Health Effects of Copper Deficiencies
THE essentiality of copper for animals was reported in 1928 in a study showing that it is essential for erythropoiesis in rats fed a milk-based diet (Hart et al. 1928). Erythropoiesis was improved when copper sulfide containing ash was added back to the diet (Hart et al. 1928). Reports of copper-deficiency in grazing livestock followed, further substantiating the essentiality of copper (Neal et al. 1931). In humans, the essentiality of copper was clearly demonstrated by studies showing anemia, neutropenia, and bone-marrow abnormalities in young children with copper deficiencies (Cordano et al. 1964). The children were responsive to copper therapy. Additional studies have demonstrated the essentiality of copper in immune function, bone formation, red- and white-blood-cell maturation, lipid metabolism, iron transport, myocardial contraction, and neurological development (Danks 1988).
TERATOGENESIS OF COPPER DEFICIENCY
Causes of Copper Deficiency
Before a discussion of the developmental effects associated with a deficit of copper, it is important to recognize the multiple ways an embryonic or fetal copper deficiency might arise. First, a deficiency can occur if the mother has a low dietary intake of copper (primary deficiency). An insufficient intake of copper in the diet (combined intake from solids and liquids)
will eventually result in a primary deficiency of copper and potentially death.
A secondary, or conditioned, deficiency might occur even if the mother's intake of copper from the diet is adequate. Conditioned deficiencies can arise by several means. First, copper deficiency can arise through an effect of drugs or other chemicals on the metabolism of copper. Second, a conditioned embryonic or fetal deficiency of copper might arise if the mother has an excessive low intake of copper as a consequence of an underlying disease or if disease-induced changes in maternal copper metabolism reduces the transfer of copper to the conceptus. Third, nutritional interactions can produce conditioned deficiencies. These interactions can be of several types. For example, copper-binding factors, such as phytate and possible fiber, in the mother's diet can potentially reduce the amount of copper absorbed from the diet. A copper deficiency can also occur if the diet contains a high concentration of a metal with physical-chemical properties similar to those of copper; zinc, cadmium and silver are examples of metals in this category. Finally, a conditioned copper deficiency can occur as a consequence of genetic factors. Those can either be a single gene defect (e.g., Menkes disease) or multiple genes that collectively affect one or more aspects of copper metabolism. In experimental animals, multiple gene effects are typically referred to as a strain or breed effect. Those effects are discussed in more detail below.
Copper in Prenatal Development
The importance of copper for the prenatal development of mammals was shown in sheep by Bennetts et al. (1948) in their demonstration that enzootic ataxia, a disease affecting the developing fetus, could be prevented by giving the ewe additional copper during pregnancy. This disorder is characterized by spastic paralysis, especially of the hind limbs, severe incoordination, blindness in some cases, and anemia. Typically, the brains of animals with enzootic ataxia are small and characterized by collapsed cerebral hemisphoresis, shallow convolutions, and a paucity of normal myelin (Hurley and Keen 1979). Similar neonatal ataxia and brain abnormalities have been reported in newborn copper-deficient deer, goats, swine, guinea pigs, and rats (Hurley and Keen 1979, Yoshikawa et al. 1996). Copper deficiency, as evidenced by low concentrations of copper in plasma, can be induced in most mammalian species by feeding a copper-deficient diet (copper at less than 1 mg/kg of body weight compared with control diets of 8 to 15 mg/kg) for 2 to 4 weeks.
Researchers have not agreed on the biochemical bases of the brain abnormalities associated with copper deficiency during early development.
One possibility is a reduction in the activity of the cuproenzyme cytochrome c oxidase. Mills and Williams (1962) found that, when copper is deficient, the activity of cytochrome c oxidase is significantly reduced in the large motor neurons of the red nucleus of the brain, an area where degeneration is often striking. It can be argued that sufficient reduction in cytochrome c oxidase activity causes cellular anoxia, resulting in tissue death. Inadequate production of ATP for normal phospholipid synthesis might explain in part the high amount of amyelination typically observed in brains of copper-deficient fetuses and neonates (Hurley and Keen 1979).
Although the functional significance of copper-deficiency-induced reductions in cytochrome c activity in the brain is not clear, such reductions in the liver and heart are associated with reduced ATP production (Weisenberg et al. 1980; Kuznetsov et al. 1996). Copper-deficiency-induced reductions in cytochrome c oxidase are in part due to low amounts of the assembled protein aa3 (Rossi et al. 1998). Cell-culture experiments show that copper-deprived cells with low cytochrome c oxidase activity can have increased manganese superoxide dismutase (MnSOD) activity, indicating increased mitochondrial oxidative stress. Moreover, the cells have increased protein carbonyls, an indicator of protein oxidation. Thus, the copper-deprived state might result in oxidative damage to respiratory chain proteins, such as complex I (Johnson and Thomas, 1999). Reduction in cytochrome c oxidase might also result in an increased leakage of electrons through the electron transport chain to molecular oxygen, thereby increasing production of reactive oxygen species (ROS) (Fantel 1996).
