The Impact of Iron Overload and Ferroptosis on Reproductive Disorders in Humans: Implications for Preeclampsia.

Errol R. Norwitz,Shu-Wing Ng,Sam G. Norwitz

doi:10.3390/ijms20133283

Abstract

Iron is an essential element for the survival of most organisms, including humans. Demand for iron increases significantly during pregnancy to support growth and development of the fetus. Paradoxically, epidemiologic studies have shown that excessive iron intake and/or high iron status can be detrimental to pregnancy and is associated with reproductive disorders ranging from endometriosis to preeclampsia. Reproductive complications resulting from iron deficiency have been reviewed elsewhere. Here, we focus on reproductive disorders associated with iron overload and the contribution of ferroptosis—programmed cell death mediated by iron-dependent lipid peroxidation within cell membranes—using preeclampsia as a model system. We propose that the clinical expressions of many reproductive disorders and pregnancy complications may be due to an underlying ferroptopathy (elemental iron-associated disease), characterized by a dysregulation in iron homeostasis leading to excessive ferroptosis.

Highlights

Iron is the most common transition metal in living cells
We present a hypothesis that may explain the underlying molecular basis for excess iron-mediated disorders of women’s health and reproduction, using preeclampsia (PE) as a model system. We hypothesize that such reproductive disorders represent an underlying ferroptopathy characterized by a dysregulation in iron homeostasis leading to excessive ferroptosis, a recently described process of programmed cell death mediated by iron-dependent lipid peroxidation of cell membranes
We propose that some pregnancies generate an exaggerated response to the acute surge in oxygen and iron caused by the physiologic hypoxia/reperfusion event that occurs in all pregnancies at 8–10 weeks of gestation resulting in cell mIenmt

Summary

Introduction

Iron is the most common transition metal in living cells. An average person requires 20 mg of elemental iron each day just to make enough erythrocytes (red blood cells) [1]. The average daily iron requirement in pregnancy increases to around 1000–1200 mg to meet the maternal and feto-placental need for erythropoiesis, growth, and development [3]. Iron-deficiency anemia is the most common nutritional deficiency worldwide, and is associated with pregnancy complications such as low birthweight (LBW) and preterm birth (PTB), as well as impaired neurodevelopment and immune function in infants, children, and adolescents [4,5]. For these reasons, much attention has focused on preventing iron-deficiency anemia, and iron supplementation has become a routine recommendation for all women throughout pregnancy. We hypothesize that such reproductive disorders represent an underlying ferroptopathy characterized by a dysregulation in iron homeostasis leading to excessive ferroptosis, a recently described process of programmed cell death mediated by iron-dependent lipid peroxidation of cell membranes

Regulation of Systemic Iron Homeostasis

Impact of Dysregulated Iron Homeostasis on Reproductive Outcomes

Maternal Iron Status and Preeclampsia

Molecular Basis for Dysregulated Iron Homeostasis in Preeclampsia

Findings

Conclusions