Characteristics of placental metabolism based on untargeted metabolomics in preeclampsia-like phenotype mouse
LIU Xiaojing, ZHANG Ziyi, ZHANG Le, LI Zhiwen, YE Rongwei, LI Nan
Department of Epidemiology and Biostatistics, School of Public Health, Peking University; Institute of Reproductive and Child Health, National Health Commission Key Laboratory of Reproductive Health, Peking University, Beijing 100191, China
摘要目的 基于非靶向代谢组学研究胎盘差异代谢物在子痫前期中的作用机制。方法 将健康ICR孕鼠分为子痫前期模型组(n=13)和对照组(n=8),在孕第7.5~17.5天腹腔注射脂多糖和生理盐水,收集产时的胎盘样本,通过超高效液相色谱-质谱联用技术非靶向检测胎盘的代谢物水平,与对照组比较得到潜在的差异代谢物并经Kyoto Encyclopedia of Genes and Genomes(KEGG)数据库富集其代谢通路。结果 相比于对照组,模型组孕鼠发生明显的流产和死产,每窝活产胎鼠的数量和重量分别降低39.4%(P<0.01)和17.2%(P<0.01);孕第15.5和18.5天的收缩压分别升高12.1(P<0.05)和20.2(P<0.01)mmHg;同时尿蛋白/肌酐的比值显著上升(P<0.05)。表明脂多糖诱导孕鼠出现不良妊娠结局、血压升高以及蛋白尿的子痫前期样表型。模型组孕鼠的胎盘中共鉴定到50种潜在的差异代谢物,其中上调的有28种,以甘油磷脂、酰基肉碱和白三烯B4为主;下调的有22种,主要包括水苏碱、丙酮酸和葫芦巴碱等组分。差异代谢物主要涉及苯丙氨酸、酪氨酸和色氨酸生物合成,泛酸和辅酶A生物合成,以及烟酸和烟酰胺代谢等通路。结论 胎盘异常代谢物可能通过炎症反应、能量合成、脂肪酸和氨基酸代谢而诱发子痫前期的发生。
Abstract：Objective To study the mechanism of different placental metabolites in the occurrence of preeclampsia based on untargeted metabolomics.Methods ICR pregnant mice were classified into preeclampsia model group (n=13) and control group (n=8), which were treated by intraperitoneal injection of lipopolysaccharide and saline at gestational day (GD) 7.5-17.5. The placental tissues were collected at GD 18.5. Ultra-performance liquid chromatography-mass spectrometry was used to detect placental metabolites of preeclampsia-like phenotype mice, and to obtain different metabolites by comparing with the control group. We further annotated metabolic pathways of the different placental metabolites in Kyoto Encyclopedia of Genes and Genomes (KEGG) database.Results Pregnant mice in preeclampsia model group showed various adverse pregnancy outcomes including the increased number of abortion and stillbirths. The number and birth weight of live fetus per litter deceased by 39.4% (P<0.01) and 17.2% (P<0.01) compared to the control group. The systolic blood pressure of pregnant mice in preeclampsia model group increased by 12.1mmHg at GD15.5 (P<0.05) plus 20.2 mmHg at GD18.5 (P<0.01), and the ratio of urine protein/creatinine increased significantly in the model group (P<0.05). The above results indicated lipopolysaccharide induced preeclampsia-like phenotype including adverse pregnancy outcomes, increased blood pressure and proteinuria, respectively. We found a total of 50 differential metabolites in the placenta. There were 28 up-regulated metabolites including phosphoglyceride, acyl carnitine and leukotrienes B4, as well as 22 down-regulated metabolites including stachydrine, pyruvate and trigonelline. The main pathways involved the biosynthesis of phenylalanine, tyrosine, tryptophan, pantothenate and CoA, as well as the metabolism of nicotinate and nicotinamide.Conclusion Abnormal metabolites in the placenta involved in the development preeclampsia through inflammation response, energy biosynthesis, fatty acid and amino acid metabolism.
刘晓静, 张子怡, 张乐, 李智文, 叶荣伟, 李楠. 子痫前期小鼠的胎盘非靶向代谢组学特征研究[J]. 中国生育健康杂志, 2023, 34(2): 107-113.
LIU Xiaojing, ZHANG Ziyi, ZHANG Le, LI Zhiwen, YE Rongwei, LI Nan. Characteristics of placental metabolism based on untargeted metabolomics in preeclampsia-like phenotype mouse. Chinese Journal of Reproductive Health, 2023, 34(2): 107-113.