Excessive cellular oxidative damage might be a second mechanism contributing to the developmental abnormalities associated with copper deficiency. Copper-zinc superoxide dismutase (CuZnSOD) in the brain was reported to be low in young copper-deficient rats (Prohaska and Wells 1975). Reductions in CuZnSOD activity are associated with excessive lipid and protein oxidative damage and cell death. Specifically, the down-regulation of CuZnSOD results in neuronal-cell death (Troy and Shelanski 1994). Similarly, mutations to the human CuZnSOD gene are linked to degeneration of the motor neurons (Gurney et al. 1994). These studies have found an increase in hydroxyl radical generating capacity in SOD1 mutants (a gene that codes for analogous proteins in yeast). The increase is likely promoted by the release of copper from the mutant enzyme, which can enhance Fenton reaction activity (Eum and Kang 1999). In addition to promoting injury of neuronal cells, reductions in CuZnSOD activity result in brain edema and focal cerebral ischemic injury in CuZnSOD mutant mice (Kondo et al. 1997). Similarly, MnSOD null mice suffer from neurological pathologies that are likely due to oxidative-stress-induced damage (Melov et al. 1998). Prion protein (PrPc), a glycoprotein normally expressed in neurons, might play a role in regulating CuZnSOD activity
(Brown et al. 1997). Copper stimulates endocytosis of PrPc from the cell surface, and the PrPc might act as a recycling receptor for copper ion uptake (Pauly and Harris 1998). Cerebellar cells of PrPc null mice (Prnp0/0) have low CuZnSOD activity and are particularly susceptible to oxidative stress.
Despite low CuZnSOD activity, the peroxidation of brain lipids in young copper-deficient rats does not appear to be excessive (Prohaska and Wells 1975). The lack of excessive lipid peroxidation can be explained by a shift in the fatty-acid profile to a less peroxidizable composition in the brains of copper-deficient rats. Alterations in the fatty-acid composition of select tissues in response to oxidative insults in adult tissues have been reported (Zidenberg-Cherr and Keen 1991). Although the type or amount of embryonic polyunsaturated fatty acid influenced by increased oxidative pressures has not been determined, a change in the fatty-acid composition to a more saturated profile could result in dysmorphogenesis. However, in in vitro embryo culture models, the teratogenic effects of copper deficiency are reduced if the medium is supplemented with antioxidant enzymes (Hawk et al. 1995).
Copper deficiency can also affect several other brain cuproenzymes. For example, the activity of peptidylglycine α-amidating monooxygenase (PAM) (EC 18.104.22.168) is markedly reduced with developmental copper deficiency (Prohaska and Bailey 1995). PAM is responsible for converting a number of precursors into their α-amide form, including gastrin, cholecystokinin, oxytocin, vasopressin, neuropeptide Y, and vasoactive intestinal peptide; therefore, a reduction in PAM activity might result in altered physiological functioning (Prohaska and Bailey 1995). PAM activity can remain low even after months of copper repletion (Prohaska and Bailey 1995). It has not been determined whether the persistence of low PAM activity in the brain after prenatal copper deficiency is due to the relatively long period of time that it takes to increase brain copper concentrations or whether it represents a more fundamental epigenetic defect. In either case, given PAM's role in hormone activation, the duration of reduced PAM activities in the brain could have a significant impact on long-term behavioral and metabolic events.
The extent to which copper-deficiency-induced changes in the activities of brain cuproenzymes contribute to the morphological damage in fetal and neonatal brains is unknown. It is reasonable to postulate, however, that copper-deficiency-induced developmental alterations in the activities of CuZnSOD, cytochrome c oxidase, and PAM are contributing factors to persistent behavioral and functional defects associated with prenatal copper deficiency (Hunt and Idso 1995; Prohaska and Hoffman 1996).
In addition to brain defects, copper-deficient fetuses and neonates are typically characterized by severe connective tissue abnormalities. Cardiac
hemorrhages are a frequent finding in copper-deficient sheep, rats, guinea pigs, and mice (Hurley and Keen 1979). The walls of the internal and common carotid arteries in copper deficient-fetuses tend to have an endothelium that appears normal but has sparse, poorly developed elastin. Cerebral arteries are also often characterized by a low elastin content. Furthermore, the elastin that is present does not have the concise fibrillar arrangements seen in control animals. The reduction in elastin content and cross-linking integrity is primarily due to a decrease in the activity of the cuproenzyme lysyl oxidase, which catalyzes the oxidation of certain peptidyl lysine and hydroxylysine residues to peptide aldehydes, initiating the cross-linking mechanisms required for connective-tissue stability (Rucker et al. 1998).
In addition, it is important to note that copper is associated with factors located in the extracellular matrix, which has angiogenic properties. Specifically, SPARC (secreted protein, acidic, rich in cysteine), an extracellular matrix protein involved in the regulation of endothelial proliferation, has an active copper-binding domain (Lane et al. 1994). The second cation region of SPARC is copper binding and stimulates angiogenesis (Lane et al. 1994). Given the angiogenic properties of copper and low-molecular-weight copper complexes, it is reasonable to suggest that altered angiogenesis can contribute to the brain dysmorphology associated with developmental copper deficiency. Finally, copper deficiency has also been associated with an acceleration of proteolysis of collagen and elastin due to nonspecific proteases that migrate from the blood compartment into vascular tissue (Romero et al. 1989). It is evident that copper deficiency can result in abnormal vascular development through a variety of mechanisms.
Skeletal defects can occur as a result of copper deficiency. Lambs with enzootic ataxia typically have poorly developed, light, brittle bones that fracture frequently. Bone abnormalities have been found in copper-deficient calves and fowls. In dogs and swine, the young born to females fed copper-deficient diets had deformed leg bones (Hurley and Keen 1979). The lesions appeared to be associated with an impairment of osteogenesis, resulting in thinning of the cortex and trabeculae of the long bones. Copper-deficient chicks are different, having severe hypoplasia of the long bones and leg weakness. Amine oxidase, cytochrome oxidase, and lysyl oxidase activities are low, and the ratio of soluble-to-insoluble collagen is high. The increased fragility of copper-deficient bones appears to result from the low number of cross-links present in the collagenous matrix (Rucker et al., 1998).
