Iron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy

Allison L. Fisher, Veena Sangkhae, Kamila Balušíková, Nicolaos J. Palaskas, Tomas Ganz and Elizabeta Nemeth ()
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Allison L. Fisher: Molecular, Cellular & Integrative Physiology Graduate Program, University of California, Los Angeles
Veena Sangkhae: Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles
Kamila Balušíková: Cell and Molecular Biology & Center for Research of Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University
Nicolaos J. Palaskas: Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles
Tomas Ganz: Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles
Elizabeta Nemeth: Center for Iron Disorders, David Geffen School of Medicine, University of California, Los Angeles

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Iron is essential for a healthy pregnancy, and iron supplementation is nearly universally recommended, regardless of maternal iron status. A signal of potential harm is the U-shaped association between maternal ferritin, a marker of iron stores, and risk of adverse pregnancy outcomes. However, ferritin is also induced by inflammation and may overestimate iron stores during inflammation or infection. In this study, we use mouse models to determine whether maternal iron loading, inflammation, or their interaction cause poor pregnancy outcomes. Only maternal exposure to both iron excess and inflammation, but not either condition alone, causes embryo malformations and demise. Maternal iron excess potentiates embryo injury during both LPS-induced acute inflammation and obesity-induced chronic mild inflammation. The adverse interaction depends on TNFα signaling, causes apoptosis of placental and embryo endothelium, and is prevented by anti-TNFα or antioxidant treatment. Our findings raise important questions about the safety of indiscriminate iron supplementation during pregnancy.

Date: 2021
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DOI: 10.1038/s41467-021-24333-z

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