{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T18:26:34Z","timestamp":1790619994697,"version":"4.1.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T00:00:00Z","timestamp":1666915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:p>Cerebral white matter is the most common anatomic location of neonatal brain injury in preterm newborns. Factors that predispose preterm newborns to white matter damage are understudied. In relation to studies of the placenta-brain-axis, dysregulated placental gene expression may play a role in preterm brain damage given its implication in programming early life origins of disease, including neurological disorders. There is a critical need to investigate the relationships between the placental transcriptome and white matter damage in the neonate. In a cohort of extremely low gestational age newborns (ELGANs), we aimed to investigate the relationship between the placental transcriptome and white matter damage as assessed by neonatal cranial ultrasound studies (echolucency and\/or ventriculomegaly). We hypothesized that genes involved in inflammatory processes would be more highly expressed in placentas of ELGANs who developed ultrasound-defined indicators of white matter damage. Relative to either form of white matter damage, 659 placental genes displayed altered transcriptional profiles. Of these white matter damage-associated genes, largely distinct patterns of gene expression were observed in the study (<jats:italic>n<\/jats:italic> = 415\/659 genes). Specifically, 381 genes were unique to echolucency and 34 genes were unique to ventriculomegaly. Pathways involved in hormone disruption and metabolism were identified among the unique echolucency or ventriculomegaly genes. Interestingly, a common set of 244 genes or 37% of all genes was similarly dysregulated in the placenta relative to both echolucency and ventriculomegaly. For this common set of white matter damage-related genes, pathways involved in inflammation, immune response and apoptosis, were enriched. Among the white matter damage-associated genes are genes known to be involved in Autism Spectrum Disorder (ASD) and endocrine system disorders. These data highlight differential mRNA expression patterning in the placenta and provide insight into potential etiologic factors that may predispose preterm newborns to white matter damage. Future studies will build upon this work to include functional measures of neurodevelopment as well as measures of brain volume later in life.<\/jats:p>","DOI":"10.3389\/fnins.2022.1017953","type":"journal-article","created":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T08:56:34Z","timestamp":1666947394000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Placental transcriptional signatures associated with cerebral white matter damage in the neonate"],"prefix":"10.3389","volume":"16","author":[{"given":"Carmen Amelia","family":"Marable","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Roell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Kuban","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"T. Michael","family":"O\u2019Shea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca C.","family":"Fry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,10,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1186\/2040-2392-4-36","article-title":"SFARI Gene 2.0: A community-driven knowledgebase for the autism spectrum disorders (ASDs).","volume":"4","author":"Abrahams","year":"2013","journal-title":"Mol. Autism"},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.1093\/eep\/dvz010","article-title":"Acetaminophen use during pregnancy and DNA methylation in the placenta of the extremely low gestational age newborn (ELGAN) cohort.","volume":"5","author":"Addo","year":"2019","journal-title":"Environ. Epigenet."},{"key":"B3","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s00401-017-1718-6","article-title":"White matter injury in the preterm infant: Pathology and mechanisms.","volume":"134","author":"Back","year":"2017","journal-title":"Acta Neuropathol."},{"key":"B4","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1002\/ana.24132","article-title":"Brain injury in premature neonates: A primary cerebral dysmaturation disorder?","volume":"75","author":"Back","year":"2014","journal-title":"Ann. Neurol."},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104468","article-title":"The brain-placental axis: Therapeutic and pharmacological relevancy to pregnancy.","volume":"149","author":"Behura","year":"2019","journal-title":"Pharmacol. Res."