Iron-dependent apoptosis causes embryotoxicity in inflamed and obese pregnancy

Because iron is essential for a healthy pregnancy, iron supplementation during pregnancy 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 so may overestimate iron stores during inflammation or infection. We used mouse models to determine whether maternal iron loading, inflammation, or their interaction caused poor pregnancy outcomes. Only maternal exposure to both iron excess and inflammation, but not either condition alone, caused embryo malformations and demise. Maternal iron excess potentiated embryo injury during both LPS-induced acute inflammation and obesity-induced chronic mild inflammation. The adverse interaction was dependent on TNFα signaling, caused apoptosis of the placental and embryo endothelium, and was prevented by anti-TNFα or antioxidant treatment in vivo. Our findings raise important questions about the safety of indiscriminate iron supplementation during pregnancy. Endothelial cells were isolated from placentas from pregnant wildtype (C57BL/6) and hepcidin-1 knockout (on the C57BL/6 background) dams after treatment with water (baseline) or 0.5ug/g lipopolysaccharide (LPS) on E15.5 for 6h. For each condition, we pooled endothelial cells from 5 placentas/pregnant mouse, from 4 different mice per group. For each group we have 4 biological replicates. The total number of samples is 16. Total RNA from placental endothelial cells was isolated and subjected to RNA-Seq.