Excess iron: considerations related to development and early growth

Abstract

What effects might arise from early life exposures to high iron? This review considers the specific effects of high iron on the brain, stem cells, and the process of erythropoiesis and identifies gaps in our knowledge of what molecular damage may be incurred by oxidative stress that is imparted by high iron status in early life. Specific areas to enhance research on this topic include the following: longitudinal behavioral studies of children to test associations between iron exposures and mood, emotion, cognition, and memory; animal studies to determine epigenetic changes that reprogram brain development and metabolic changes in early life that could be followed through the life course; and the establishment of human epigenetic markers of iron exposures and oxidative stress that could be monitored for early origins of adult chronic diseases. In addition, efforts to understand how iron exposure influences stem cell biology could be enhanced by establishing platforms to collect biological specimens, including umbilical cord blood and amniotic fluid, to be made available to the research community. At the molecular level, there is a need to better understand stress erythropoiesis and changes in iron metabolism during pregnancy and development, especially with respect to regulatory control under high iron conditions that might promote ineffective erythropoiesis and iron-loading anemia. These investigations should focus not only on factors such as hepcidin and erythroferrone but should also include newly identified interactions between transferrin receptor-2 and the erythropoietin receptor. Finally, despite our understanding that several key micronutrients (e.g., vitamin A, copper, manganese, and zinc) support iron's function in erythropoiesis, how these nutrients interact remains, to our knowledge, unknown. It is necessary to consider many factors when formulating recommendations on iron supplementation.

Keywords: brain; early growth; erythropoiesis; excess iron; iron metabolism; iron toxicity; pregnancy; stem cells.

FIGURE 1

Targets of iron toxicity. Iron promotes Fenton chemistry, which promotes ROS. Organs that have high oxidative metabolism are the most susceptible to ROS damage and include the liver, heart, and pancreas. In early life, the brain may also be a sensitive target. Epigenetic changes that are induced by early life exposures may present in adult chronic diseases. ROS, reactive oxygen species.

FIGURE 2

Bone marrow stem cell niche is hypoxic and sensitive to oxidative stress. Bone marrow MSPCs provide a stromal niche for HSCs that can differentiate into erythroid cells. This hypoxic microenvironment keeps ROS concentrations low, protecting against DNA damage for cell renewal and hematopoiesis and promoting events that lead to an early metabolic switch from glycolytic to oxidative metabolism during proliferation and lineage commitment (i.e., metabolic memory). MSPCs also differentiate to adipocytes and osteoblasts, and lineage development is sensitive to iron and ROS. HSC, hematopoietic stem cell; MSPC, mesenchymal stem/progenitor cell; ROS, reactive oxygen species.

FIGURE 3

Erythropoiesis and iron metabolism are connected by red blood cell production. Iron intake is controlled by the actions of erythroferrone, a hormone produced by erythroblasts as a positive regulator of intestinal iron absorption. EPO also positively regulates iron absorption, thereby inducing the proliferation of proerythroblasts, which, in turn, differentiate into erythroblasts. This process is negatively regulated by excess iron or heme. The iron saturation of transferrin modulates TfR2, which interacts with the EPO receptor and reduces EPO sensitivity. EPO, erythropoietin; TfR2, transferrin receptor-2.