},{"key":"B6","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1001\/jama.288.6.728","article-title":"Cognitive and behavioral outcomes of school-aged children who were born preterm: A meta-analysis.","volume":"288","author":"Bhutta","year":"2002","journal-title":"JAMA"},{"key":"B7","doi-asserted-by":"publisher","first-page":"197","DOI":"10.1016\/j.jpeds.2021.05.059","article-title":"Neonatal cranial ultrasound findings among infants born extremely preterm: Associations with neurodevelopmental outcomes at 10 years of age.","volume":"237","author":"Campbell","year":"2021","journal-title":"J. Pediatr."},{"key":"B8","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1177\/197140091302600305","article-title":"Accuracy of transcranial ultrasound in the detection of mild white matter lesions in newborns.","volume":"26","author":"Ciambra","year":"2013","journal-title":"Neuroradiol. J."},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-95051-1","article-title":"Pre-pregnancy BMI-associated miRNA and mRNA expression signatures in the placenta highlight a sexually-dimorphic response to maternal underweight status.","volume":"11","author":"Clark","year":"2021","journal-title":"Sci. Rep."},{"key":"B10","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1089\/brain.2015.0385","article-title":"Investigating the microstructural correlation of white matter in autism spectrum disorder.","volume":"6","author":"Dean","year":"2016","journal-title":"Brain Connect"},{"key":"B11","author":"Dimes","year":"2021","journal-title":"Fighting premature birth: The prematurity campain."},{"key":"B12","doi-asserted-by":"publisher","first-page":"1543","DOI":"10.2217\/epi-2020-0062","article-title":"A role for microRNAs in the epigenetic control of sexually dimorphic gene expression in the human placenta.","volume":"12","author":"Eaves","year":"2020","journal-title":"Epigenomics"},{"key":"B13","doi-asserted-by":"publisher","first-page":"1464","DOI":"10.1210\/en.2011-1673","article-title":"Differential regulation of glucose transporters mediated by CRH receptor type 1 and type 2 in human placental trophoblasts.","volume":"153","author":"Gao","year":"2012","journal-title":"Endocrinology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1038\/pr.2013.135","article-title":"Circulatory insulin-like growth factor-I and brain volumes in relation to neurodevelopmental outcome in very preterm infants.","volume":"74","author":"Hansen-Pupp","year":"2013","journal-title":"Pediatr. Res."},{"key":"B15","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1093\/intimm\/dxaa078","article-title":"IL-6 in inflammation, autoimmunity and cancer.","volume":"33","author":"Hirano","year":"2020","journal-title":"Int. Immunol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1016\/j.pediatrneurol.2017.11.002","article-title":"Co-occurrence and Severity of neurodevelopmental Burden (Cognitive Impairment, Cerebral Palsy, Autism Spectrum Disorder, and Epilepsy) at age ten years in children born extremely preterm.","volume":"79","author":"Hirschberger","year":"2018","journal-title":"Pediatr. Neurol."},{"key":"B17","doi-asserted-by":"publisher","first-page":"579","DOI":"10.1586\/eci.11.51","article-title":"Prenatal programming of the innate immune response following in utero exposure to inflammation: A sexually dimorphic process?","volume":"7","author":"Hodyl","year":"2011","journal-title":"Expert Rev. Clin. Immunol."},{"key":"B18","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1001\/jama.2021.0003","article-title":"Recalibrating the use of race in medical research.","volume":"325","author":"Ioannidis","year":"2021","journal-title":"JAMA"},{"key":"B19","year":"","journal-title":"Data were analyzed with the use of QIAGEN IPA"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.714214","article-title":"Placental CRH as a signal of pregnancy adversity and impact on fetal neurodevelopment.","volume":"12","author":"Kassotaki","year":"2021","journal-title":"Front. Endocrinol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"3774","DOI":"10.1210\/en.2009-0213","article-title":"Brain-derived neurotrophic factor promotes implantation and subsequent placental development by stimulating trophoblast cell growth and survival.","volume":"150","author":"Kawamura","year":"2009","journal-title":"Endocrinology"},{"key":"B22","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1515\/jpm-2014-0250","article-title":"A \u201cmulti-hit\u201d model of neonatal white matter injury: Cumulative contributions of chronic placental inflammation, acute fetal inflammation and postnatal inflammatory events.","volume":"42","author":"Korzeniewski","year":"2014","journal-title":"J. Perinat. Med."