{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T23:50:11Z","timestamp":1792021811995,"version":"4.4.0"},"reference-count":45,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,16]],"date-time":"2024-09-16T00:00:00Z","timestamp":1726444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81973596"],"award-info":[{"award-number":["81973596"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82204789"],"award-info":[{"award-number":["82204789"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Maternal stress experienced during prenatal development is recognized as a significant risk factor for neurodevelopmental and neuropsychiatric disorders across the offspring\u2019s lifespan. The placental barrier serves a crucial function in safeguarding the fetus from detrimental exposures during gestation. However, previous investigations have not yet comprehensively elucidated the extensive connections between prenatal stress and the expression of placental proteins. In this study, we used iTRAQ-based quantitative proteomics to elucidate the placental adaptive mechanisms of pregnant rats in response to fear-induced stress. Our results showed that during pregnancy, exposure to fear-induced stress led to a pathological hypercoagulable state in the mother\u2019s body. Placental circulation was also disrupted, significantly reducing placental efficiency and blood oxygen saturation in newborn rats. Proteomic analyses showed that most of the DEPs were annotated to the PI3K-Akt and ECM-receptor interaction signaling pathway. In addition, the expressions of CDC37, HSP90\u03b2, AKT, p-AKT and p-mTOR were down-regulated significantly in the placenta. Our results demonstrated that prenatal fear-induced stress led to inhibition of the cellular signal transduction of placental PI3K\/AKT\/mTOR, which affected biological processes such as rRNA processing, translation, protein folding, protein stability, and oxygen transport in the placenta. These abnormalities in biological functions could potentially damage the barrier function of the placenta and thereby result in abnormal development in the offspring.<\/jats:p>","DOI":"10.3390\/ijms25189978","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T01:52:31Z","timestamp":1726624351000},"page":"9978","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["ITRAQ Based Proteomics Reveals the Potential Mechanism of Placental Injury Induced by Prenatal Stress"],"prefix":"10.3390","volume":"25","author":[{"given":"Yujie","family":"Li","sequence":"first","affiliation":[{"name":"Department of Biochemistry, School of Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junlin","family":"Hou","sequence":"additional","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, School of Traditional Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2528-0729","authenticated-orcid":false,"given":"Liping","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, School of Traditional Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, School of Traditional Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, School of Traditional Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7778-2264","authenticated-orcid":false,"given":"Zhixing","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, School of Traditional Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huizi","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, School of Traditional Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gai","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, School of Traditional Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianghui","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Integrated Traditional Chinese and Western Medicine, School of Traditional Medicine, Henan University of Chinese Medicine, Zhengzhou 450046, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ping","family":"Chen","sequence":"additional","affiliation":[{"name":"Gynaecology and Obstetrics, College of First Clinical Medical, Henan University of Chinese Medicine, Zhengzhou 450003, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.biopsych.2017.10.005","article-title":"Parental Advisory: Maternal and Paternal Stress Can Impact Offspring Neurodevelopment","volume":"83","author":"Chan","year":"2018","journal-title":"Biol. Psychiatry"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Li, Y.J., Yang, L.P., Hou, J.L., Li, X.M., Chen, L., Zhu, J.H., Wang, Q.Y., Li, G., Zhao, P.Y., and Liu, X.H. (2020). Prenatal Stress Impairs Postnatal Learning and Memory Development via Disturbance of the cGMP-PKG Pathway and Oxidative Phosphorylation in the Hippocampus of Rats. Front. Mol. Neurosci., 13.","DOI":"10.3389\/fnmol.2020.00158"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Dahlerup, B.R., Egsmose, E.L., Siersma, V., Mortensen, E.L., Hedegaard, M., Knudsen, L.E., and Mathiesen, L. (2018). Maternal stress and placental function, a study using questionnaires and biomarkers at birth. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0207184"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.neubiorev.2017.07.003","article-title":"Prenatal developmental origins of behavior and mental health: The influence of maternal stress in pregnancy","volume":"117","author":"Lahti","year":"2020","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Mathiesen, L., Bay-Richter, C., Wegener, G., Liebenberg, N., and Knudsen, L.E. (2020). Maternal stress and placental function; ex vivo placental perfusion studying cortisol, cortisone, tryptophan and serotonin. PLoS ONE, 15.","DOI":"10.1371\/journal.pone.0233979"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Lund, R.J., Kyl\u00e4niemi, M., Pettersson, N., Kaukonen, R., Konki, M., Scheinin, N.M., Karlsson, L., Karlsson, H., and Ekholm, E. (2021). Placental DNA methylation marks are associated with maternal depressive symptoms during early pregnancy. Neurobiol. Stress, 15.","DOI":"10.1016\/j.ynstr.2021.100374"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Wang, Q., Pan, M., Zhang, T., Jiang, Y., Zhao, P., Liu, X., Gao, A., Yang, L., and Hou, J. (2022). Fear Stress During Pregnancy Affects Placental m6A-Modifying Enzyme Expression and Epigenetic Modification Levels. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.927615"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Aushev, V.N., Li, Q., Deyssenroth, M., Zhang, W., Finik, J., Hurd, Y.L., Nomura, Y., and Chen, J. (2021). Placental gene network modules are associated with maternal stress during pregnancy and infant temperament. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol., 35.","DOI":"10.1096\/fj.202100144RRR"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.1016\/j.molcel.2024.02.037","article-title":"FAM86A methylation of eEF2 links mRNA translation elongation to tumorigenesis","volume":"84","author":"Francis","year":"2024","journal-title":"Mol. Cell"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3295","DOI":"10.1111\/1759-7714.15121","article-title":"Identification of a coagulation-related signature correlated with immune infiltration and their prognostic implications in lung adenocarcinoma","volume":"14","author":"Yang","year":"2023","journal-title":"Thorac. Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/j.bbrc.2023.06.076","article-title":"Proliferation, migration, and resistance to oxidative and thermal stresses of HT1080 cells with knocked out genes encoding Hsp90\u03b1 and Hsp90\u03b2","volume":"674","author":"Petrenko","year":"2023","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1038\/s41417-024-00806-3","article-title":"CCT6A promotes cell proliferation in colon cancer by targeting BIRC5 associated with p53 status","volume":"31","author":"Zhang","year":"2024","journal-title":"Cancer Gene Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1111\/acps.12996","article-title":"The association between subjective maternal stress during pregnancy and offspring clinically diagnosed psychiatric disorders","volume":"139","author":"Brannigan","year":"2019","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Jensen Pena, C., Monk, C., and Champagne, F.A. (2012). Epigenetic effects of prenatal stress on 11beta-hydroxysteroid dehydrogenase-2 in the placenta and fetal brain. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039791"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.ando.2016.04.002","article-title":"Neuroendocrine control of maternal behavior in non-human and human mammals","volume":"77","year":"2016","journal-title":"Ann. D\u2019endocrinologie"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1055\/s-2003-38897","article-title":"Hemostasis during normal pregnancy and puerperium","volume":"29","author":"Hellgren","year":"2003","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_17","first-page":"85","article-title":"Morphological Survey of Placenta in Trombophilia Related Hypoperfusion of Maternal-Fetal Blood Flow","volume":"44","author":"Ciurea","year":"2018","journal-title":"Curr. Health Sci. J."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"902","DOI":"10.1055\/s-0033-1357487","article-title":"Stress and hemostasis: An update","volume":"39","author":"Austin","year":"2013","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"S52","DOI":"10.1016\/S0049-3848(15)50444-1","article-title":"Acute mental stress and hemostasis: When physiology becomes vascular harm","volume":"135","year":"2015","journal-title":"Thromb. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"28418","DOI":"10.3390\/ijms161226104","article-title":"Thrombophilia and Pregnancy Complications","volume":"16","author":"Simcox","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Kupferminc, M.J. (2003). Thrombophilia and pregnancy. Reprod. Biol. Endocrinol. RB&E, 1.","DOI":"10.1186\/1477-7827-1-111"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.placenta.2017.02.015","article-title":"Effect of glucocorticoids on mechanisms of placental angiogenesis","volume":"52","author":"Ozmen","year":"2017","journal-title":"Placenta"},{"key":"ref_23","first-page":"33","article-title":"Placental morphology in inherited thrombophilia","volume":"76","author":"Drobinskaia","year":"2014","journal-title":"Arkhiv Patol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.placenta.2023.01.007","article-title":"CPT1A modulates PI3K\/Akt\/mTOR pathway to promote preeclampsia","volume":"133","author":"Chen","year":"2023","journal-title":"Placenta"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Liu, Z., Hong, Z., and Qu, P. (2020). Proteomic Analysis of Human Endometrial Tissues Reveals the Roles of PI3K\/AKT\/mTOR Pathway and Tumor Angiogenesis Molecules in the Pathogenesis of Endometrial Cancer. BioMed Res. Int., 2020.","DOI":"10.1155\/2020\/5273969"},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Zhao, H., Wong, R.J., and Stevenson, D.K. (2021). The Impact of Hypoxia in Early Pregnancy on Placental Cells. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22189675"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e230035","DOI":"10.1530\/JME-23-0035","article-title":"Impact of placental mTOR deficiency on peripheral insulin signaling in adult mice offspring","volume":"71","author":"Beetch","year":"2023","journal-title":"J. Mol. Endocrinol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"872","DOI":"10.1093\/biolre\/ioy249","article-title":"Novel roles of mechanistic target of rapamycin signaling in regulating fetal growth\u2020","volume":"100","author":"Gupta","year":"2019","journal-title":"Biol. Reprod."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1113\/jphysiol.2014.287177","article-title":"Corticosterone alters materno-fetal glucose partitioning and insulin signalling in pregnant mice","volume":"593","author":"Vaughan","year":"2015","journal-title":"J. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"39858","DOI":"10.1074\/jbc.M206322200","article-title":"Akt forms an intracellular complex with heat shock protein 90 (Hsp90) and Cdc37 and is destabilized by inhibitors of Hsp90 function","volume":"277","author":"Basso","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1007\/s11064-018-2535-6","article-title":"Up-Regulation of Cdc37 Contributes to Schwann Cell Proliferation and Migration After Sciatic Nerve Crush","volume":"43","author":"Liu","year":"2018","journal-title":"Neurochem. Res."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Wu, F., Hu, J., Xu, Y., Zhang, J., Li, Y., Lin, Y., and Liu, X. (2023). LDHA deficiency inhibits trophoblast proliferation via the PI3K\/AKT\/FOXO1\/CyclinD1 signaling pathway in unexplained recurrent spontaneous abortion. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol., 37.","DOI":"10.1096\/fj.202201219RR"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"134680","DOI":"10.1016\/j.neulet.2019.134680","article-title":"Hsp90 and complex birth defects: A plausible mechanism for the interaction of genes and environment","volume":"716","author":"Zohn","year":"2020","journal-title":"Neurosci. Lett."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Chang, C., Tang, X., Woodley, D.T., Chen, M., and Li, W. (2023). The Distinct Assignments for Hsp90\u03b1 and Hsp90\u03b2: More Than Skin Deep. Cells, 12.","DOI":"10.3390\/cells12020277"},{"key":"ref_35","first-page":"10","article-title":"Correlation between cognitive development and levels of dopamine and 3, 4-dihydroxyphenylacetic acid in the hippocampus in 80-day-old neonatal rats born of fear-impaired pregnant rats","volume":"11","author":"Xinmin","year":"2017","journal-title":"Chin. J. Comp. Med."},{"key":"ref_36","first-page":"62","article-title":"Effects of terror stress of the pregnant rats on emotional changes of 21-day-old neonatal offspring","volume":"01","author":"Liping","year":"2018","journal-title":"CJTCMP"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Geng, S., Yang, L., Cheng, F., Zhang, Z., Li, J., Liu, W., Li, Y., Chen, Y., Bao, Y., and Chen, L. (2019). Gut Microbiota Are Associated with Psychological Stress-Induced Defections in Intestinal and Blood-Brain Barriers. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.03067"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/S0006-8993(02)04113-6","article-title":"Possible regulatory mechanism of DHA-induced anti-stress reaction in rats","volume":"964","author":"Takeuchi","year":"2003","journal-title":"Brain Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/0006-8993(71)90526-9","article-title":"Vulnerability of developing brain. II. Effects of early nutritional deprivation on reflex ontogeny and development of behaviour in the rat","volume":"28","author":"Smart","year":"1971","journal-title":"Brain Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.bbr.2015.12.030","article-title":"Sulforaphane produces antidepressant- and anxiolytic-like effects in adult mice","volume":"301","author":"Wu","year":"2016","journal-title":"Behav. Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.jprot.2017.03.013","article-title":"iTRAQ-based proteomics analysis of hippocampus in spatial memory deficiency rats induced by simulated microgravity","volume":"160","author":"Wang","year":"2017","journal-title":"J. Proteom."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3053458","DOI":"10.1155\/2019\/3053458","article-title":"A Network Pharmacology Approach to Uncover the Molecular Mechanisms of Herbal Formula Kang-Bai-Ling for Treatment of Vitiligo","volume":"2019","author":"Xu","year":"2019","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_44","first-page":"227","article-title":"Mechanism of Shenbing decoction III in the treatment of proteinuria in chronic kidney disease: A network pharmacology-based study","volume":"39","author":"Liu","year":"2019","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1093\/bioinformatics\/btp101","article-title":"ClueGO: A Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks","volume":"25","author":"Bindea","year":"2009","journal-title":"Bioinformatics"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/9978\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:57:32Z","timestamp":1760111852000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/18\/9978"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,9,16]]},"references-count":45,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2024,9]]}},"alternative-id":["ijms25189978"],"URL":"https:\/\/doi.org\/10.3390\/ijms25189978","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,9,16]]}}}