Consumption of a high-iron diet disrupts homeostatic regulation of intestinal copper absorption in adolescent mice

Abstract

High-iron feeding of rodents has been commonly used to model human iron-overload disorders. We recently noted that high-iron consumption impaired growth and caused severe systemic copper deficiency in growing rats, but the mechanism by which this occurred could not be determined due to technical limitations. In the current investigation, we thus utilized mice; first to determine if the same phenomenon occurred in another mammalian species, and second since we could assess in vivo copper absorption in mice. We hypothesized that excessive dietary iron impaired intestinal copper absorption. Weanling, male mice were thus fed AIN-93G-based diets containing high (HFe) (~8,800 ppm) or adequate (AdFe) (~80 ppm) iron in combination with low (~0.9 ppm), adequate (~9 ppm), or high (~180 ppm) copper for several weeks. Iron and copper homeostasis was subsequently assessed. Mice consuming the HFe diets grew slower, were anemic, and had lower hepatic copper levels and serum ceruloplasmin activity. These physiological perturbations were all prevented by higher dietary copper, demonstrating that copper depletion was the underlying cause. Furthermore, homeostatic regulation of copper absorption was noted in the mice consuming the AdFe diets, with absorption increasing as dietary copper decreased. HFe-fed mice did not have impaired copper absorption (disproving our hypothesis), but homeostatic control of absorption was disrupted. There were also noted perturbations in the tissue distribution of copper in the HFe-fed mice, suggesting that altered storage and thus bioavailability contributed to the noted copper deficiency. Dietary iron loading thus antagonizes copper homeostasis leading to pathological symptoms of severe copper depletion. NEW & NOTEWORTHY High-iron feeding is a common experimental method to model human iron-overload disorders in rodents. Here, we show that dietary iron loading causes severe copper deficiency due to perturbations in the homeostatic regulation of intestinal copper absorption and tissue distribution, which may decrease the bioavailability of copper for use in cuproenzyme synthesis. Whether high-dose iron supplementation in humans antagonizes copper homeostasis is worthy of consideration.