Liu Hao, Chen Huijia, Han Ting, Wang Xin, Dai Jingcong, Yang Xiaojia, Chan ShanAn, Cannon Richard D, Yang Yang, Mousa Hatem, Chang Shufang, Chang Ruiqi, Han Ting-Li
Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
The Center for Reproductive Medicine, Department of Obstetrics and Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Heliyon. 2024 Nov 19;10(24):e40515. doi: 10.1016/j.heliyon.2024.e40515. eCollection 2024 Dec 30.
Recurrent spontaneous abortion (RSA) is intricately linked to metabolic dysregulation at the maternal-fetal interface during early gestation. Abnormal levels of essential fatty acids and downstream oxylipins in decidua and chorionic villi have been identified as potential risk factors for RSA. Oxylipins have been linked to excessive inflammation, which might disrupt maternal-fetal immune tolerance, potentially contributing to RSA. Nonetheless, the exact fatty acid-oxylipin metabolic pathway at the matrernal-fetal interface in RSA occurrence remains unknown. Therefore, this research aimed to explore the effect of essential fatty acids, their transport, and downstream oxylipins at the maternal-fetal interface on RSA pathogenesis.
Plasma, chorionic villus, and decidual tissue samples from the first trimester were collected from healthy pregnant women undergoing elective pregnancy terminations, as well as from patients experiencing spontaneous abortion. The concentrations of essential fatty acids and their downstream oxylipins in the villi and decidua were quantified using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS). The expression of enzymes related to metabolic pathways was investigated by q-PCR. The ratios of M1/M2 macrophages were assessed by flow cytometry (FCM).
This study found elevated concentrations of omega-6 fatty acids, encompassing arachidonic acid (AA), linoleic acid (LA), and dihomo-gamma-linolenic acid (DGLA) in maternal plasma and chorionic villi, whereas lower concentrations were observed in the decidua, than in samples from normal pregnancies. Further analysis revealed that the transport of these fatty acids was dysregulated at the maternal-fetal interface in RSA women, possibly due to the aberrant expression of the fatty acid translocase (FAT/CD36). In addition, this study revealed that RSA patients displayed higher levels of downstream oxylipins, such as prostaglandin F2a (PGF2a), prostaglandin E2 (PGE2), and leukotriene B4 (LTB4) in chorionic villi and decidua. These compounds may contribute to M1 inflammatory macrophage polarization in RSA, thereby forming a highly inflammatory environment and influencing immunomodulation at the maternal-fetal interface.
The study revealed alterations in omega-6 fatty acids, CD36 transport, and AA downstream oxylipins in RSA, which in turn promote M1 macrophage polarization. Thus, this research has established a foundation for identifying potential biomarkers for, and providing novel insights into, the diagnosis and pathophysiology of RSA.
复发性自然流产（RSA）与妊娠早期母胎界面的代谢失调密切相关。蜕膜和绒毛膜绒毛中必需脂肪酸及其下游氧化脂质的异常水平已被确定为RSA的潜在危险因素。氧化脂质与过度炎症有关，这可能会破坏母胎免疫耐受，从而可能导致RSA。然而，RSA发生时母胎界面的确切脂肪酸-氧化脂质代谢途径仍不清楚。因此，本研究旨在探讨必需脂肪酸及其转运以及母胎界面处的下游氧化脂质对RSA发病机制的影响。
收集接受选择性妊娠终止的健康孕妇以及自然流产患者孕早期的血浆、绒毛膜绒毛和蜕膜组织样本。使用气相色谱-质谱联用仪（GC-MS）和液相色谱-串联质谱仪（LC-MS）对绒毛和蜕膜中必需脂肪酸及其下游氧化脂质的浓度进行定量。通过q-PCR研究与代谢途径相关的酶的表达。通过流式细胞术（FCM）评估M1/M2巨噬细胞的比例。
本研究发现，与正常妊娠样本相比，孕妇血浆和绒毛膜绒毛中ω-6脂肪酸（包括花生四烯酸（AA）、亚油酸（LA）和二高-γ-亚麻酸（DGLA））的浓度升高，而在蜕膜中的浓度较低。进一步分析表明，RSA女性母胎界面处这些脂肪酸的转运失调，这可能是由于脂肪酸转运蛋白（FAT/CD36）的异常表达所致。此外，本研究表明，RSA患者绒毛膜绒毛和蜕膜中前列腺素F2α（PGF2α）、前列腺素E2（PGE2）和白三烯B4（LTB4）等下游氧化脂质水平较高。这些化合物可能导致RSA中M1炎性巨噬细胞极化，从而形成高度炎性环境并影响母胎界面处的免疫调节。
该研究揭示了RSA中ω-6脂肪酸、CD36转运及AA下游氧化脂质的改变，进而促进M1巨噬细胞极化。因此，本研究为识别RSA的潜在生物标志物以及为其诊断和病理生理学提供新见解奠定了基础。