Finally, lung abnormalities are a frequent consequence of prenatal and early postnatal copper deficiency. Lungs from neonatal rabbits born to dams fed copper-deficient diets were characterized by low concentrations of copper and lysyl oxidase activity and high proportions of poorly cross-
linked elastin and collagen. The lungs were also characterized by low concentrations of surfactant phospholipids (Abdel-Mageed et al. 1994). Similar results have been reported in copper-deficient rats (Dubick et al. 1985).
Drug-Induced Copper Deficiency
Rosa (1986) reviewed a series of cases of infants born to women who received d-penicillamine (DPA) during pregnancy for a variety of conditions, including connective-tissue abnormalities and rheumatoid arthritis. Abnormalities observed in the infants included lax skin, hyperflexibility of the joints, fragility of the veins, and numerous soft tissue abnormalities. It was suggested that the malformations were in part due to a drug-induced copper deficiency during embryonic or fetal development. Similar abnormalities were produced with DPA in rodent models (Keen et al., 1983b), and the teratogenicity of the drug can be modulated by maternal dietary copper intake (Mark-Savage et al., 1983). The above suggest that in humans maternal copper status should be monitored when DPA is taken during pregnancy.
Little is known about the influence of other copper chelating drugs such as captopril, disulfiram, dimercaptosuccinic acid (DMSA), and triethylenetetramine (TETA) on human prenatal development. Given the significant teratogenic effects that can be associated with similar drugs in experimental animals, it is reasonable to suggest that these drugs can pose a substantial risk to the conceptus if maternal dietary copper intake is low.
A condition of severe copper deficiency can be rapidly induced in experimental animals through the use of a number of chelating drugs, including disulfiram, DPA, TETA, and DMSA (Salgo and Oster 1974; Keen et al. 1983a,b; Taubeneck et al. 1992; Jasim et al. 1985). Each of those drugs is known to be teratogenic. The abnormalities produced are reminiscent of those induced by dietary copper deficiency. Although the teratogenicity of DPA, TETA, and DMSA can be modulated by the amount of copper in the mother's diet (Cohen et al. 1983; Mark-Savage et al. 1983), it is important to note that drugs that bind copper typically also bind zinc. Thus, the teratogenic effects of those drugs might be due to a combination of copper and zinc deficiencies.
In contrast to the effects of zinc, drugs and chemicals that induce an acute-phase response in the mother do not necessarily influence copper uptake by the embryo or fetus, and in most cases, fetal copper concentrations are unaffected by chemicals that induce transitory acute-phase responses (Keen 1996). That is not surprising, because maternal plasma copper concentrations are increased during an acute-phase response (due to the hepatic production and release of the cuproenzyme ceruloplasmin),
and zinc concentrations are decreased. Ceruloplasmin has been postulated to be involved directly in copper transport to the embryo and fetus (Lee et al. 1993). It must be noted that the mechanisms underlying copper transport into the embryo and fetus is an area of active research.
Disease-Induced Copper Deficiency
Copper deficiency can occur secondarily to such diseases as chronic diarrhea, diabetes, alcoholism, and hypertension (Rosa 1986; Dubick et al. 1987; Turnlund 1994). In the case of maternal diabetes and alcoholism, disease-induced deficiencies of copper in the embryo or fetus have been postulated to contribute to the teratogenesis (Uriu-Hare et al. 1989; Zidenberg-Cherr et al. 1988; Dubick et al. 1999). Mothers with diabetes are reported to have low concentrations of copper in erythrocytes (Speich et al. 1992). In addition, maternal hypocupremia is often noted in cases of spontaneous abortion or rupture of the fetal and placental membranes (Kiilholma et al. 1984; Artal et al. 1979).
To date, there have been no reports of zinc-induced copper deficiencies affecting human pregnancy outcomes. However, zinc-induced fetal copper deficiencies are relatively easy to produce in experimental animals, and care should be taken to monitor women who consume zinc supplements during pregnancy. The Institute of Medicine recommends that copper supplements (2 mg) be provided to women taking zinc supplements (25 mg) during their pregnancies (IOM 1990).
In ruminants, copper deficiency can also be induced by the feeding of high concentrations of molybdenum, which, along with sulfate, can form a complex with copper that limits its absorption. The copper deficiency induced in this manner can be sufficient to pose a developmental risk (Howell et al. 1993).
Shavlovski et al. (1995) reported that embryonic copper deficiency can occur as a consequence of maternal silver toxicity. The above is of particular interest given that the authors provided data suggesting that silver-induced fetal copper deficiency occurs as a consequence of silver-induced alterations in ceruloplasmin synthesis. Shavlovski et al. (1995) postulated that the observed fetal copper deficiency was a consequence of a reduction in ceruloplasmin-mediated placental copper transport. Although the above hypothesis is attractive, it is in sharp contrast to the observation of normal copper transport in patients with the genetic disorder acerulo-
plasminemia (see Chapter 4). One interpretation of the above is that when there are genetic defects in ceruloplasmin synthesis, the embryo might be able to expand alternative pathways for copper transport. For example, it could be argued that there is an increase in the amount of copper transported by copper ATPases. However, the ability to modulate those pathways might be lost by the fetal stage.
