Dietary Iron Intake in Excess of Requirements Impairs Intestinal Copper Absorption in Sprague Dawley Rat Dams, Causing Copper Deficiency in Suckling Pups

Abstract

Physiologically relevant iron-copper interactions have been frequently documented. For example, excess enteral iron inhibits copper absorption in laboratory rodents and humans. Whether this also occurs during pregnancy and lactation, when iron supplementation is frequently recommended, is, however, unknown. Here, the hypothesis that high dietary iron will perturb copper homeostasis in pregnant and lactating dams and their pups was tested. We utilized a rat model of iron-deficiency/iron supplementation during pregnancy and lactation to assess this possibility. Rat dams were fed low-iron diets early in pregnancy, and then switched to one of 5 diets with normal (1×) to high iron (20×) until pups were 14 days old. Subsequently, copper and iron homeostasis, and intestinal copper absorption (by oral, intragastric gavage with 64Cu), were assessed. Copper depletion/deficiency occurred in the dams and pups as dietary iron increased, as evidenced by decrements in plasma ceruloplasmin (Cp) and superoxide dismutase 1 (SOD1) activity, depletion of hepatic copper, and liver iron loading. Intestinal copper transport and tissue 64Cu accumulation were lower in dams consuming excess iron, and tissue 64Cu was also low in suckling pups. In some cases, physiological disturbances were noted when dietary iron was only ~3-fold in excess, while for others, effects were observed when dietary iron was 10–20-fold in excess. Excess enteral iron thus antagonizes the absorption of dietary copper, causing copper depletion in dams and their suckling pups. Low milk copper is a likely explanation for copper depletion in the pups, but experimental proof of this awaits future experimentation.

Gestational Iron Supplementation Improves Fetal Outcomes in a Rat Model of Prenatal Alcohol Exposure

“…We found no overtly adverse consequences of gestational iron supplementation. Although excessive iron can disrupt the absorption and metabolism of divalent metals [40,41], we found no impact upon copper or zinc content in either dam or fetus, suggesting that our iron dose was not excessive. Moreover, the hepatic iron stores and hematology of the iron-supplemented dams remained within standard rat values [50].…”

“…In the male fetal brain, PAE and iron intera to alter total iron (p = 0.041), wherein the CON + Iron brains had the highest total iron there were no individual significant differences among groups. Neither alcohol nor affected the iron content in female brains Excess iron intake during pregnancy im fetal copper transfer and decreases maternal zinc absorption [40,41], but we found no pact of iron supplementation on the copper or zinc content of fetal liver (Copper: p = 0 Zinc: p = 0.352; Table S4) or brain (Copper: p = 0.491; Zinc: p = 0.883; Table S5). PAE alters fetal iron distribution, reducing its content in the fetal brain and increasing its content in liver [12,39].…”

The Dark Side of Iron: The Relationship between Iron, Inflammation and Gut Microbiota in Selected Diseases Associated with Iron Deficiency Anaemia—A Narrative Review

“…It is also worth mentioning that excess dietary iron may affect the ingestion of other divalent metals. For example, in murine and rat models, the high nutritional iron intake contributed to copper deficiency [ 34 , 35 , 36 , 37 ]. However, the clinical significance of this finding in humans requires further investigation.…”

Issues pertaining to Mg, Zn and Cu in the 2020 Dietary Reference Intakes for Koreans

“…In Fe deficiency, Cu absorption and utilization are remarkably increased due to elevated intestinal Cu transport and hepatic ceruloplasmin synthesis [ 59 ], both clinically [ 64 ] and pre-clinically [ 65 66 ]. Conversely, excess Fe exposure suppresses the Cu homeostasis in infants [ 64 67 68 ] and rapidly growing rodents [ 65 66 69 70 ]. Due to competitive interactions among divalent minerals in their intestinal absorption, distribution, and metabolism, the dietary Cu absorption and distribution might be enhanced or reduced by other divalent metal consumptions.…”