Effect of dietary copper deficiency on iron metabolism in the pregnant rat

Cu and Fe metabolism are known to be linked, but the interactions during pregnancy are less well studied. In the present study we used rats to examine the effect of Cu deficiency during pregnancy on Fe and Cu levels in maternal and fetal tissue and on the gene expression profile of proteins involved in Cu and Fe metabolism in the placenta. Rats were fed diets with different Cu contents before and during pregnancy. Samples were collected on day 21 of gestation. Cu levels, ceruloplasmin activity and serum Fe all decreased in maternal serum of Cu-deficient animals. Maternal liver Fe inversely correlated with liver Cu. Placental Cu levels decreased with no change in Fe. Fe and Cu levels both decreased in the fetal liver. The drop in maternal liver Cu was significantly correlated with a decrease in organ weight of fetal liver, lung and kidney. No changes were observed in mRNA expression of Cu transporter 1, Menkes P-type Cu-ATPase 7A, Wilson P-type Cu-ATPase 7B, cytochrome-c oxidase, and Cu chaperone Atox1 in the placenta of Cu-deficient dams. Transferrin receptor 1 and the Fe-responsive element (IRE)-regulated divalent metal transporter 1 (DMT1) were up regulated; while ferroportin and non-IRE1-regulated DMT1 levels did not change. These data show that Cu deficiency during pregnancy not only has a direct effect on Fe levels but also regulates the expression of Fe transporters. The pattern closely mirrors that seen in Fe deficiency, suggesting that the changes are a consequence of the decrease in serum Fe, implying that the developing fetus not only suffers from Cu, but also from Fe deficiency.