Gene-Induced Copper Deficiency
There are at least two genetic defects that are expressed as copper-deficiency syndromes (Menkes disease and occipital horn syndrome). Both disorders are due to defects in a copper-transporting P-type ATPase. Infants with Menkes disease are characterized by progressive degeneration of the brain and spinal cord, hypothermia, connective-tissue abnormalities, and failure to thrive. Menkes disease has been recognized as a disorder of copper metabolism for over 20 years. The prognosis for infants with the disorder is poor and death typically occurs before 3 years of age (Danks 1988; Turnlund 1994). Similar to the blotchy mouse, the developmental abnormalities associated with Menkes disease are thought to be the consequence of low activity of numerous cuproenzymes during embryonic and fetal development. Those cuproenzymes include dopamine-B-monoxygenase (DBH), PAM, cytochrome c oxidase, lysyl oxidase, and CuZnSOD (Kaler 1998; Prohaska et al. 1997; Medeiros and Wildman 1997; Mercer 1998). The aberrant pattern of the plasma and cerebrospinal fluid of Menkes patients has been attributed to low activity of DBH (Kaler 1998). Moreover, individuals with Menkes disease are characterized by low activity of ceruloplasmin and PAM (Prohaska et al. 1997). Thus, low activity of numerous enzymes that rely on the amidation of peptides for their activity might occur as a secondary effect of low PAM activity.
The development of connective tissue abnormalities, such as bladder diverticula and vascular tortuosity, is likely attributable to alterations in lysyl oxidase activity. Abnormalities in connective tissues of Menkes sufferers are overt and might be more pronounced because, unlike other copper-dependent enzymes that draw copper from cytoplasmic carriers. It is postulated that lysyl oxidase incorporates its copper from the ATP7A once it crosses into the trans-Golgi (Mercer 1998).
Even though Menkes disease and occipital horn syndrome are the result of mutations in the same gene, they differ in their expression. Menkes syndrome is expressed at birth, and individuals with occipital horn syndrome are reported to be phenotypically normal at birth. However, detailed biochemical studies of infants with occipital horn syndrome at birth have not been reported (Proud et al. 1996).
Aceruloplasminemia is a rare autosomal recessive genetic defect that results in a lack of holoceruloplasmin production and an alteration in iron metabolism (Yoshida et al. 1995; Harris et al. 1995). One form of the mutation has been characterized by a mutation in the ceruloplasmin gene. The mutation results in a condition in which there is essentially no holoceruloplasmin (Harris et al. 1998). Ceruloplasmin functions as a ferroxidase. A deficiency of ceruloplasmin results in the accumulation of iron in select tissues, including the brain and pancreas. Individuals suffering from hereditary ceruloplasmin deficiency often develop diabetes mellitus secondary to iron-induced pancreatic damage (Kato et al. 1997). The hematochromatosis-like symptoms of aceruloplasminemia include an ataxic gait, dysarthria, retinal degeneration, neuropathy, and diabetes mellitus (Miyajima et al. 1996; Takahashi et al. 1996). Although the specific effects of aceruloplasminemia on embryonic and fetal development have yet to be delineated, women with this defect are able to conceive and have normal pregnancies.
A number of strains of mice, rats, and sheep are characterized by abnormal copper metabolism, and for several of these strains, the abnormality can influence embryonic or fetal development.
Interactions between copper and genetic factors can be classified into two groups. The first type involves strain differences that produce a differential response to diets that are deficient or marginal in copper, and the second type involves a single mutant gene, the expression of which can resemble the signs of a deficiency or a toxicity of the element. That expression can be reduced or prevented by nutritional manipulation. Those two types of phenomena can interact. Thus, the phenotypic expression of a mutant gene can be modulated by the strain background.
Examples of the first type of gene-nutrient interaction are certain mutant genes in mice. For example, the mottled (Mo) mouse is characterized by a defect in cellular copper transport, which is phenotypically expressed by signs of copper deficiency (Mercer et al. 1994). Over 10 alleles at the mottled locus have been described. They range in severity from hypopigmentation of hair at birth to death in utero. The blotchy mutant (MoB) is typically characterized by severe connective-tissue defects and neurological abnormalities, similar to those observed with severe maternal copper deficiency. The primary genetic defect in the blotchy mouse is thought to involve a mutation in a copper-transporting ATPase gene that is homologous to the Menkes gene in humans (Das et al. 1995). The phenotypic expression is thought to result from the reduced activity of several cuproenzymes.
Representative of the second category of gene-nutrient interaction is the observed influence of the breed of sheep on the incidence of enzootic ataxia within a geographical area (Wiener et al. 1978). For example, the off-
spring of Welsh sheep often have a lower incidence of enzootic ataxia than do offspring of blackface sheep, even when the ewes are maintained on the same pasture. The difference in the occurrence of enzootic ataxia has been correlated with the mother's ability to absorb copper (Wiener et al. 1978).
Human Copper Deficiency and Teratogenesis
Primary Dietary Copper Deficiency
In the United States, the adult population typically has an intake of copper that is below the estimated safe and adequate dietary recommendation of 1.5–3.0 mg of copper per day (Milne 1998). Women of childbearing age are also unlikely to meet their putative copper requirement (NRC 1989). Although overt copper deficiency is not commonly seen in the United States, some authors argue that moderate copper deficiency is more prevalent (Danks 1988; Reiser et al. 1985; Kelley et al. 1995; Milne and Nielsen 1996). According to Klevay (1998), consumption of diets providing less than 1 mg of copper per day can be associated with adverse health effects. Copper deficiency occurs in a variety of conditions, including diabetes, hypertension, alcoholism, and total parental nutrition feedings (Tokuda et al. 1986; Danks 1988; Shaw 1992: Olivares and Uauy 1996; Uauy et al. 1998). There is considerable debate however, on the extent to which copper deficiency influences human prenatal development. Brewer et al. (2000) studied 26 pregnancies of 19 women with Wilson disease. All were treated with zinc as their sole anticopper drug. Of the 26 newborns, 24 were normal, one had a surgically correctable heart defect, and another had anencephaly. Buamah et al. (1984) reported that the finding of low serum copper concentrations in pregnant women during mid-gestation was a risk factor for anencephaly. Morton et al. (1976) reported a significant correlation between low copper content in drinking water and the occurrence of neural-tube defects in South Wales. Dietary copper intake was not considered, and the observation has not been confirmed.
