Iron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy

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.

Inhibition of Heme Oxygenase-1 by Zinc Protoporphyrin IX Improves Adverse Pregnancy Outcomes in Malaria During Early Gestation

“…In this sense, Fisher et al. ( 74 ) demonstrated that iron overload causes increased expression of HO-1 in placental endothelial cells, and exposure to iron overload and inflammation have a synergistic effect on the induction of oxidative stress and cell death in a TNF-α-dependent manner. In fact, increased levels of circulating TNF have been associated with fetal loss in the first trimester of human pregnancy ( 75 ).…”

Iron Metabolism in Normal and Pathological Pregnancies and Fetal Consequences

“…Furthermore, TNF-α is produced by adipose tissue and its secretion correlates with the degree of adiposity [144]. In a model of obese pregnant mice, Fisher et al showed that excess iron promotes TNF-α production and embryotoxicity [6].…”

“…However, excess iron generates reactive oxygen species through the Fenton reaction [2], leading to cellular and tissue injury [3,4]. This can ultimately lead to cell death by ferroptosis [5] or iron-dependent apoptosis [6]. Both excess iron and iron deficiency can be observed in humans.…”

Association of low birthweight and small for gestational age with maternal ferritin levels: A retrospective cohort study in China

“…Serum ferritin is a protein that indicates the level of iron reserve in the body ( 3 ). Poor ferritin level is a common nutritional problem during pregnancy and is associated with inadequate intake anemia or certain chronic diseases ( 4 ). Ferritin itself has important physiological activities which is not only a carrier of iron ( 3 ).…”

“…Iron, on the other hand, is a powerful pro-oxidant that catalyzes the production of reactive oxidative species (ROS) ( 5 ). Excess iron intake can lead to impaired placenta function because of oxidative damage ( 4 ). Existing epidemiological evidence demonstrates that higher serum ferritin is associated with an increased risk of LBW in late pregnancy ( 6 ).…”