1 中华医学会妇产科学分会妊娠期高血压疾病学组,妊娠期高血压疾病诊治指南(2020).中华妇产科杂志,2020,55:227-238. 2 Chappell LC,Cluver CA,Kingdom J,et al.Pre-eclampsia.Lancet,2021,398:341-354. 3 Duley L.The global impact of pre-eclampsia and eclampsia.Semin Perinatol,2009,33:130-137. 4 吕莉娟,段红丽,李慧,等.子痫前期对子代远期不良影响.中华围产医学杂志,2019,5:357-360. 5 Yang Y,Le Ray I,Zhu J,et al.Preeclampsia Prevalence,Risk Factors,and Pregnancy Outcomes in Sweden and China.JAMA Netw Open,2021,4:e218401. 6 Xiao J,Shen F,Xue Q,et al.Is ethnicity a risk factor for developing preeclampsia? An analysis of the prevalence of preeclampsia in China.J Hum Hypertens,2014,28:694-698. 7 Hoang G,Udupa S,Le A.Application of metabolomics technologies toward cancer prognosis and therapy.Int Rev Cell Mol Biol,2019,347:191-223. 8 Nalbantoglu S,Karadag A.Metabolomics bridging proteomics along metabolites/oncometabolites and protein modifications:Paving the way toward integrative multiomics.J Pharm Biomed Anal,2021,199:114031. 9 Stanley JL,Karolina S,Irene JA,et al.Sildenafil Therapy Normalizes the Aberrant Metabolomic Profile in theComt(-/-) Mouse Model of Preeclampsia/Fetal Growth Restriction Sci Rep,2015,5:18241. 10 Stojanovska V,Dijkstra DJ,Vogtmann R,et al.A double-hit pre-eclampsia model results in sex-specific growth restriction patterns.Dis Model Mech,2019,12:dmm035980. 11 Morillon AC,Williamson RD,Baker PN,et al.Effect of L-Ergothioneine on the metabolic plasma profile of the RUPP rat model of pre-eclampsia.PLoS One,2020,15:e0230977. 12 Sato E,Tsunokuni Y,Kaneko M,et al.Metabolomics of a mouse model of preeclampsia induced by overexpressing soluble fms-like tyrosine kinase 1.Biochem Biophys Res Commun,2020,527:1064-1071. 13 McClements L,Richards C,Patel N,et al.Impact of reduced uterine perfusion pressuremodel of preeclampsia on metabolism of placenta,maternal and fetal hearts.Sci Rep,2022,12:1111. 14 Li G,Wei W,Suo L,et al.Low-Dose Aspirin Prevents Kidney Damage in LPS-Induced Preeclampsia by Inhibiting the WNT5A and NF-κB Signaling Pathways.Front Endocrinol,2021,11:639592. 15 Roberts JM,Hubel CA.Thetwo stage model of preeclampsia:variations on the theme.Placenta,2009,30:32-37. 16 Hossain MS,Mineno K,Katafuchi,T.Neuronal Orphan G-Protein Coupled Receptor Proteins Mediate Plasmalogens-Induced Activation of ERK and Akt Signaling.PLoS One,2016,11:e0150846. 17 Farooqui AA,Horrocks LA,Farooqui T.Interactions between neural membrane glycerophospholipid and sphingolipid mediators:a recipe for neural cell survival or suicide.J Neurosci Res,2007,85:1834-1850. 18 Sang Y,Roest M,de Laat B,et al.Interplay between platelets and coagulation.Blood Rev,2021,46:100733. 19 Konyshev VA,Marokko IN,Shaternikov VA.Arachidonic acid metabolites,leukotrienes--mediators of hypersensitivity and inflammation.Nauchnye Doki Vyss Shkoly Biol Nauki,1985,12:14-24. 20 Szczuko M,Kikut J,Komorniak N,et al.The Role of Arachidonic and Linoleic Acid Derivatives in Pathological Pregnancies and the Human Reproduction Process.Int J Mol Sci,2020,21:9628. 21 Francois H,Coffman TM.Prostanoids and blood pressure:which way is up?.J Clin Invest,2004,114:757-759. 22 Yao K,Fang J,Yin YL,et al.Tryptophan metabolism in animals:important roles in nutrition and health.Front Biosci (Schol Ed),2011,3:286-297. 23 张静,王宇光.多巴胺在子痫前期及妊娠期高血压中的作用及其研究的进展.心血管康复医学杂志,2022,31:111-114. 24 Nikas IP,Paschou SA,Ryu HS.The Role of Nicotinamide in Cancer Chemoprevention and Therapy.Biomolecules,2020,10:477-497. 25 Naquet P,Kerr EW,Vickers SD,et al.Regulation of coenzyme A levels by degradation:the 'Ins and Outs'.Prog Lipid Res,2020,78:101028. 26 Pekala J,Patkowska-Sokola B,Bodkowski R,et al.L-carnitine--metabolic functions and meaning in humans life.Curr Drug Metab,2011,12:667-678. 27 董升栋,杨祖菁.子痫前期与血肉碱关系的研究.山西医药杂志,2009,38:494-496.