HEALTH EFFECTS OF COPPER DEFICIENCIES IN ADULTS
Clinical copper deficiency in adults can occur, but it is rare. Data on clinical copper deficiency is to be differentiated from copper intake data, which infer a certain frequency of copper deficiency which may be higher than that which actually occurs. Clinical copper deficiency in the United States is also to be differentiated from hypotheses suggesting that low intake of copper leads to an increased risk of atherosclerosis. Clinical copper deficiency is most often due to zinc ingestion, which blocks copper absorp-
tion (see section on zinc treatment of Wilson disease). To produce copper deficiency, zinc ingestion has to occur over a period of time, probably a minimum of 2 months. Therefore, ingestion of zinc (e.g., to treat of colds with zinc lozenges) is not a risk if ingested for a few days only per episode. In addition, zinc taken with food tends to get bound to substances in food and has much less effect on copper absorption. Occasionally, zinc ingestion results from intentional swallowing of foreign objects that contain zinc and that remain in the stomach for long periods. More rarely, copper deficiency can result from surgical removal of a large section of the small intestine, thus greatly reducing absorption of copper.
The most sensitive indicator of clinical copper deficiency is the serum ceruloplasmin level. The synthesis and release of this copper-containing protein into the blood by the liver is dependent upon copper availability. As availability decreases, plasma ceruloplasmin decreases. The consequence of modest reductions in serum ceruloplasmin have not been defined.
As levels of copper, or copper availability, decrease further, there can be effects on the bone marrow. A sensitive cell line with regard to copper deficiency is the red cell line, perhaps because copper is required for heme synthesis. Thus, anemia is often thought to be an early bone-marrow effect. The more long-standing the copper deficiency the more likely the red cell indices will become hypochromic microcytic. Because copper is also required for cellular proliferation, the effect on the bone marrow can also produce leukopenia, particularly neutropenia, and thrombocytopenia (Cordano 1998).
In addition to its effect on the erythrocyte pool, an early effect of copper deficiency can be significant changes in the immune system (Percival 1998). In rats, an early sign of copper deficiency can be an impairment in the respiratory burst and candidacidal activity of macrophages (Babu and Failla 1990). Although the mechanisms that underlie the effects of copper deficiency on immune cells have not been defined, it is known that one early effect is alterations in interleukin 2 as well as interleukin 1 production (Bala and Failla 1992). The extent to which those effects occur in humans is not known.
Long-standing severe copper deficiency produces a neurological syndrome that appears to be primarily a peripheral neuropathy, in which loss of sensation and muscle weakness occurs.
Severe deficiency of copper can have adverse developmental consequences.
Copper deficiency can arise through a multitude of mechanisms, in
cluding low dietary intake, genetic abnormalities, nutrient-nutrient interactions (e.g., copper and zinc), and nutrient-drug interactions.
The frequency of copper deficiency or sufficiency in the United States has not been well defined for any age group.
Clinical cases of copper deficiency in adults can occur as a result of poor absorption due to removal of a large section of the small intestine or excessive zinc intake.
Marginal copper intake might have adverse health effects, on the vascular and immune system.
Abdel-Mageed, A.B., R. Welti, F.W. Oehme, and J.A. Pickrell. 1994. Perinatal hypocuprosis affects synthesis and composition of neonatal lung collagen, elastin and surfactant. Am. J. Physiol. 267(6 Pt 1):L679–685.
Artal, R., R. Burgeson, F.J. Fernandez, and C.J. Hobel. 1979. Fetal and maternal copper levels in patients at term with and without premature rupture of membranes. Obstet. Gynecol. 53(5):608–610.
Babu, U. and M.L. Failla. 1990. Respiratory burst and candidacidal activity of peritoneal macrophages are impaired in copper-deficient rats. J. Nutr. 120(12):1692–1699.
Bala, S. and M.L. Failla. 1992. Copper deficiency reversibly impairs DNA synthesis in activated T lymphocytes by limiting interleukin 2 activity. Proc. Natl. Acad. Sci. (USA) 89(15):6794–6797.
Bennetts, H.W., A.B. Beck, and R. Harley. 1948. The pathogenesis of ''falling disease": studies of copper deficiency in cattle. Aust. Vet. J. 24(9):237–244.
Brewer, G.J., V.D. Johnson, R.D. Dick, K.J. Fink, K.J. Kluin, and P. Hedera. 2000. Treatment of Wilson's disease with zinc XVII: Treatment during pregnancy. Hepatology 31(2):364–370.
Brown, D., W.J. Schulz-Schaeffer, B. Schmidt, and H.A. Kretzschmar. 1997. Prion protein-deficient cells show altered response to oxidative stress due to decreased SOD1 activity. Exp. Neurol. 146(1):104–112.
Buamah, P.K., M. Russell, A. Milford-Ward, P. Taylor, and D.F. Roberts. 1984. Serum copper concentrations significantly less in abnormal pregnancies. Clin. Chem. 30(10):1676–1677.
Cohen, N., C.L. Keen, B. Lonnerdal, and L.S. Hurley. 1983. The effect of copper supplementation on the teratogenic effects of triethylenetetramine in rats. Drug Nutr. Interact. 2(3):203–210.
Cordano, A. 1998. Clinical manifestations of nutritional copper deficiency in infants and children. Am. J. Clin. Nutr. 67(5 Suppl.):1012S–1065S.
