Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Street, Cambridge, CB2 3EG, UK.
Institute of Biochemistry and Molecular Medicine, University of Bern, Bühlstrasse 28, CH-3012, Bern, Switzerland.
Cell Mol Life Sci. 2024 Mar 25;81(1):151. doi: 10.1007/s00018-024-05192-5.
Obesity and gestational diabetes (GDM) impact fetal growth during pregnancy. Iron is an essential micronutrient needed for energy-intense feto-placental development, but if mis-handled can lead to oxidative stress and ferroptosis (iron-dependent cell death). In a mouse model showing maternal obesity and glucose intolerance, we investigated the association of materno-fetal iron handling and placental ferroptosis, oxidative damage and stress signalling activation with fetal growth. Female mice were fed a standard chow or high fat, high sugar (HFHS) diet during pregnancy and outcomes were measured at day (d)16 or d19 of pregnancy. In HFHS-fed mice, maternal hepcidin was reduced and iron status maintained (tissue iron levels) at both d16 and d19. However, fetal weight, placental iron transfer capacity, iron deposition, TFR1 expression and ERK2-mediated signalling were reduced and oxidative damage-related lipofuscin accumulation in the placenta was increased in HFHS-fed mice. At d19, whilst TFR1 remained decreased, fetal weight was normal and placental weight, iron content and iron transporter genes (Dmt1, Zip14, and Fpn1) were reduced in HFHS-fed mice. Furthermore, there was stress kinase activation (increased phosphorylated p38MAPK, total ERK and JNK) in the placenta from HFHS-fed mice at d19. In summary, a maternal HFHS diet during pregnancy impacts fetal growth trajectory in association with changes in placental iron handling, ferroptosis and stress signalling. Downregulation of placental iron transporters in HFHS mice may protect the fetus from excessive oxidative iron. These findings suggest a role for alterations in placental iron homeostasis in determining perinatal outcomes of pregnancies associated with GDM and/or maternal obesity.
肥胖和妊娠期糖尿病（GDM）会影响胎儿在孕期的生长。铁是胎儿-胎盘发育所需的一种必需微量营养素，但如果处理不当，会导致氧化应激和铁死亡（铁依赖性细胞死亡）。在一个表现出母体肥胖和葡萄糖不耐受的小鼠模型中，我们研究了母胎铁处理与胎盘铁死亡、氧化损伤和应激信号激活与胎儿生长的关联。在妊娠期间，雌性小鼠分别喂食标准食物或高脂肪、高糖（HFHS）饮食，在妊娠第 16 天或第 19 天测量结果。在 HFHS 喂养的小鼠中，母鼠的铁调素减少，铁状态在第 16 天和第 19 天都保持不变（组织铁水平）。然而，HFHS 喂养的小鼠的胎儿体重、胎盘铁转运能力、铁沉积、TFR1 表达和 ERK2 介导的信号均降低，并且胎盘内与氧化损伤相关的脂褐素积累增加。在第 19 天，尽管 TFR1 仍然降低，但胎儿体重正常，胎盘重量、铁含量和铁转运蛋白基因（Dmt1、Zip14 和 Fpn1）在 HFHS 喂养的小鼠中减少。此外，在 HFHS 喂养的小鼠的胎盘中还存在应激激酶激活（磷酸化 p38MAPK、总 ERK 和 JNK 增加）。总之，妊娠期间的母体 HFHS 饮食会影响胎儿的生长轨迹，与胎盘铁处理、铁死亡和应激信号的变化有关。HFHS 小鼠中胎盘铁转运蛋白的下调可能会保护胎儿免受过度氧化的铁的影响。这些发现表明，胎盘铁稳态的改变可能在决定与 GDM 和/或母体肥胖相关的妊娠的围产期结局方面发挥作用。
