Hernández Marta Hita, Santos Esther Dos, Rodriguez Yoann, Ferchaud-Roucher Véronique, Rousseau-Ralliard Delphine, Frambourg Anne, Berveiller Paul, Vialard François, Couturier-Tarrade Anne, Dieudonne Marie-Noëlle
Université Paris-Saclay, UVSQ, INRAE, BREED, 78350, Jouy-en-Josas, France; Ecole Nationale Vétérinaire d'Alfort, BREED, 94700, Maisons-Alfort, France.
Université Paris-Saclay, UVSQ, INRAE, BREED, 78350, Jouy-en-Josas, France; Ecole Nationale Vétérinaire d'Alfort, BREED, 94700, Maisons-Alfort, France; Service de Biologie Médicale, Centre Hospitalier de Poissy-Saint-Germain, Poissy, France.
Mol Cell Endocrinol. 2025 Oct 1;608:112640. doi: 10.1016/j.mce.2025.112640. Epub 2025 Aug 6.
Although maternal obesity influences placental and fetal development, the underlying molecular mechanisms have yet to be determined. Oxidative and inflammatory status at the fetal-placental unit appear to be involved in the early fetal metabolic programming. The objective of the present study is to reveal a potential role of sphingolipids in stablishing an oxidative and inflammatory status in the maternal-placental-fetal unit, as function of fetal sex. Term placenta and maternal and fetal plasma were collected from lean (BMI 18-25 kg/m) and obese women (BMI 30-40 kg/m) without gestational diabetes aged from 20 to 40 having undergone a cesarean section. Firstly, key markers of oxidative stress and inflammation were studied with immunoblotting and biochemical assays. Secondly, the maternal-placental-fetal unit's sphingolipid profile was determined by mass spectrometry. Lastly, the placental samples' transcriptome was analyzed by RNA sequencing. Obese mothers showed lower plasma levels of ceramide Cer 20:0 (p = 0.02). Surprisingly, placental ceramide content was not influenced by maternal obesity. Nevertheless, male placentas from obese women showed a higher sphingomyelin content and hypo-inflammation as showed by RNAseq. Both males and female placentas from obese women showed higher levels of oxidative stress as showed by the oxidative stress markers (protein carbonylation and lipid peroxidation). However, RNAseq revealed an upregulation of oxidative stress mechanisms only in female placentas. Whatever the newborn's sex, maternal obesity was associated with higher fetal plasma oxidative stress. In conclusion, our results revealed sex-specific features in the placental transcriptome, highlighted placental metabolic adaptations, and provided insights into the underlying molecular mechanisms of fetal programming.
尽管母体肥胖会影响胎盘和胎儿发育，但其潜在的分子机制尚未确定。胎儿 - 胎盘单位的氧化和炎症状态似乎参与了早期胎儿代谢编程。本研究的目的是揭示鞘脂在建立母 - 胎盘 - 胎儿单位氧化和炎症状态中的潜在作用，作为胎儿性别的函数。从20至40岁、未患妊娠糖尿病且接受剖宫产的体重正常（BMI 18 - 25 kg/m）和肥胖女性（BMI 30 - 40 kg/m）中收集足月胎盘以及母体和胎儿血浆。首先，通过免疫印迹和生化分析研究氧化应激和炎症的关键标志物。其次，通过质谱法测定母 - 胎盘 - 胎儿单位的鞘脂谱。最后，通过RNA测序分析胎盘样本的转录组。肥胖母亲的血浆神经酰胺Cer 20:0水平较低（p = 0.02）。令人惊讶的是，胎盘神经酰胺含量不受母体肥胖的影响。然而，肥胖女性的雄性胎盘显示出较高的鞘磷脂含量和RNA测序显示的炎症减轻。肥胖女性的雄性和雌性胎盘均显示出氧化应激标志物所显示的较高氧化应激水平。然而，RNA测序显示仅在雌性胎盘中氧化应激机制上调。无论新生儿性别如何，母体肥胖都与胎儿血浆氧化应激增加有关。总之，我们的结果揭示了胎盘转录组中的性别特异性特征，突出了胎盘代谢适应性，并为胎儿编程的潜在分子机制提供了见解。