Cordano, A., J.M. Baertl, and G.G. Graham. 1964. Copper deficiency in infants. Pediatrics 34:324–326.
Danks, D.M. 1988. Copper deficiency in humans. Annu. Rev. Nutr. 8: 235–257.
Das, S., B. Levinson, C. Vulpe, S. Whitney, J. Gitschier, and S. Packman S. 1995. Similar splicing mutations of the Menkes/mottled copper-transporting ATPase gene in occipital horn syndrome and the blotchy mouse. Am. J. Hum. Genet. 56(3):570–576.
Dubick, M.A., C.L. Keen, and R.B. Rucker. 1985. Elastin metabolism during perinatal lung development in the copper-deficient rat. Exp. Lung Res. 8(4):227–241.
Dubick, M.A., G.C. Hunger, S.M. Casey, and C.L. Keen. 1987. Aortic
ascorbic acid, trace elements, and superoxide dismutase activity in human aneurysmal and occlusive disease. Proc. Soc. Exp. Biol. Med. 184(2):138–143.
Dubick, M.A., C.L. Keen, R.A. DiSilvestro, C.D. Eskelson, J. Ireton, G.C. Hunter. 1999. Antioxidant enzyme activity in human abdominal aortic aneurysmal and occlusive disease. Proc. Soc. Exp. Biol. Med. 220(1): 39–45.
Eum, W.S., and J.H. Kang. 1999. Release of copper ions from the familial amyotrophic lateral sclerosis-associated Cu,Znsuperoxide dismutase mutants. Mol. Cells 9(1):110–114.
Fantel, A.G. 1996. Reactive oxygen species in developmental toxicity: review and hypothesis. Teratology 53(3):196–217.
Gurney, M.E., H. Pu, A.Y. Chiu, M.C. Dal Canto, C.Y. Polchow, D.D. Alexander, J. Caliendo, A. Hentati, Y.W. Kwon, and H.X. Deng. 1994. Motor neuron degeneration in mice tht express a human Cu,Zn superoxide dismutase mutation. Science 264(5166):1772–1775.
Harris, A.L., L.W. Klomp, and J.D. Gitlin. 1998. Aceruloplasminemia: An inherited neurodegenerative disease with impairment of iron homeostasis. Am. J. Clin. Nutr. 67(5 Suppl.):972S–977S.
Harris, Z.L., H. Takahashi, H. Miyajima, M. Serizawa, R.T. MacGillivray, and J.D. Gitlin. 1995. Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc. Natl. Acad. Sci. (USA) 92(7):2539–2543.
Hart, E.B., H. Steenbock, J. Waddell, C.A. Elvehjem. 1928. Iron in nutrition. VII: Copper as a supplement to iron for hemoglobin building in the rat. J. Biol. Chem. 77(April 1):797–812.
Hawk S.N., J.Y. Uriu-Hare, G.P. Daston, and C.L. Keen. 1995. Oxidative damage as a potential mechanism contributing to Cu deficiency-induced defects in rat embryos. Teratology 51(3):171–172.
Howell, J.M., Y. Shunxiang, and J.M. Gawthorne. 1993. Effect of thiomolybdate and ammonium molybdate in pregnant guinea pigs and their offspring. Res. Vet. Sci. 55(2):224–230.
Hunt, C.D., and J.P. Idso. 1995. Moderate copper deprivation during gestation and lactation affects dentate gyrus and hippocampal maturation in immatue male rats. J. Nutr. 125(10):2700–2710.
Hurley, L.S. and C.L. Keen. 1979. Teratogenic effects of copper. Pp. 33–56 in Copper in the Environment. Part II: Health Effects, J.O. Nriagu, ed. New York: John Wiley & Sons.
IOM (Institute of Medicine). 1990. Nutrition during pregnancy. Part I: Weight Gain. Part II: Nutrient Supplements. Washington, DC: National Academy Press.
Jasim, S., B.R. Danielsson, H. Tjalve, and L. Dencker. 1985. Distribution of Cu in foetal and adult tissues in mice: influence of sodium diethyl-
dithiocarbamate. Acta Pharmacol. Toxicol. (Copenhagen) 57(4): 262–270.
Johnson, W.T., and A.C. Thomas. 1999. Copper deprivation potentiates oxidative stress in HL-60 cell mitochondria. Proc. Soc. Exp. Biol. Med. 221(2):147–152.
Kaler, S.G. 1998. Diagnosis and therapy of Menkes syndrome, a genetic form of copper deficiency. Am. J. Clin. Nutr. 67(5 Suppl.):1029S–1034S.
Kato, T., M. Daimon, T. Kawanami, Y. Ikezawa, H. Sasaki, and K. Maeda. 1997. Islet changes in hereditary ceruloplasmin deficiency. Hum. Pathol. 28(4):499–502.
Keen, C.L. 1996. Teratogenic effects of essential trace metals: deficiencies and excesses. Pp. 977–1001 in Toxicology of Metals, L.W. Chang, L. Magos, and T. Suzuki, eds. New York: CRC Press.
Keen, C.L., N.L. Cohen, B. Lonnerdal, L.S. Hurley. 1983a. Teratogenesis and low copper status resulting from triethylenetetramine in rats. Proc. Soc. Exp. Biol. Med. 173(4):598–605.
Keen, C.L., P. Mark-Savage, B. Lonnerdal, L.S. Hurley. 1983b. Teratogenic effects of D-penicillamine in rats: relation to copper deficiency. Drug Nutr. Interact. 2(1):17–34.
Kelley, D.S., P.A. Daudu, P.C. Taylor, B.E. Mackey, and J.R. Turnlund. 1995. Effects of low-copper diets on human immune response. Am. J. Clin. Nutr. 62(2):412–416.
