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Underwood Memorial Lectures |
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TEMA 5 |
Richard Smith Biochemical criteria of deficiency and toxicity It is my privilege to deliver the memorial lecture to the late Eric John Underwood, FRS. Underwood died in Perth, Western Australia on 19th August 1980, aged 74 years, whilst actively engaged in preparations for the Fourth International Symposium on Trace Elements in Man and Animals, TEMA 4, held in Perth in May 1981. As one of the pioneers of trace element research, as author of the classical text on the subject Trace Elements in Human and Animal Nutrition and as a personal friend or acquaintance of very many of us here, his name will long remain at the centre of the field. A man of outstanding intellect and with an enviable orderliness of mind his immense grasp of all facets of his subject will perhaps not be matched again.
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| TEMA 6 May-June 1987 |
Bo Lönnerdal Trace elements in infancy: a supply/demand perspective Although our understanding of the dietary factors affecting trace element absorption has been growing considerably, much less is known about the infant's ability to respond to a situation where the body's demand for an element is not met by the supply. Can a breast-fed. infant which admittedly is receiving a diet low in iron up-regulate absorptive mechanisms? Will a formula low in zinc or copper cause homeostatic regulation of zinc or copper metabolism by increasing uptake and/or decreasing endogenous losses? Is it possible that a high intake of manganese can down-regulate iron absorption? It is obvious from these questions that our understanding of adaptive mechanisms in infants is limited and that further long-term studies are needed.
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TEMA 7 |
Ian Bremner A molecular approach to the study of copper and zinc metallothionein This review has provided examples of the benefits that can result from the study of the molecular association of trace elements. Measurement of total metal concentrations in tissues is of limited value in understanding the complex mechanisms that control the absorption and utilisation of metals. However, elucidation of the speciation of metals, such as copper and zinc, can provide insight into the mechanisms of interaction between them. As a consequence, it can lead to the development of new therapeutic measures to control metal toxicity states or to novel methods for the diagnosis of imbalance in trace element status. This review has concentrated on only two molecular species, namely thiomolybdates and metallothionein. There are many others that merit the same attention and which will be equally rewarding to the determined investigator.
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TEMA 8 |
Manfred Kirchgessner Homeostasis and homeorhesis in trace element metabolism The trace element metabolism is under homeostatic and homeorhetic control. This mechanisms cause an adaptation of absorption and endogenous fecal and renal excretion to changes in the dietary trace element supply and stabilize the intermediate concentration and retention of trace elements at a physiological level. The trace elements differ greatly with regard to the priority of regulation (absorption: Zn. Mn, Fe. Cu; endogenous fecal excretion: Zn. Mn; renal excretion: Co. Ni, anionic trace elements). The mode of action of the regulatory mechanisms and the effects on retention, diagnosis of the supply status, estimation of trace element requirement and measurement of bioavailability are described with reference to experimental findings.
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TEMA 9 |
John Arthur Selenium biochemistry and function The last 25 years have seen a major increase in our understanding of the function of selenium in animals. Many of these advances have derived from understanding the biochemical function of selenium in an ever increasing variety of metabolic processes. This approach to trace element research, mechanistic rather than observational, is one that was pioneered and encouraged by Underwood. In conclusion, many questions still remain to be answered as to the biochemical functions of selenium. Further characterisation of the mechanisms which control selenoprotein expression in selenium deficiency will help to identify the most important selenoproteins and our recognition of subtle responses to selenium deficiency. More selenoproteins will be identified and characterised, perhaps revealing other cell functions and metabolic pathways which may be influenced by selenium. In the immediate future much remains to be understood about the role of selenium in influencing immune function, prevention of cancer and interactions with thyroid hormone metabolism. The biochemical approach to trace element research advocated by Underwood will provide important information for the clarification of these issues.
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TEMA 10 |
Bob Cousins Integrative aspects of zinc metabolism and function Evolution of our understanding of trace element metabolism and function has increased exponentially since TEMA-I was held in Aberdeen, Scotland, three decades ago. The increase in knowledge clearly parallels the tremendous strides that have been made in our understanding of biologic processes. Nevertheless, much remains to be learned. In the case of zinc, we have three biologic functions: catalytic; structural; and regulatory. Yet, in each category, we have only begun to touch the surface with respect to understanding the basic biochemistry involved. Similarly, when we consider the important physiologic outcomes of zinc in regulating the immune system, cellular growth and differentiation, and neurologic behavior, we must proceed toward understanding these outcomes without, in most cases, having a clear understanding of the biochemical basis responsible. It is clear that the increasing complexity with which biological research is approached will require an ever-increasing reliance on collaborations with individuals from a variety of fields for research in the field of trace elements. Hopefully, as this knowledge base increases, we will have a better appreciation for optimal dietary intake levels of trace elements, based on sound assessment criteria, and an unequivocal answer to the value of trace element supplements in certain intervention and health promotion situations.
