Repletion of Copper-Deficient Mice and Brindled Mice with Copper or Iron

Abstract

Studies were conducted in suckling mice to investigate copper-dependent anemia. Brindled (Mobr/y) mice, which have a genetic defect that affects copper metabolism, were compared to their normal brothers (Mo+/y) as well as to anemic suckling mice that were copper-deficient (-Cu) because their dams were consuming a diet low in copper and to a fourth group of control suckling mice (+Cu) from copper-supplemented dams. Mice were given a subcutaneous injection of NaCl, FeCl2 or CuCl2 providing 50 micrograms of Na, Fe or Cu, respectively, when 7 days old and were killed 5 days later. Injection of FeCl2 into -Cu mice elevated liver iron 2.7-fold and raised hemoglobin levels to those observed in the +Cu and Mo+/y mice. Ceruloplasmin activity remained low at 5% of control levels. Injection of CuCl2 into -Cu mice resulted in significant increases in body and brain weight, elevations in serum copper and ceruloplasmin activities and hemoglobin levels. Liver copper rose and iron fell, both to levels observed in +Cu and Mo+/y mice. Brain copper and norepinephrine concentrations rose to control levels. Injection of CuCl2 into Mobr/y mice, although resulting in darker pigmentation and normal serum copper and ceruloplasmin levels, failed to stimulate growth or change brain weight. Furthermore, liver and brain copper levels did not rise to normal levels despite significant improvements. Similarly, brain norepinephrine levels rose, but were still below normal. Brindled mice do not respond to copper therapy to the same degree as do -Cu mice. Iron therapy was successful in reversing the anemia of -Cu mice but was without effect on growth or brain development.

Lack of ceruloplasmin expression alters aspects of copper transport to the fetus and newborn, as determined in mice

“…These concentrations are not normally seen again during the lifespan of the species, where in rats and humans liver concentrations are held close to 20 lg Cu/g (dry weight), or 5 lg Cu/g wet weight. Our values for the 2-4 day old mouse pups from wild type dams were 25 lg Cu/g wet weight, in rough agreement with those of others, Rauch (1983) reporting 47.8 lg Cu/g (age unspecified), and Prohaska (1984Prohaska ( , 1989 47-65 lg Cu/g for 11-12 day old C57BL/6 male mice. Recalculating newborn liver values of Michalczyk et al (2000) on the basis of 25% dry weight gives 32 lg Cu/g in DL mice at 4 days of age, quite close to our values and those in another report (Allen et al 2006).…”

Copper deficiency increases iron absorption in the rat

“…It also eliminated plasma ferroxidase I activity, produced anemia, and doubled hepatic iron stores. These findings support previous studies on the effect and extent of copper deficiency on iron metabolism in the rat and mouse (7,8,13,14,24,25,30,33,45). Because liver iron levels are raised in copper-deficient rats, it suggests that total iron absorption is increased; however, previous direct measurements have produced conflicting results (5,7,9).…”

“…It has been shown that adequate copper stores are necessary for the efflux of iron from the liver. Thus, during copper deficiency in rats, iron accumulated within hepatocytes (7,8,13,14,24,25,30,33,45). The finding that liver iron was increased in proportion to dietary iron content suggests that iron absorption may be normal or even increased by copper deficiency.…”

Copper deficient rats and mice both develop anemia but only rats have lower plasma and brain iron levels

“…This is borne out by several studies in which iron injections failed to raise hemoglobin levels in Cu-rodents (Williams et al, 1983;Prohaska et al, 1985;Reeves and DeMars, 2006). In contrast, iron injection of Cu-suckling pups did correct the hemoglobin deficit (Prohaska, 1984). Thus, it is possible that Cu-suckling mammals are iron deficient (Pyatskowit and Prohaska, 2008).…”