Kiilholma, P., M. Gronroos, R. Erkkola, P. Pakarinen, and V. Nanto. 1984. The role of calcium, copper, iron and zinc in preterm delivery and premature rupture of fetal membranes. Gynecol. Obstet. Invest. 17(4):194–201.
Klevay, L.M. 1998. Lack of a recommended dietary allowance for copper amy be hazardous to your health. J. Am. Coll. Nutr. 17(4):322–326.
Kondo, T., A.G. Reaume, T.T. Huang, E. Carlson, K. Murakami, S.F. Chen, E.K. Hoffman, R.W. Scott, C.J. Epstein, and P.H. Chan. 1997. Reduction of CuZn-superoxide dismutase activity exacerbates neuronal cell injury and edem formation after transient focal cerebral ischemia. J. Neurosci. 17(11):4180–4189.
Kuznetsov, A.V., J.F. Clark, K. Winkler, W.S. Kunz. 1996. Increase of flux control cytochrome c oxidase in copper-deficient mottled brindled mice. J. Biol. Chem. 271(1):283–288.
Lane, T.F., M.L. Iruela-Arispe, R.S. Johnson, and H. Sage. 1994. SPARC is a source of copper-binding peptides that stimulate angiogenesis. J. Cell Biol. 125(4):929–943.
Lee S.H., R. Lancey, A. Montaser, N. Madani, M.C. Linder. 1993. Ceruloplasmin and copper transport during the latter part of gestation in the rat. Proc. Soc. Exp. Biol. Med. 203(4):428–39.
Mark-Savage, P., C.L. Keen, and L.S. Hurley. 1983. Reduction by copper
supplementation of teratogenic effects of D-penicillamine. J. Nutr. 113(3):501–510.
Medeiros, D.M., R.E. Wildman. 1997. Newer findings on a unified perspective of copper restriction and cardiomyopathy. Proc. Soc. Exp. Biol. Med. 215(4):299–313.
Melov, S., J.A. Schneider, B.J. Day, D. Hinerfeld, P. Coskun, S.S. Mirra, J.D. Crapo, and D.C. Wallace. 1998. A novel neurological phenotype in mice lacking mitochondrial manganase superoxide dismutase. Nat. Genet. 18(2):159–163.
Mercer, J.F. 1998. Menkes syndrome and animal models. Am. J. Clin. Nutr. 67(5 Suppl.):1022S–1028S.
Mercer, J.F., A. Grimes, L. Ambrosini, P. Lockhart, J.A. Paynter, H. Dierick, and T.W. Glover. 1994. Mutations in murine homologue of the Menkes gene dappled and blotchy mice. Nat. Genet. 6(4):374–378.
Mills, C.F., and R.B. Williams. 1962. Copper concentrations and cytochrome-oxidase and ribonuclease activities in the brains of copper deficient lambs. Biochem. J. 85:629–632.
Milne, D.B. 1998. Copper intake and assessment of copper status. Am. J. Clin. Nutr. 67(5 Suppl.):1041S–1045S.
Milne, D.B., and F.H. Nielsen. 1996. Effects of a diet low in copper on copper status indicators in postmenopausal women. Am. J. Clin. Nutr. 63(3):358–364.
Miyajima, H., Y. Takahashi, M. Serizawa, E. Kaneko, and J. D. Gitlin. 1996. Increased plasma lipid peroxidation in patients with aceruloplasminemia. Free Radic. Biol. Med. 20(5):757–760.
Morton, M.S., P.C. Elwood, and M. Abernethy. 1976. Trace elements in water and congenital malformations of the central nervous system in South Wales. Br. J. Prev. Soc. Med. 30(1):36–39.
Neal, W.M., R.B. Becker, and A.L. Shealy. 1931. A natural copper deficiency in cattle rations. Science 74(1921):418–419.
NRC (National Research Council). 1989. Recommended Dietary Allowances, 10th Ed. Washington, DC: National Academy Press.
Olivares, M., and R. Uauy. 1996. Copper as an essential nutrient. Am. J. Clin. Nutr. 63(5 Suppl.):791S–796S.
Pauly, P.C., and D.A. Harris. 1998. Copper stimulates endocytosis of the prion protein. J. Biol. Chem. 273(50):33107–33110.
Percival, S.S. 1998. Copper and immunity. Am. J. Clin. Nutr. 67(5 Suppl.): 1064S–1068S.
Prohaska, J.R., and W.R. Bailey. 1995. Alterations of rat brain peptidylglycine a-amidating monooxygenase and other cuproenzyme activities following perinatal copper deficiency. Proc. Soc. Exp. Biol. Med. 210(2): 107–116.
Prohaska, J.R., and R.G. Hoffman. 1996. Auditory startle response is di
minished in rats after recovery from perinatal copper deficiency. O. Nutr. 126(3):618–627.
Prohaska, J.R., and W.W. Wells. 1975. Copper deficiency in the developing rat brain: Evidence for abnormal mitochondria. J. Neurochem. 25(3):221–228.
Prohaska, J.R., T. Tamura, A.K. Percy, and J.R. Turnlund. 1997. In vitro copper stimulation of plasma peptidylglycine a-amidating monooxygenase in Menkes disease variant with occipital horns. Pediatr. Res. 42(6):862–865.
Proud, V.K., H.G. Mussell, S.G. Kaler, D.W. Young, and A.K. Percy. 1996. Distinctive Menkes disease variant with occipital horns: Delineation of natural history and clinical phenotype. Am. J. Med. Genet. 65(1):44–51.
