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

Background: Consumption of a high-iron diet causes copper deficiency in weanling rodents; however, the minimum amount of dietary iron that disrupts copper homeostasis has not been established. Objective: We tested the hypothesis that dietary iron at only several-fold above physiologic requirements would cause copper depletion. Methods: Weanling male Sprague-Dawley rats (n = 6/group) were fed AIN-93G-based diets with adequate (88 mu g Fe/g = 1x), or excessive (4x, 9.5x, 18.5x, 38x, or 110x) iron content for 7 wk (110x group, due to notable morbidity) or 8 wk (all other groups). Copper-related physiologic parameters were then assessed. Results: A hierarchy of copper-related, pathologic symptoms was noted as dietary iron concentrations increased. All statistical comparisons reported here refer to differences from the 1x (i.e., control) group. The highest iron concentration (110x) impaired growth (final body weights decreased similar to 40%; P < 0.0001), and caused anemia (blood hemoglobin and hematocrit decreased similar to 65%; P < 0.0001) and hepatic copper depletion (>85% reduction; P < 0.01). Cardiac hypertrophy occurred in the 110x (similar to 130% increase in mass; P < 0.0001) and 38x (similar to 25% increase; P < 0.05) groups, whereas cardiac copper content was lower in the 110x (P < 0.01), 38x (P < 0.01), and 18.5x (P < 0.05) groups (similar to 70% reductions). Splenic copper was also depleted in the 110x (>90% reduction; P < 0.0001), and in the 38x (P < 0.001) and 18.5x (P < 0.01) groups (similar to 70% reductions). Moreover, serum ceruloplasmin activity was decreased in the 110x and 38x (>90% reductions; P < 0.0001), and 18.5x (P < 0.001) and 9.5x (P < 0.05) (similar to 50% reductions) groups, typifying moderate to severe copper deficiency. Conclusions: Increasing dietary iron intakes to similar to 9.5-fold above dietary recommendations caused copper deficiency. Importantly, human iron supplementation is common, and recommended intakes for at-risk individuals may be <= 10-fold above the RDA. Whether these iron intakes perturb copper metabolism isworth considering, especially since copper deficiency can impair iron utilization (e.g., by decreasing the ferroxidase activity of ceruloplasmin).