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TEMA 11 |
Michael Hambidge Human zinc homeostasis: good but not perfect Currently, there is an apparent dichotomy between the extensively documented occurrence of human zinc deficiency and the widely held perception that regulation of human zinc homeostasis is effective in maintaining zinc balance, including appropriate retention, over a wide range of dietary zinc intake. Factors that contribute to this dichotomy include: (1) the effect of dietary inhibitors, notably phytic acid, which have an adverse effect on the bioavailability of dietary zinc; (2) losses of endogenous zinc that are disproportionately high in relation to the quantity of zinc absorbed orland to zinc status. Examples of both excessive losses and of conservation of endogenous zinc are considered in relation to a template that accounts for the interrelationship between these endogenous zinc losses and the quantity of zinc absorbed; (3) imperfect regulation of zinc homeostasis which maybe inadequate to protect from some extent of zinc depletion when dietary zinc is low. In addressing these factors, special consideration will be given to relevant research of the author and his colleagues, including data derived from studies in communities whose habitual diet is low in zinc and/or high in phytic acid.
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TEMA 12 |
Joe Prohaska Rodent models demonstrate biochemical and behavioral consequences of maternal copper deficiency Neonatal ataxia in lambs, infant death in Menkes disease, and gross brain abnormalities in laboratory copper-deficient guinea pigs stimulated studies to identify copper-dependent neurochemical mechanisms. Offspring ofcopper-deficient rat dams exhibit significant decreases in brain copper and iron and reductions in the activity and levels of cuproenzymes CCO, OHM, PAM. and SOD. Six months of copper repletion failed to restore metals to control levels and resulted in rats with abnormal sensory motor function including impaired auditory startIe, exaggerated foot splay, and poor performance in accelerating rntorod tests. Cerebellar development is cun'ently being monitored to test specific hypotheses related to altered brain iron and cuproenzymes by evaluating energy metabolism, norepinephrine deficiency, neuropeptide amidation, and antioxidant status. Studies with several wild-type murine strains and mutants have confirmed and extended rat work. Mice are more sensitive to perinatal copper deprivation than rats. One notable difference is that m ice do not have altered brain iron. Cuproenzyme function is also altered in brains of copper deficient mouse neonates. Though dietary copper deficiency is rare in adult humans, based on studies in rodents it is possible that current recommendations for intake during pregnancy and lactation may be too low. It seems clear that both diet and genotype impact the phenotypic expression of copper status.
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| TEMA 13 Pucon, Chile November 2008 |
Janet King Why are indicators of zinc status so elusive? Although human zinc deficiency was identified nearly 50 years ago, sensitive indicators of human zinc status, or the ratio of tissue zinc need to supply, remain unknown. The complexity of systems involved in sustaining tissue zinc steady-state levels with changes in intake has made it difficult to determine actual zinc status among individuals, especially during modest deficiency. Changes in gastrointestinal zinc absorption and excretion quickly re-establish whole body zinc balance with moderate decreases or increases in zinc intake. Subtle changes in tissue zinc content may also occur. Nevertheless, plasma zinc concentrations, the usual marker of zinc status, typically do not change, and there is little clinical evidence of any impairment in zinc status. However, severe zinc depletion, with intakes less than 1 mg/d, does cause plasma and extracellular pool zinc levels to decline and, in some cases, the onset of clinical signs of zinc deficiency. In addition to robust systems for maintaining whole body zinc balance with changes in zinc intake, the emerging literature has revealed a second level of regulation at the cellular level. This system is extremely important since 95% of the whole body zinc is intracellular and involved in numerous metabolic functions. The complexity of cellular zinc homeostasis is reflected by the large number of proteins dedicated to zinc transport and buffering, including at least 10 members of the ZnT (SLC30A) family, 14 members of the ZIP (SLC39A) family, and 2 of the 4 isoforms of metallothionein (MT). The zinc transporter proteins modulate cellular zinc influx, efflux, and vesicular sequestration. ZnT transporters reduce cytosolic zinc bioavailability by promoting zinc export, while ZIP transporters import zinc to the cytosol. Studies in humans show that the expression of some of these transporters in specific cell types changes with moderate zinc inadequacy or supplementation. Furthermore, the induction of MT expression rapidly adjusts to cellular zinc imbalances to buffer the amount of cellular labile zinc. Although these 2 separate systems couple zinc homeostasis tightly with changes in dietary zinc supply, preliminary data suggest that zinc-dependent functions at the cellular level may still be altered. For example, the incidence of DNA strand breaks increased significantly in young men fed a diet providing 4.5 mg zinc/d for 6 weeks, while other measures of whole body zinc regulation were not altered. Furthermore, evidence is accumulating that the normal aging process alters the capacity of the zinc homeostasic regulatory systems to adequately respond to changes in zinc intake. The increased demand for zinc during growth may also affect the response of the cellular and whole body systems to inadequate or excessive intakes. Comprehensive studies of zinc homeostasis are needed, therefore, in growing children, the elderly, and in mature adults to identify the biomarkers most sensitive to changes in zinc status throughout the lifecycle. Components of both the cellular and whole body systems will likely need to be assessed to fully evaluate an individual's zinc nutrition.
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| TEMA 14 Enshi, China September 2011 |
Ray Burk |  |