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 secondly 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) (~8800 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 physiologic 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.

Copper deficiency, a new triad: anemia, leucopenia, and myeloneuropathy

“…Copper deficiency has not been reported in hemochromatosis, which is an autosomal recessive disease characterized by increased intestinal iron absorption. Excessive dietary iron ingestion caused sever copper deficiency in mice [21]. …”

Intersection of Iron and Copper Metabolism in the Mammalian Intestine and Liver

“…For example, immunoreactive CP was reported to be decreased in hereditary hemochromatosis (HH), a genetic iron-loading disorder (67). Additional recent investigations in rats (112) and mice (110) demonstrated that high-iron intake can lead to copper depletion. In these studies, high-iron fed rodents developed severe copper deficiency-related pathologies, including growth retardation, cardiac hypertrophy, anemia, and impaired production of the liver-derived circulating FOX CP, which is a biomarker of moderate to severe copper deficiency (110, 112).…”

“…Additional recent investigations in rats (112) and mice (110) demonstrated that high-iron intake can lead to copper depletion. In these studies, high-iron fed rodents developed severe copper deficiency-related pathologies, including growth retardation, cardiac hypertrophy, anemia, and impaired production of the liver-derived circulating FOX CP, which is a biomarker of moderate to severe copper deficiency (110, 112). Increasing dietary Cu prevented the development of these pathologies in rats, proving that copper deficiency was the underlying cause (112).…”

“…Increasing dietary Cu prevented the development of these pathologies in rats, proving that copper deficiency was the underlying cause (112). In mice, high iron intake was suggested to interfere with copper absorption and tissue distribution (110). Collectively, these observations may be of particular physiological relevance since: (i) many Americans may have marginal copper intakes (148, 150); (ii) refined grain products are fortified with iron in the United States, increasing dietary iron consumption; and (iii) many individuals also consume iron supplements.…”

Progressive Increases in Dietary Iron Are Associated with the Emergence of Pathologic Disturbances of Copper Homeostasis in Growing Rats

“…Many of these pathological symptoms typify severe copper deficiency (2,3). Notably, these abnormalities did not occur in animals consuming the high-iron diet with excess copper (4,5), essentially proving that these pathologies were caused by copper depletion. The threshold of dietary iron necessary to disrupt copper metabolism has not, however, been experimentally determined.…”