Reiser, S., J.C.J. Smith, W. Mertz, J.T. Holbrook, D.J. Scholfield, A.S. Powell, W.K. Canfield, and J.J. Canary. 1985. Indices of copper status in humans consuming a typical American diet containing either fructose or starch. Am. O. Clin. Nutr. 42(2):245–251.
Romero, N., D. Tinker, D. Hyde, and R.B. Rucker. 1989. Role of plasma and serum proteinases in the degradation of elastin. Arch. Biochem. Biophys. 244(1):161–168.
Rosa, F.W. 1986. Teratogen update: Penacillamine. Teratology 33(1):127–31.
Rossi, L., G. Lippe, E. Marchese, A. De Martino, I. Mavelh, G. Rotiho, M.R. Ciriolo. 1998. Decrease in cytochrome c oxidase protein in heart mitochondria of copper-deficient rats. Biometals 11(3):207–212.
Rucker, R.B., T. Kosonen, M.S. Clegg, A.E. Mitchell, B.R. Rucker, J.Y. Uriu-Hare, and C.L. Keen. 1998. Copper, lysyl oxidase, and extracellular matrix protein cross-linking. Am. J. Clin. Nutr. 67(5 Suppl.): 996S–1002S.
Salgo, M.P., and G. Oster. 1974. Fetal resorption induced by disulfiram in rats. O. Reprod. Fertil. 39(2):375–377.
Shavlovski, M.M., N.A. Chebotar, L.A. Konopistseva, E.T. Zakharova, A.M. Kachourin, V.B. Vassiliev, and V.S. Gaitskhoki. 1995. Embryotoxicity of silver ions is diminished by ceruloplasmin—Further evidence for its role in the transport of copper. Biometals 8(2):122–128.
Shaw, J.C.L. 1992. Copper deficiency in term and preterm infants. Pp. 105–119 in Nestle Nutrition Workshop Series. Vol. 30, Nutritional Anemias, S.J. Fomon, and S. Zlotkin, eds. New York: Raven Press.
Speich, M., A. Murat, J.L. Auget, B. Bousquet, and P. Arnaud. 1992. Magnesium, total calcium, phosphorous, copper and Zn in plasma and erythrocytes of venous cord blood from infants of diabetic mothers: Comparison with a reference group by logistic discriminant analysis. Clin Chem. 38(10):2002–2007.
Takahashi, Y., H. Miyajima, S. Shirabe, S. Nagataki, A. Suenaga, and J.D.
Gitlin. 1996. Characterization of a nonsense mutation in the ceruloplasmin gene resulting in diabetes and neurodegenerative disease. Hum. Mol. Genet. 5(1):81–84.
Taubeneck, M.W., J.L. Domingo, J.M. Llobet, and C.L. Keen. 1992. Meso-2,3-dimercaptosuccinic acid (DMSA) affects maternal and fetal copper metabolism in Swiss mice. Toxicology 72(1):27–40.
Tokuda, Y., S. Yokoyama, M. Tsuji, T. Sugita, T. Tajima, and T. Mitomi. 1986. Copper deficiency in an infant on prolonged total parenteral nutrition. J. Parenter. Enteral. Nutr. 10(2):242–244.
Troy, C.M., and M.L. Shelanski. 1994. Down-regulation of copper/zinc superoxide dismutase causes apoptotic death in PC12 neuronal cells. Proc. Natl. Acad. Sci. (USA) 91(14):6384–6387.
Turnlund, J.P. 1994. Copper. Pp. 231–241 in Modern Nutrition in Health and Disease, Vol. I., 8th Ed., M.E. Shils, J.A. Olson, and M. Shike, eds. Philadelphia: Lea and Febiger.
Uauy, R., M. Olivares, and M. Gonzalez. 1998. Essentiality of copper in humans. Am. J. Clin. Nutr. 67(5 Suppl.):952S–959S.
Uriu-Hare, J.Y., J.S. Stern, and C.L. Keen. 1989. Influence of maternal dietary Zn intake on expression of diabetes-induced teratogenicity in rats. Diabetes 38(10):1282–1290.
Weisenberg, E., A. Harbreich, and J. Mager. 1980. Biochemical lesions in copper-deficient rats caused by secondary iron deficiency. Derangement of protein synthesis and impairment of energy metabolism. Biochem. J. 188(3):633–641.
Wiener, G., I. Wilmut, and A.C. Field. 1978. Maternal and lamb breed interactions in the concentration of copper in tissues and plasma of sheep. Pp. 469–472 in Trace Element Metabolism in Man and Animals—3, M. Kirchgessner, ed. Freising-Weihenstephan, Germany: Technische Universitat Munchen.
Yoshida, K., K. Furihata, S. Takeda, A. Nakamura, K. Yamamoto, H. Morita, S. Hiyamuta, S. Ikeda, N. Shimizu, and N. Yanagisawa. 1995. A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat. Genet. 9(3):267–272.
Yoshikawa, H., H. Seo, T. Oyamada, T. Ogasawara, T. Oyamada, T. Yoshikawa, X. Wei, S. Wang, and Y. Li. 1996. Histopathology of enzootic ataxia in Sika deer (Cervus mippon Temminck). J. Vet. Med. Sci. 58:849–854.
Zidenberg-Cherr, S., and C.L. Keen. 1991. Essential trace elements in antioxidant processes. Pp. 107–127 in Trace Elements, Micronutrients and Free Radicals, I.E. Dreosti, ed. Clifton, NJ: Human Press.
Zidenberg-Cherr, S., P.A. Benak, L.S. Hurley, and C.L. Keen. 1988. Altered mineral metabolism: A mechanism underlying the fetal alcohol syndrome in rats. Drug Nutr. Interact. 5(4):257–274.