Szczuko Małgorzata, Kikut Justyna, Komorniak Natalia, Bilicki Jacek, Celewicz Zbigniew, Ziętek Maciej
Department of Human Nutrition and Metabolomics, Pomeranian Medical University, Broniewskiego 24 Street, 71-460 Szczecin, Poland.
Department of Neurosurgery and Pediatric Neurosurgery, Pomeranian Medical University, Unii Lubelskiej 1 Street, 71-252 Szczecin, Poland.
Int J Mol Sci. 2020 Dec 17;21(24):9628. doi: 10.3390/ijms21249628.
The aim of the available literature review was to focus on the role of the proinflammatory mediators of AA and LA derivatives in pathological conditions related to reproduction and pregnancy. Arachidonic (AA) and linoleic acid (LA) derivatives play important roles in human fertility and the course of pathological pregnancies. Recent studies have demonstrated that uncontrolled inflammation has a significant impact on reproduction, spermatogenesis, endometriosis, polycystic ovary syndrome (PCOS) genesis, implantation, pregnancy and labor. In addition, cyclooxygenase-mediated prostaglandins and AA metabolite levels are higher in women's ovarian tissue when suffering from PCOS. It has been demonstrated that abnormal cyclooxygenase-2 (COX-2) levels are associated with ovulation failure, infertility, and implantation disorders and the increase in 9-HODE/13-HODE was a feature recognized in PCOS patients. Maintaining inflammation without neutrophil participation allows pregnant women to tolerate the fetus, while excessive inflammatory activation may lead to miscarriages and other pathological complications in pregnancies. Additionally AA and LA derivatives play an important role in pregnancy pathologies, e.g., gestational diabetes mellitus, preeclampsia (PE), and fetal growth, among others. The pathogenesis of PE and other pathological states in pregnancy involving eicosanoids have not been fully identified. A significant expression of 15-LOX-1,2 was found in women with PE, leading to an increase in the synthesis of AA and LA derivatives, such as hydroxyeicozatetraenoic acids (HETE) and hydroxyoctadecadiene acids (HODE). Synthesis of the metabolites 5-, 8-, 12-, and 15-HETE increased in the placenta, while 20-HETE increased only in umbilical cord blood in women with preeclampsia compared to normal pregnancies. In obese women with gestational diabetes mellitus (GDM) an increase in epoxygenase products in the cytochrome P450 (CYP) and the level of 20-HETE associated with the occurrence of insulin resistance (IR) were found. In addition, 12- and 20-HETE levels were associated with arterial vasoconstriction and epoxyeicosatrienoic acids (EETs) with arterial vasodilatation and uterine relaxation. Furthermore, higher levels of 5- and 15-HETE were associated with premature labor. By analyzing the influence of free fatty acids (FFA) and their derivatives on male reproduction, it was found that an increase in the AA in semen reduces its amount and the ratio of omega-6 to omega-3 fatty acids showed higher values in infertile men compared to the fertile control group. There are several studies on the role of HETE/HODE in relation to male fertility. 15-Hydroperoxyeicosatetraenoic acid may affect the integrity of the membrane and sperm function. Moreover, the incubation of sperm with physiologically low levels of prostaglandins (PGE2/PGF2α) improves the functionality of human sperm. Undoubtedly, these problems are still insufficiently understood and require further research. However, HETE and HODE could serve as predictive and diagnostic biomarkers for pregnancy pathologies (especially in women with risk factors for overweight and obesity). Such knowledge may be helpful in finding new treatment strategies for infertility and the course of high-risk pregnancies.
现有文献综述的目的是聚焦于花生四烯酸（AA）和亚油酸（LA）衍生物的促炎介质在与生殖和妊娠相关的病理状况中的作用。花生四烯酸（AA）和亚油酸（LA）衍生物在人类生育能力及病理妊娠过程中发挥着重要作用。近期研究表明，不受控制的炎症对生殖、精子发生、子宫内膜异位症、多囊卵巢综合征（PCOS）的发生、着床、妊娠及分娩均有显著影响。此外，患有PCOS的女性卵巢组织中，环氧化酶介导的前列腺素和AA代谢产物水平较高。已证实，环氧化酶-2（COX-2）水平异常与排卵障碍、不孕及着床障碍相关，且9-羟基十八碳二烯酸/13-羟基十八碳二烯酸（9-HODE/13-HODE）升高是PCOS患者的一个特征。在无中性粒细胞参与的情况下维持炎症反应可使孕妇耐受胎儿，而过度的炎症激活可能导致妊娠流产及其他病理并发症。此外，AA和LA衍生物在妊娠病理状况中也发挥着重要作用，例如妊娠期糖尿病、先兆子痫（PE）及胎儿生长等。PE及其他涉及类二十烷酸的妊娠病理状态的发病机制尚未完全明确。在患有PE的女性中发现15-脂氧合酶-1、2有显著表达，导致AA和LA衍生物如羟基二十碳四烯酸（HETE）和羟基十八碳二烯酸（HODE）的合成增加。与正常妊娠相比，先兆子痫女性胎盘组织中5-、8-、12-和15-HETE的代谢产物合成增加，而20-HETE仅在脐血中增加。在患有妊娠期糖尿病（GDM）的肥胖女性中，发现细胞色素P450（CYP）中环氧化酶产物增加以及与胰岛素抵抗（IR）发生相关的20-HETE水平升高。此外，12-和20-HETE水平与动脉血管收缩相关，而环氧二十碳三烯酸（EETs）与动脉血管舒张及子宫松弛相关。此外，较高水平的5-和15-HETE与早产相关。通过分析游离脂肪酸（FFA）及其衍生物对男性生殖的影响，发现精液中AA增加会减少其含量，且与生育对照组相比，不育男性中ω-6与ω-3脂肪酸的比例更高。关于HETE/HODE在男性生育能力方面的作用有多项研究。15-氢过氧化二十碳四烯酸可能影响细胞膜完整性及精子功能。此外，用生理水平低的前列腺素（PGE2/PGF2α）孵育精子可改善人类精子的功能。毫无疑问，这些问题仍未得到充分理解，需要进一步研究。然而，HETE和HODE可作为妊娠病理状况（尤其是有超重和肥胖风险因素的女性）的预测和诊断生物标志物。此类知识可能有助于找到治疗不孕及高危妊娠过程的新策略。
