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To test whether exposure to an environment in utero often associated with obesity modifies placental proteome and function, we performed untargeted proteomics (LC-MS\/MS) in placentas from 19 women (gestational age 35\u201348 days, i.e. 5+0\u20136+6 weeks). Maternal clinical traits (body mass index, leptin, glucose, C-peptide and insulin sensitivity) and gestational age were recorded. DNA replication and cell cycle pathways were enriched in the proteome of placentas of women with low maternal insulin sensitivity. Driving these pathways were the minichromosome maintenance (MCM) proteins MCM2, MCM3, MCM4, MCM5, MCM6 and MCM7 (MCM-complex). These proteins are part of the pre-replicative complex and participate in DNA damage repair. Indeed, MCM6 and \u03b3H2AX (DNA-damage marker) protein levels correlated in first trimester placental tissue (r = 0.514, P&amp;lt;0.01). MCM6 and \u03b3H2AX co-localized to nuclei of villous cytotrophoblast cells, the proliferative cell type of the placenta, suggesting increased DNA damage in this cell type. To mimic key features of the intrauterine obesogenic environment, a first trimester trophoblast cell line, i.e., ACH-3P, was exposed to high insulin (10 nM) or low oxygen tension (2.5% O2). There was a significant correlation between MCM6 and \u03b3H2AX protein levels, but these were independent of insulin or oxygen exposure. These findings show that chronic exposure in utero to reduced maternal insulin sensitivity during early pregnancy induces changes in the early first trimester placental proteome. Pathways related to DNA replication, cell cycle and DNA damage repair appear especially sensitive to such an in utero environment.<\/jats:p>","DOI":"10.1042\/bsr20240430","type":"journal-article","created":{"date-parts":[[2024,9,13]],"date-time":"2024-09-13T12:12:57Z","timestamp":1726229577000},"update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["MCM proteins are up-regulated in placentas of women with reduced insulin sensitivity"],"prefix":"10.1042","volume":"44","author":[{"given":"Julia","family":"Bandres-Meriz","sequence":"first","affiliation":[{"name":"1Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta\u00a0Inmaculada","family":"Sanz-Cuadrado","sequence":"additional","affiliation":[{"name":"1Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Hurtado de Mendoza","sequence":"additional","affiliation":[{"name":"1Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Majali-Martinez","sequence":"additional","affiliation":[{"name":"1Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria"},{"name":"2Departamento de Medicina, Facultad de Ciencias Biom\u00e9dicas y de la Salud. Universidad Europea de Madrid, Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophie\u00a0Elisabeth","family":"Honeder","sequence":"additional","affiliation":[{"name":"3Institute of Pathology, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Graz, Austria"},{"name":"4Institute of Chemical Technologies and Analytics, Technische Universit\u00e4t Wien, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tereza","family":"Cindrova-Davies","sequence":"additional","affiliation":[{"name":"5Centre for Trophoblast Research, Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruth","family":"Birner-Gruenberger","sequence":"additional","affiliation":[{"name":"3Institute of Pathology, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, Graz, Austria"},{"name":"4Institute of Chemical Technologies and Analytics, Technische Universit\u00e4t Wien, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise\u00a0Torp","family":"Dalgaard","sequence":"additional","affiliation":[{"name":"6Department of Science and Environment, Roskilde University, Roskilde, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5715-3230","authenticated-orcid":false,"given":"Gernot","family":"Desoye","sequence":"additional","affiliation":[{"name":"1Department of Obstetrics and Gynaecology, Medical University of Graz, Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2024,10,8]]},"reference":[{"key":"2024100815062093000_B1","doi-asserted-by":"publisher","first-page":"1965","DOI":"10.1152\/physrev.00050.2021","article-title":"The human periconceptional maternal-embryonic space in health and disease","volume":"103","author":"Moreno","year":"2023","journal-title":"Physiol. 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