Effect of Maternal Iron Overload on Milk Iron Transport in Dams and Brain Iron Status in Offspring
Authors: Ye Qi , Kim Jonghan 
Published: June 2021

While mounting evidence has demonstrated that increased iron (Fe) in the brain is associated with neurodegenerative diseases, studies have suggested that elevated brain Fe during development, likely due to incomplete blood‐brain barrier (BBB), is related to brain dysfunction later in life. Notably, it has been shown that most infant formulas on the market contain 13 times greater iron compared with breast milk, but there is no regulation about the content/form of iron in the infant formula. Furthermore, the effect of maternal iron loading found in various types of iron overload disorders on iron transport into the developing brain, especially during the lactation period, is largely unknown. Thus, the goal of the study was to investigate whether maternal iron overload increases brain iron in the offspring during lactation and its underlying mechanisms. First, we investigated the effect of maternal iron overload on the blood‐to‐milk transport of iron in dams using lactating HFE‐H67D mutant mice, a mouse model of genetic iron overload, and their control wild‐type (WT) mice. Lactating H67D mice showed increased milk iron by 70% with no change in serum iron at postnatal day (PND) 14 compared with WT mice. Intravenous injection of 59Fe into lactating dams at PND14 also showed the greater milk/blood ratio of iron (64% increase; p = 0.044) in H67D dams compared with WT controls. These results indicate that H67D mutation increases iron transport from blood to milk. We then examined if high milk iron in H67D dams promotes iron uptake into the brain of pups by cross‐fostering newborn H67D and WT pups. At PND14, while H67D pups fostered by WT dams showed normal brain iron, WT pups fostered by H67D dams showed a 12% increase in brain iron (p = 0.048), compared with WT pups fostered by WT dams. To further investigate if increased Fe transport into the brain in H67D mice is due to different milk components, we added 59FeCl3 into the milk collected from H67D and WT dams and orally administrated into WT pups. WT pups fed H67D milk showed a 34% increase in brain 59Fe accumulation compared with those fed WT milk (p = 0.050). These results suggest that, in addition to increased blood‐to‐milk Fe transport in H67D dams, the milk components in H67D dams also enhance Fe transport into the brain of the offspring. Finally, we analyzed the levels of transferrin (Tf) and lactoferrin (Lf), two major iron transport proteins, in the milk. The H67D milk showed a trend of decreased Lf (21%, p = 0.07) with no change in Tf, indicating that insufficient Lf in lactating H67D dams could predispose brain iron loading in the offspring during development. Our findings suggest that Lf could protect the developing brain from iron loading, providing potential benefits of Lf supplementation to infants who are breastfed by moms with iron overload disorders or who are dependent on iron‐fortified infant formulas.Support or Funding InformationNortheastern University TIER 1 Interdisciplinary Research GrantsThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.