Iron deficiency (ID) is common in the U.S, causing significant morbidity. The inability to assimilate adequate amounts of dietary iron, due to increased demands (e.g. with excessive menstrual blood loss) or impaired utilization (e.g. iron malabsorption after gastric bypass surgery), frequently underlies ID. Women of child- bearing age, pregnant women, the elderly (in whom achlorhydria is common), and children and adolescents are commonly iron deficient; in these individuals, iron supplementation may be recommended. During pregnancy, anemia is common since dietary iron assimilation is often inadequate to meet iron demands to supply the developing fetus and for expansion of the maternal blood supply; iron supplementation is thus almost universally recommended. Importantly, we recently noted that high dietary iron caused severe copper deficiency, in rats and mice, with pathological consequences. These initial studies utilized supraphysiologic iron levels (>100-fold excess), but a subsequent experiment demonstrated that iron at ~4X above requirements resulted in moderate copper deficiency in rats. ID humans may consume iron at 4 times the RDA from dietary and supplemental sources. It was previously suggested that high-iron intake can antagonize copper, but this has not been validated by rigorous experimentation in animals or humans. This background then provides the rationale for this investigation in which we will test the central hypothesis that consumption of supplemental iron, at levels similar to what ID humans may consume, disrupts copper metabolism with likely pathological outcomes. Notably, copper deficiency mimics ID, as both conditions cause microcytic, hypochromic anemia. Lack of adequate iron impairs erythropoiesis in ID, while impaired iron utilization by developing erythrocytes underlies copper-deficiency anemia. Physicians may recommend higher iron dosing in patients that are refractory to supplemental iron, thus potentiating the copper deficiency. This investigation could change the existing paradigm of iron supplementation, with added copper accelerating resolution of the anemia and also preventing other pathophysiological effects of copper deficiency, including cardiomyopathy, cognitive dysfunction, and impaired immunity.
Three specific aims will be pursued.
Aim 1 will define the minimum amount of supplemental iron that perturbs copper homeostasis in rats and mice of both sexes.
Aim 2 will identify the mechanism(s) by which supplemental iron perturbs copper homeostasis, possibly involving inhibition of intestinal copper transporters.
Aim 3 will evaluate the efficacy of Fe + Cu for preventing the copper depletion associated with high-iron intake in preclinical models of human ID. This investigation may establish an argument for adding copper to iron supplements. Consuming extra copper should be without negative physiologic consequence, and could increase the effectiveness of iron supplementation programs, especially since many Americans may have marginal dietary copper intakes. This investigation could serve as a prelude to intervention trials in humans, which would be a logical extension of the experimentation proposed here.

Public Health Relevance

Iron deficiency and iron-deficiency anemia are common in the U.S., occurring most frequently in minorities, children from economically-challenged families and low-income pregnant women. In many cases, high-dose, oral iron supplementation is recommended for such individuals. Emerging evidence demonstrates that high- iron intake disrupts copper homeostasis with possible pathological consequences, so this investigation seeks to assess the effectiveness of providing iron supplements with added copper at improving disease outcomes.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Special Emphasis Panel (ZRG1)
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Maruvada, Padma
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University of Florida
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Ha, Jung-Heun; Doguer, Caglar; Collins, James F (2017) Consumption of a High-Iron Diet Disrupts Homeostatic Regulation of Intestinal Copper Absorption in Adolescent Mice. Am J Physiol Gastrointest Liver Physiol :ajpgi.00169.2017
Doguer, Caglar; Ha, Jung-Heun; Gulec, Sukru et al. (2017) Intestinal hephaestin potentiates iron absorption in weanling, adult, and pregnant mice under physiological conditions. Blood Adv 1:1335-1346
Zhang, Mingzhen; Wang, Xiaoyu; Han, Moon Kwon et al. (2017) Oral administration of ginger-derived nanolipids loaded with siRNA as a novel approach for efficient siRNA drug delivery to treat ulcerative colitis. Nanomedicine (Lond) 12:1927-1943
Ha, Jung-Heun; Doguer, Caglar; Collins, James F (2016) Knockdown of copper-transporting ATPase 1 (Atp7a) impairs iron flux in fully-differentiated rat (IEC-6) and human (Caco-2) intestinal epithelial cells. Metallomics 8:963-972
Ha, Jung-Heun; Doguer, Caglar; Wang, Xiaoyu et al. (2016) High-Iron Consumption Impairs Growth and Causes Copper-Deficiency Anemia in Weanling Sprague-Dawley Rats. PLoS One 11:e0161033
Zhang, Mingzhen; Collins, James F; Merlin, Didier (2016) Do ginger-derived nanoparticles represent an attractive treatment strategy for inflammatory bowel diseases? Nanomedicine (Lond) 11:3035-3037
Collins, James F (2015) Long noncoding RNAs and hepatocellular carcinoma. Gastroenterology 148:291-4
Gulec, Sukru; Collins, James F (2014) Molecular mediators governing iron-copper interactions. Annu Rev Nutr 34:95-116
Gulec, Sukru; Collins, James F (2014) Silencing of the Menkes copper-transporting ATPase (Atp7a) gene increases cyclin D1 protein expression and impairs proliferation of rat intestinal epithelial (IEC-6) cells. J Trace Elem Med Biol 28:459-64
Prasad, Ananda S; Brewer, George; Collins, James F (2014) The history of the International Society for Trace Element Research in Humans (ISTERH) and summary of the 10th ISTERH meeting in Tokyo, Japan (November 2013). J Trace Elem Med Biol 28:355-6

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