conspectus of researchon copper metabolism and requirements

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2002 KARL E. MASON Placental transfer Nonceruloplasmin copper readily crosses the placenta by passive diffusion, and its concentration in erythrocytes and plasma of mother and fetus is relatively constant throughout gestation (181, 673). Total copper in cord blood is about 1/4 to 1/5 that in maternal blood (181, 464, 552, 556, 561, 660, 673, 686). Studies in which blood of the umbilical vein (placenta to fetus) and umbilical artery (fetus to placenta) have been analyzed for copper give values of 53.4 to 40.0 fig/100 ml (556), 54.9 and 40.2 Mg/100 ml (167) and 74.4 and 41.8 /ig/100 ml (770), respectively. Such find ings clearly indicate an important role of the placenta in transfer of copper from mother to fetus. The high copper concen tration in the placenta (525, 605), liver and other fetal organs and tissues, referred to later, indicates the efficiency of this transfer. Questions of placental transfer and of fetal synthesis of ceruloplasmin have never been satisfactorily clarified. It has been assumed that its large molecular size pre cludes placental transfer (673), although this may not be a valid conclusion (339). There are possibilities that with pro nounced thinning of the hemoendothelial membrane of placental villi, and/or tiny breaks therein during late phases of ges tation, some ceruloplasmin may be trans ferred to the fetal circulation (552). Also, one cannot exclude the possibility that ceruloplasmin may actually cross the pla centa, and that its rate of utilization and breakdown may be equivalent to or greater than its rate of transfer (666). Although apoceruloplasmin can be identified immunologically in plasma of the newborn (496, 714), there is no evidence that ce ruloplasmin can be synthesized by the fetus. It is assumed that synthesis by the fetal liver does not begin until shortly after birth. In the domestic pig neither apoceruloplasmin nor ceruloplasmin ap pear in die piglet serum until about 15 hours after birth (108, 109). In view of these facts, the presence of small amounts of ceruloplasmin in cord blood of the new born (338, 606, 639, 673) suggests its transport from placenta to fetus. If this be so, the time over which this transfer may take place and its magnitude is unknown, and almost impossible to determine. A question which naturally arises is whether the fetus has or needs a ferroxidase type of enzyme, as a substitute for lack of ceruloplasmin, to provide for the intensive hemopoietic activities of the fetal liver, spleen and bone marrow during fetal life. Somewhat ancillary to this discussion are observations of Widdowson et al. (842) that copper concentration in the liver of 30 fetuses representing the 20th to 41st weeks of gestation were consistently high (aver age 6.4, range 3.5-9.3 mg/100 g fresh tissue), as compared to values of 0.5 mg/ 100 g fresh tissue for adult human liver, lyengar and Apte (377) give values of 4.76, 4.37, 4.38 and 4.23 mg/100 g fresh tissue for livers of 38 fetuses of gestational ages less than 28, 28 to 32, 33 to 36 and 37 to 40 weeks, respectively. On the other hand, Sultanova (761) reports that the more premature the infant the lower are the fetal liver reserves, while Butt et al. (85) find lower hepatic copper values in full term infants than in prematures. Neither study provides the firm data char acterizing the first two studies (377, 842) mentioned. Significantly lower levels of total copper and ceruloplasmin in cord blood of neonates of undernourished mothers compared to those of well nour ished mothers suggest that poor nutri tional states of the mother are reflected in reduced capacity of the fetal liver to syn thesize proteins in general, and cerulo plasmin in particular (429). According to one investigator (526), amniotic fluid contains copper and other bioelements in about the same concen tration as in the maternal plasma and, by virtue of its being swallowed in appre ciable amounts, provides an additional supply to the developing fetus. However, other investigators report the presence of very small amounts or only traces of cop per in this fluid (303, 321, 324, 564), which is in accord with the concept of the amniotic fluid as a protein-poor dialysate diluted with fetal urine. Infanctj and childhood Following normal delivery a series of in teresting and not fully explained events Downloaded from jn.nutrition.org by guest on February 27, 2013
