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 µg Fe/g = 1×), or excessive (4×, 9.5×, 18.5×, 38×, or 110×) iron content for 7 wk (110× 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 1× (i.e., control) group. The highest iron concentration (110×) impaired growth (final body weights decreased ∼40%; P < 0.0001), and caused anemia (blood hemoglobin and hematocrit decreased ∼65%; P < 0.0001) and hepatic copper depletion (>85% reduction; P < 0.01). Cardiac hypertrophy occurred in the 110× (∼130% increase in mass; P < 0.0001) and 38× (∼25% increase; P < 0.05) groups, whereas cardiac copper content was lower in the 110× (P < 0.01), 38× (P < 0.01), and 18.5× (P < 0.05) groups (∼70% reductions). Splenic copper was also depleted in the 110× (>90% reduction; P < 0.0001), and in the 38× (P < 0.001) and 18.5× (P < 0.01) groups (∼70% reductions). Moreover, serum ceruloplasmin activity was decreased in the 110× and 38× (>90% reductions; P < 0.0001), and 18.5× (P < 0.001) and 9.5× (P < 0.05) (∼50% reductions) groups, typifying moderate to severe copper deficiency. Conclusions: Increasing dietary iron intakes 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 is worth considering, especially since copper defi-ciency can impair iron utilization (e.g., by decreasing the ferroxidase activity of ceruloplasmin).
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 µg Fe/g = 1×), or excessive (4×, 9.5×, 18.5×, 38×, or 110×) iron content for 7 wk (110× 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 1× (i.e., control) group. The highest iron concentration (110×) impaired growth (final body weights decreased ∼40%; P < 0.0001), and caused anemia (blood hemoglobin and hematocrit decreased ∼65%; P < 0.0001) and hepatic copper depletion (>85% reduction; P < 0.01). Cardiac hypertrophy occurred in the 110× (∼130% increase in mass; P < 0.0001) and 38× (∼25% increase; P < 0.05) groups, whereas cardiac copper content was lower in the 110× (P < 0.01), 38× (P < 0.01), and 18.5× (P < 0.05) groups (∼70% reductions). Splenic copper was also depleted in the 110× (>90% reduction; P < 0.0001), and in the 38× (P < 0.001) and 18.5× (P < 0.01) groups (∼70% reductions). Moreover, serum ceruloplasmin activity was decreased in the 110× and 38× (>90% reductions; P < 0.0001), and 18.5× (P < 0.001) and 9.5× (P < 0.05) (∼50% reductions) groups, typifying moderate to severe copper deficiency. Conclusions: Increasing dietary iron intakes to ∼9.5-fold above dietary recommendations caused copper deficiency. Importantly, humaniron supplementation is common, and recommended intakes for at-risk individuals may be ≤10-fold above the RDA. Whether these iron intakes perturb copper metabolism is worth considering, especially since copper defi-ciency can impair iron utilization (e.g., by decreasing the ferroxidase activity of ceruloplasmin).
Authors: Xiaoyu Wang; Mingzhen Zhang; Shireen R L Flores; Regina R Woloshun; Chunhua Yang; Liangjie Yin; Ping Xiang; Xiaodong Xu; Michael D Garrick; Sadasivan Vidyasagar; Didier Merlin; James F Collins Journal: Mol Ther Date: 2019-01-12 Impact factor: 11.454
Authors: Regina R Woloshun; Yang Yu; Xiaodong Xu; Jennifer K Lee; Sean Zhu; Jacob S Shine; Pearl Ebea; Bruce R Stevens; Sadasivan Vidyasagar; James F Collins Journal: Blood Adv Date: 2022-05-24