In pigs, iron deficiency anemia (IDA) is the most prevalent deficiency disorder during the early postnatal period, frequently developing into a serious illness. On the other hand, in humans, only low-birth-weight infants, including premature infants, are especially susceptible to developing IDA. In both human and pig neonates, the initial cause of IDA is low birth iron stores. In piglets this shortage of stored iron results mainly from genetic selection over the past few decades for large litter sizes and high birth weights. As a consequence, pregnant sows cannot provide a sufficient amount of iron to the increasing number of developing fetuses. Supplementation with iron is a common practice for the treatment of IDA in piglets. For decades, the preferred procedure for delivering iron supplements during early life stages has been through the intramuscular injection of a large amount of iron dextran. However, this relatively simple therapy, which in general, efficiently corrects IDA, may generate toxic effects, and by inducing hepcidin expression, may decrease bioavailability of supplemental iron. New iron supplements are considered herein with the aim to combine the improvement of hematological status, blunting of hepcidin expression, and minimizing the toxicity of the administered iron. We propose that iron-deficient piglets constitute a convenient animal model for performing pre-clinical studies with iron supplements.

Menkes disease is a fatal neurodegenerative disorder in infants caused by mutations in the gene ATP7A which encodes a copper (Cu) transporter. Defects in ATP7A lead to accumulated copper in the small intestine and kidneys and to copper deficiencies in the brain and the liver. The copper level in the kidney in postnatal copper-treated Menkes patients may reach toxic levels. The mouse model, mosaic Atp7a ^mo-ms recapitulates the Menkes phenotype and die about 15.75±1.5 days of age. In the present study we found that prenatal treatment of mosaic murine fetuses throughout gestation days 7, 11, 15 and 18 with a combination of CuCl₂ (50 mg/kg) and dimethyldithiocarbamate (DMDTC) (280 mg/kg) leads to an increase in survival to about 76±25.3 days, whereas treatment with CuCl₂ alone (50 mg/kg) only leads to survival for about 21 days ±5 days. These copper-DMDTC treated mutants showed an improved locomotor activity performance and a gain in body mass. In contrast to treatment with CuCl₂ alone, a significant increase in the amount of copper was observed in the brain after prenatal copper-DMDTC treatment as well as a decrease in the amount of accumulated copper in the kidney, both leading towards a normalization of the copper level. Although copper-DMDTC prenatal treatment only leads to a small increase in the sub-normal copper concentration in the liver and to an increase of copper in the already overloaded small intestine, the combined results suggest that prenatal copper-DMDTC treatment also should be considered for humans.

Copper is an essential micronutrient for all living organisms. ATP7 Aprotein is a copper-transporting ATPase which plays a vital role in the maintenance of cellular copper homeostasis in mammals. This protein is retained within the trans-Golgi network, but after binding copper it can be translocated to the cell membrane to participate in the efflux of excess Cu. Mutation of the ATP7Agene in humans results in the severe neurodegenerative disorder, Menkes disease. The mouse ATP7Ahomolog encodes a protein that plays the same role in coppertransport. Mosaic mutant mice display a lethal phenotype which resembles Menkes disease, although the underlying molecular defect has not been characterized until now. In the present study we identified a G to C nucleotide exchange in exon 15 of the Atp7agene in mosaic mutants, which resulted in an arginine to proline substitution in the highly conserved 6th transmembrane domain of the ATP7Aprotein. This mutated protein was mislocalized in kidney cells isolated from mosaic mutant mice, and following exposure of these cells to increased copper concentrations it was not translocated to the plasma membrane. Disturbance of ATP7A function in mosaic mice results in increased copper accumulation in the small intestine and kidneys, and in Cu deficiency in the brain, liver and heart. Mouse models of Menkes disease belong to the mottled mutant group. The mosaic mutant represents another interesting animal model for Menkes disease that will be of value in research on coppermetabolism and transport in mammals.