Department of Pathology, Boston Children's Hospital, Boston, MA, USA.
Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
J Nutr. 2021 May 11;151(5):1073-1083. doi: 10.1093/jn/nxab005.
Maternal iron deficiency (ID) is associated with poor pregnancy and fetal outcomes. The effect is thought to be mediated by the placenta but there is no comprehensive assessment of placental responses to maternal ID. Additionally, whether the influence of maternal ID on the placenta differs by fetal sex is unknown.
To identify gene and protein signatures of ID mouse placentas at mid-gestation. A secondary objective was to profile the expression of iron genes in mouse placentas across gestation.
We used a real-time PCR-based array to determine the mRNA expression of all known iron genes in mouse placentas at embryonic day (E) 12.5, E14.5, E16.5, and E19.5 (n = 3 placentas/time point). To determine the effect of maternal ID, we performed RNA sequencing and proteomics in male and female placentas from ID and iron-adequate mice at E12.5 (n = 8 dams/diet).
In female placentas, 6 genes, including transferrin receptor (Tfrc) and solute carrier family 11 member 2, were significantly changed by maternal ID. An additional 154 genes were altered in male ID placentas. A proteomic analysis quantified 7662 proteins in the placenta. Proteins translated from iron-responsive element (IRE)-containing mRNA were altered in abundance; ferritin and ferroportin 1 decreased, while TFRC increased in ID placentas. Less than 4% of the significantly altered genes in ID placentas occurred both at the transcriptional and translational levels.
Our data demonstrate that the impact of maternal ID on placental gene expression in mice is limited in scope and magnitude at mid-gestation. We provide strong evidence for IRE-based transcriptional and translational coordination of iron gene expression in the mouse placenta. Finally, we discover sexually dimorphic effects of maternal ID on placental gene expression, with more genes and pathways altered in male compared with female mouse placentas.
母体缺铁（ID）与不良妊娠和胎儿结局有关。这种影响被认为是由胎盘介导的，但目前还没有对母体 ID 对胎盘反应的全面评估。此外，母体 ID 对胎盘的影响是否因胎儿性别而异尚不清楚。
确定中期 ID 小鼠胎盘的基因和蛋白质特征。次要目标是分析小鼠胎盘在整个妊娠过程中铁基因的表达情况。
我们使用实时 PCR 阵列来确定 E12.5、E14.5、E16.5 和 E19.5 （n = 3 个胎盘/时间点）胚胎日（E）小鼠胎盘所有已知铁基因的 mRNA 表达。为了确定母体 ID 的影响，我们在 E12.5 时对 ID 和铁充足的雄性和雌性小鼠的胎盘进行了 RNA 测序和蛋白质组学分析（n = 8 个母体/饮食）。
在雌性胎盘中，有 6 个基因，包括转铁蛋白受体（Tfrc）和溶质载体家族 11 成员 2，受到母体 ID 的显著改变。雄性 ID 胎盘中还有 154 个基因发生改变。蛋白质组学分析定量了胎盘中的 7662 种蛋白质。含有铁反应元件（IRE）的 mRNA 翻译的蛋白质丰度发生改变；铁蛋白和亚铁转运蛋白 1 减少，而 ID 胎盘中 TFRC 增加。在 ID 胎盘中，转录和翻译水平均发生显著改变的基因不到 4%。
我们的数据表明，在妊娠中期，母体 ID 对小鼠胎盘基因表达的影响范围和程度有限。我们为铁基因在小鼠胎盘中的 IRE 基于转录和翻译协调提供了强有力的证据。最后，我们发现母体 ID 对胎盘基因表达存在性别二态性影响，与雌性小鼠胎盘相比，雄性小鼠胎盘中改变的基因和途径更多。
