Dysregulation of Iron Homeostasis in Beta‐thalassemia Intermedia (Th3/+) Mice During Pregnancy

Abstract

Beta‐thalassemia is a disease associated with decreased β‐globin production due to mutations in the β‐globin gene and characterized by chronic anemia, ineffective erythropoiesis, low hepcidin levels, and systemic iron overload. In β‐thalassemia intermedia, some β‐globin is still produced, preventing the need for regular blood transfusions. These patients, however, still show systemic iron overload because of increased intestinal iron absorption, likely due to increased erythropoietic demand and consequent low hepcidin. Recent advances in the management of β‐thalassemia have significantly improved life expectancy and quality of life of patients suffering from this disease. An increasing number of women with this disease thus desire to have children. Pregnancy is characterized by dynamic multiple organ system physiological changes. Cardiac, hepatic, and endocrine disorders due to oxidative stress caused by iron overload negatively impact both mother and fetus. Therefore, understanding iron metabolism during pregnancy may improve management of iron overload and pregnancy outcomes. Objective We sought to quantify intestinal iron absorption and distribution in β‐thalassemia intermedia mice during pregnancy plus iron transport across the placenta to developing fetuses. Hypothesis we hypothesized that iron absorption increases due to increased erythropoietic demand and consequent low hepcidin in β‐thalassemia intermedia mice during pregnancy. Methods Pregnant Th3/+ and WT female mice, at 16–18 days of gestation, were gavaged with a 59Fe transport solution. After 24 hours, blood samples were collected and the stomach, and small and large intestines were removed from the carcass, and the 59Fe activity was measured. Then, uterus, liver, spleen, kidney, heart, pancreas, bone, muscle, fetus, and placenta were removed from the carcass and the 59Fe activity was measured individually. The study was repeated, and the pregnant female mice were gavaged with saline instead of 59Fe. Blood and tissue samples were collected for molecular biology assays. Results Pregnant Th3/+ mice were iron loaded, as exemplified by increases in tissue and serum non‐heme iron levels, and TSAT. Consistent with iron loading, the serum hepcidin level was increased and iron absorption was depressed. Hepcidin was elevated in Th3/+ mice despite increases in serum Epo and bone marrow Erfe expression (which would normally depress hepcidin transcription). Distribution of absorbed iron also varied between pregnant Th3/+ and WT mice. In WT mice, most absorbed 59Fe went to the developing fetuses (>65%), while iron delivery to the fetuses was lower in Th3/+ mice. Liver hepcidin expression and non‐heme iron content was high in the Th3/+ fetuses compared with WT fetuses, even though they were from the same Th3/+ dams. Conclusion Regulation of iron homeostasis is perturbed in pregnant Th3/+ mice and also possibly in developing fetal Th3/+ mice. Support or Funding Information This work was supported by NIH grants R01 DK074867 and R01 DK109717 (to JFC).