| Popis: |
Objective Metabolic diseases during pregnancy, including obesity and gestational diabetes mellitus (GDM), adversely impact fetal growth and maternal health. Prior work has shown that placentas from pregnancies complicated by GDM exhibit altered expression of iron homeostasis genes and reduced iron uptake in vitro. Using a mouse model of maternal metabolic disease, in which pregnant dams show excess adiposity, glucose intolerance and insulin resistance, we investigated the association of materno-fetal iron handling and placental ferroptosis and stress signalling activation with fetal growth. Methods From day (d)1 of pregnancy, female mice were fed a standard control chow or high fat, high sugar (HFHS) diet. At d16 or d19, tissue iron-levels were determined using a ferrozine-based assay and iron deposition in the placenta measured by Prussian Blue staining. Lipid peroxidation, protein carbonylation and antioxidant capacity were determined using biochemical and/or activity assays. The abundance of ferroptosis and stress kinase-related proteins (ERK, JNK and p38MAPK) were analysed by immunoblotting and expression of iron homeostasis genes were determined by RT-qPCR. Results Fetal weight, placental iron transfer capacity (placental to maternal liver iron content ratio), iron deposition in the maternal decidua and placental ERK2-mediated signalling were reduced by a maternal HFHS diet at d16. In contrast at d19, fetal weight was increased in HFHS-fed mice despite reductions in placental weight, placental iron content and placental expression of iron transporter genes Dmt1, Zip14, and Fpn1. There was also stress kinase activation, namely increased levels of phosphorylated p38MAPK, total ERK and JNK, in the placenta from HFHS-fed mice at d19. Placental oxidative stress was not increased, and antioxidant capacity remained unaffected at either gestational age. There was no effect of the HFHS diet on maternal liver iron levels. Conclusions A maternal HFHS diet during pregnancy impacts fetal growth trajectory in association with changes in placental iron handling, ferroptosis and stress signalling. Downregulation of iron transporter genes in placentas from HFHS mice may protect the fetus from excessive oxidative iron levels, but induces placental iron insufficiency. These findings suggest a role for alterations in placental iron homeostasis in determining perinatal outcomes of pregnancies associated with GDM and/or maternal obesity. |
