# Iron Pathobiology in β-thalassemia Pregnancy

> **NIH NIH R56** · UNIVERSITY OF FLORIDA · 2023 · $100,000

## Abstract

PROJECT SUMMARY
Iron overload is a major cause of morbidity and mortality in iron-loading anemias, such as β-thalassemia. Iron
overload develops due to inappropriately low production of the iron-regulatory hormone hepcidin, resulting in
elevated intestinal iron absorption. Blood transfusions further exacerbate iron loading. Pregnancy is a natural
condition in which iron homeostasis is altered to meet increased iron demands associated with expansion of
maternal erythropoiesis and fetal development. Although iron metabolism has been extensively investigated in
healthy pregnancy, how it is altered in thalassemic pregnancy and to what extent iron overload contributes to
adverse pregnancy outcomes is unknown. Patients with β-thalassemia are increasingly able to bear children,
however, these pregnancies are considered high risk. Investigation in this area is thus of clinical significance.
Here, a pre-clinical animal model of β-thalassemia (Th3/+ mice) was studied to define pathophysiological
outcomes associated with pregnancy. Key pilot data demonstrated that thalassemia leads to highly disordered
maternal and fetal iron homeostasis. Compared to wild-type (WT) dams, thalassemic mothers were iron-loaded
and had altered systemic iron handling. High serum iron in dams precipitated in utero iron loading of placentas
and WT and Th3/+ fetuses. Iron loading in turn altered the fetal iron-regulatory system. This initial
characterization of thalassemic pregnancy will be expanded upon in this investigation, and generation of new
mouse models that will accelerate novel discovery. In Aim 1, the hypothesis that maternal factors cause fetal
iron imbalance in thalassemic pregnancy will be tested. The approach is to quantify biomarkers of iron, oxygen
and hematological status, and the degree of fetal iron loading, throughout pregnancy. Additional experimentation
will define whether the iron-regulatory hormone erythroferrone (ERFE), blood transfusions, and maternal
anemia/hypoxia impact fetal iron homeostasis. In Aim 2, the hypothesis that fetal iron loading in thalassemic
pregnancies exacerbates development of pre- and postnatal pathologies will be considered. The approach
includes examination of biomarkers of oxidative stress in dams, placentas, and fetuses throughout pregnancy
and during postnatal development. Placental and fetal endothelial cell injury will also be assessed. Effects on
DNA will be evaluated by assaying for global epigenetic changes and mutational burden. Physiological
phenotyping will include detailed analysis of cognitive and renal function. In Aim 3, the hypothesis that lowering
serum iron in Th3/+ dams will prevent fetal iron loading will be tested. Two approaches will be utilized: peroral
delivery of nanoparticle/siRNA complexes to blunt expression of the main intestinal iron transporter DMT1 (to
block iron absorption); and systemic administration of hepcidin mimetics (to decrease iron absorption and release
of storage iron). Both approaches ar...

## Key facts

- **NIH application ID:** 10923418
- **Project number:** 1R56DK137863-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** James F. Collins
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $100,000
- **Award type:** 1
- **Project period:** 2023-09-21 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10923418

## Citation

> US National Institutes of Health, RePORTER application 10923418, Iron Pathobiology in β-thalassemia Pregnancy (1R56DK137863-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10923418. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*