Maternal iron deficiency perturbs embryonic cardiovascular development in mice

Jacinta I Kalisch-Smith,Jack J Miller,Aimée Jacquemot,Dorota Szumska,Eva Lana-Elola,Rifdat Aoidi,Michael Troup,Sarah De Val,Timothy J Mohun,Magda Wolna,Victor L J Tybulewicz,Eleanor M Stuart,Nikita Ved,Emily Hardman,Elizabeth Fisher ,Shelley Harris ,Jacob E Munro ,Samira Lakhal‐Littleton ,Fabrice Prin,Helena Rodriguez-Caro,Eleni Giannoulatou,Duncan B Sparrow

doi:10.1038/s41467-021-23660-5

Abstract

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene–environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women.

Highlights

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births
Macroscopic observation at dissection revealed that 12/80 iron deficiency (ID) embryos had died recently (0/58 controls, P = 0.0010) and 26/68 of the surviving ID embryos had significant subcutaneous oedema (0/58 controls, P < 0.0001).To determine the developmental progression of these phenotypes, we examined ID embryos between E9.5 and E14.5 (Fig. 1c)
We show in mice that maternal ID causes severe embryonic cardiovascular defects via premature differentiation of a subset of cardiac progenitor cells

Summary

Introduction

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. In the past 20 years, several populations of cardiac progenitor cells have been identified, and the molecular events driving heart formation in the mammalian embryo have been described in great detail[4] This knowledge provides a scaffold for understanding how environmental factors cause CHD. We and others have described at the molecular level in mice how maternal exposure to hypoxia during gestation[5] or pharmacological activation of HIF1 signalling[6] causes the most common subtype of CHD, cardiac outflow tract (OFT) defects These hypoxia studies were done in animal models and do not replicate any particular clinical condition, and it is uncertain how relevant these findings are to human populations. In support of this hypothesis, we show a strong gene–environment interaction in a mouse model of Down syndrome

Methods

Results

Conclusion