Dietary Iron Intake in Excess of Requirements Impairs Intestinal Copper Absorption in Sprague Dawley Rat Dams, Causing Copper Deficiency in Suckling Pups

Physiologically relevant iron-copper interactions have been frequently documented. For example, excess enteral iron inhibits copper absorption in laboratory rodents and humans. Whether this also occurs during pregnancy and lactation, when iron supplementation is frequently recommended, is, however, unknown. Here, the hypothesis that high dietary iron will perturb copper homeostasis in pregnant and lactating dams and their pups was tested. We utilized a rat model of iron-deficiency/iron supplementation during pregnancy and lactation to assess this possibility. Rat dams were fed low-iron diets early in pregnancy, and then switched to one of 5 diets with normal (1×) to high iron (20×) until pups were 14 days old. Subsequently, copper and iron homeostasis, and intestinal copper absorption (by oral, intragastric gavage with 64Cu), were assessed. Copper depletion/deficiency occurred in the dams and pups as dietary iron increased, as evidenced by decrements in plasma ceruloplasmin (Cp) and superoxide dismutase 1 (SOD1) activity, depletion of hepatic copper, and liver iron loading. Intestinal copper transport and tissue 64Cu accumulation were lower in dams consuming excess iron, and tissue 64Cu was also low in suckling pups. In some cases, physiological disturbances were noted when dietary iron was only ~3-fold in excess, while for others, effects were observed when dietary iron was 10–20-fold in excess. Excess enteral iron thus antagonizes the absorption of dietary copper, causing copper depletion in dams and their suckling pups. Low milk copper is a likely explanation for copper depletion in the pups, but experimental proof of this awaits future experimentation.

Regulation of murine copper homeostasis by members of the COMMD protein family

ABSTRACTCopper is an essential transition metal for all eukaryotes. In mammals, intestinal copper absorption is mediated by the ATP7A copper transporter, whereas copper excretion occurs predominantly through the biliary route and is mediated by the paralog ATP7B. Both transporters have been shown to be recycled actively between the endosomal network and the plasma membrane by a molecular machinery known as the COMMD/CCDC22/CCDC93 or CCC complex. In fact, mutations in COMMD1 can lead to impaired biliary copper excretion and liver pathology in dogs and in mice with liver-specific Commd1 deficiency, recapitulating aspects of this phenotype. Nonetheless, the role of the CCC complex in intestinal copper absorption in vivo has not been studied, and the potential redundancy of various COMMD family members has not been tested. In this study, we examined copper homeostasis in enterocyte-specific and hepatocyte-specific COMMD gene-deficient mice. We found that, in contrast to effects in cell lines in culture, COMMD protein deficiency induced minimal changes in ATP7A in enterocytes and did not lead to altered copper levels under low- or high-copper diets, suggesting that regulation of ATP7A in enterocytes is not of physiological consequence. By contrast, deficiency of any of three COMMD genes (Commd1, Commd6 or Commd9) resulted in hepatic copper accumulation under high-copper diets. We found that each of these deficiencies caused destabilization of the entire CCC complex and suggest that this might explain their shared phenotype. Overall, we conclude that the CCC complex plays an important role in ATP7B endosomal recycling and function.