COPPER METABOLISM AND REQUIREMENTS OF MAN 2003 occur in mother and infant. Maternal levels of serum copper decrease to non-pregnant levels during the first 2 weeks postpartum (100, 206, 293, 294, 561). This is ascribed to the abrupt cessation of estrogenic stimuli for ceruloplasmin synthesis. At the same time, infant levels of serum copper, which are lower at birth than at any pe riod of life, promptly increase until adult levels are attained between the 2nd and 3rd months of life (91, 293, 325, 690). This is due almost entirely to increased synthesis of ceruloplasmin by the infant's liver. In other studies, estimates of the age at which adult values are reached vary from about 3 to 6 months (338, 494, 638), to 9 to 12 months (411, 606). Several in vestigators report that after adult serum copper levels are attained during the first 2 or 3 months of life, these levels rise sig nificantly above normal after the 4th month (758 ) or during the 2nd year of life (131, 362, 656), and then gradually de cline to adult levels at puberty. Sass- Kortsak (666) gives mean values of 140, 129 and 117 /Â¿g/100ml for 2-, 6- and 10year old children. Hrgovic and Hrgovic (362) record mean values of 179, 151, 133 and 111 Mg/100 ml for age groups 0 to 5, 5 to 10, 10 to 15 and 15 to 18 years. No sex differences are apparent until puberty, after which the effect of female estrogens on increased serum copper levels becomes manifest. Similar observations have been reported by other investigators (573, 776). Neither the reason for, nor the significance of these fluctuations in early life has been elucidated. Immunological methods have identified an apoceruloplasmin in newborn infant plasma in concentrations similar to that of ceruloplasmin in the adult, thus indi cating that only the inability to charge the apoprotein with its normal complement of copper is underdeveloped at birth (714). Similar observations have been made in studies with piglets (108, 109, 523). On the other hand, remarkable changes occur in the liver of the newborn, which contains about one-half the copper in the body and a concentration, in terms of cop per per unit weight, 5 to 10 times that of the adult liver (843, 846). A large com ponent of this copper is bound to hepatic initochondrocuprein, first isolated and de scribed by Porter et al. (615). This cop per-storage protein, found only in the fetus and newborn, is thought to represent a copper-rich polymerized form of metallothionein which sequesters copper prior to birth (611, 614). Liver copper rapidly disappears during the first few months of life (69, 627, 846), releasing copper for ceruloplasmin synthesis and the general needs of tissues of the rapidly growing in fant. The ceruloplasmin synthesized by the neonate is identical to that of the adult (870). Thus there is a logical explanation for the early reports of Kleinman and Klinke (414) and Morrison and Nash (538) that the concentration of copper in the liver of newborn and young infants is 6- to 18-fold that of adults. Although copper and ceruloplasmin blood levels are lower in the newborn than at any other period of life, the copper con centration in fetal and neonatal organs and tissues is much higher than in the adult (207, 248, 414, 565, 781). The studies of Fazekas (207), based upon analysis of 29 different organs and tissues of 109 fetuses and full-term infants of varied gestational age, indicate that in addition to liver, the concentration of copper in muscle, skin, adrenal glands and thyroid is particularly high compared to that of adults. The cop per content of the placenta is also rather high (525, 605). The high concentrations of copper in organs and tissues of the newborn decrease gradually to normal levels during the first year of postnatal life (69, 248, 565). The unusually high concentrations of copper in liver and other tissues of the neonate appear to represent a reserve to assure an adequacy of copper for syn thesis of ceruloplasmin and other coppercontaining proteins to meet metabolic needs for hematopoietic, maturational and other functions in the rapidly growing in fant and adolescent prior to puberty. These changes naturally create difficulties in reaching definitive conclusions concerning the dietary requirements during these early years of human development. For other details concerning the role of copper in pregnancy, and in prenatal and postnatal development, the reader is referred to a Downloaded from jn.nutrition.org by guest on February 27, 2013
Page 1 and 2: A CONSPECTUS OF RESEARCH ON COPPER
Page 3 and 4: INTRODUCTION The discovery of coppe
Page 5 and 6: COPPER METABOLISM AND REQUIREMENTS
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Page 55 and 56: Ã®1co 1stW Â»aÂ«a3 COPPER MET
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COPPER METABOLISM AND REQUIREMENTS
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