zinc and alpha-2 macroglobulin interaction in health
and Alzheimer's Disease?
Development of simple, useful, serum-based measure reflecting body zinc
stores (like serum ferritin for iron status) and of tissue zinc deficiency
(like serum transferrin receptor for iron deficiency).
Will aggressive zinc supplementation significantly reduce the destruction
of the immune system that occurs in chronic diseases and dietary deficiencies
where zinc is suboptimal? Will it reduce the incidence of infections, inflammatory
responses and mortality in deficient hosts?
Can zinc be used in combination with cytokine and/or drug therapy in clinical
settings to bring about even better protection of the immune system then
zinc supplementation alone?
Will zinc supplementation bring about full repair of an immune system altered
by zinc deficiency during fetal-neonatal development, pregnancy, or aging?
Is the use of zinc supplements associated with improved fertility, reductions
in early fetal wastage and fetal malformations?
What are the risks associated with the use of zinc supplements prior to,
and during pregnancy?
Support clinical studies examining nutrient supplementation during anorexia.
Given the observation that an early effect of zinc deficiency in the developing
conceptus is oxidative damage, will the antioxidant status of an individual
modulate their response to tertriatogenic insults which influence maternal-conceptus
Examine the effects of zinc on apoptosis, particularly in ischemic injury.
In many instances, techniques are available that will allow accelerated
progress to be achieved. In some instances however, progress will
be dependent on the development of new techniques and adaptation of existing
technologies to zinc-related research.