},{"key":"B23","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in ingenuity pathway analysis","volume":"30","author":"Kr\u00e4mer","year":"2014","journal-title":"Bioinformatics"},{"key":"B24","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1177\/0883073808321048","article-title":"Cranial ultrasound lesions in the NICU predict cerebral palsy at age 2 years in children born at extremely low gestational age.","volume":"24","author":"Kuban","year":"2009","journal-title":"J. Child Neurol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1007\/s00247-007-0605-z","article-title":"Observer variability assessing US scans of the preterm brain: The ELGAN study.","volume":"37","author":"Kuban","year":"2007","journal-title":"Pediatr. Radiol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"7170","DOI":"10.1128\/MCB.25.16.7170-7180.2005","article-title":"Glycogen synthase kinase 3-dependent phosphorylation of Mdm2 regulates p53 abundance.","volume":"25","author":"Kulikov","year":"2005","journal-title":"Mol. Cell. Biol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1724","DOI":"10.1371\/journal.pgen.0030161","article-title":"Capturing heterogeneity in gene expression studies by surrogate variable analysis.","volume":"3","author":"Leek","year":"2007","journal-title":"PLoS Genet."},{"key":"B28","doi-asserted-by":"crossref","first-page":"321","DOI":"10.2217\/epi-2016-0171","article-title":"Epigenetic mechanisms in the placenta related to infant neurodevelopment.","volume":"10","author":"Lester","year":"2018","journal-title":"Epigenomics"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"B30","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/978-3-642-45106-5_9","article-title":"BDNF and synaptic plasticity, cognitive function, and dysfunction.","volume":"220","author":"Lu","year":"2014","journal-title":"Handb. Exp. Pharmacol."},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9082564","article-title":"Maternal-autoantibody-related (MAR) autism: Identifying neuronal antigens and approaching prospects for intervention.","volume":"9","author":"Marks","year":"2020","journal-title":"J. Clin. Med."},{"key":"B32","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1152\/physrev.00010.2007","article-title":"Estradiol and the developing brain.","volume":"88","author":"McCarthy","year":"2008","journal-title":"Physiol. Rev."},{"key":"B33","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.yhbeh.2018.02.007","article-title":"Placental CpG methylation of HPA-axis genes is associated with cognitive impairment at age 10 among children born extremely preterm.","volume":"101","author":"Meakin","year":"2018","journal-title":"Horm. Behav."},{"key":"B34","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1177\/1947601911409736","article-title":"p53 in the CNS: Perspectives on development, stem cells, and cancer.","volume":"2","author":"Mendrysa","year":"2011","journal-title":"Genes Cancer"},{"key":"B35","year":"2020","journal-title":"Geo gene expression omnibus. Placental genomic and epigenomic signatures in infants borns at extremely lowgestational age."},{"key":"B36","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.earlhumdev.2009.08.060","article-title":"The ELGAN study of the brain and related disorders in extremely low gestational age newborns.","volume":"85","author":"O\u2019Shea","year":"2009","journal-title":"Early Hum. Dev."},{"key":"B37","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1111\/j.1469-8749.1993.tb11611.x","article-title":"Reliability of interpretation of cranial ultrasound examinations of very low-birthweight neonates.","volume":"35","author":"O\u2019Shea","year":"1993","journal-title":"Dev. Med. Child Neurol."},{"key":"B38","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1053\/j.semperi.2017.07.009","article-title":"Epidemiology of preterm birth.","volume":"41","author":"Purisch","year":"2017","journal-title":"Semin. Perinatol."},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2020.00098","article-title":"Immune and apoptosis mechanisms regulating placental development and vascularization in preeclampsia.","volume":"11","author":"Raguema","year":"2020","journal-title":"Front. Physiol."},{"key":"B40","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.placenta.2013.11.007","article-title":"A comprehensive analysis of the human placenta transcriptome.","volume":"35","author":"Saben","year":"2014","journal-title":"Placenta"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1186\/s13229-020-00402-w","article-title":"Evidence for the placenta-brain axis: Multi-omic kernel aggregation predicts intellectual and social impairment in children born extremely preterm.","volume":"11","author":"Santos","year":"2020","journal-title":"Mol. Autism"},{"key":"B42","doi-asserted-by":"publisher","first-page":"751","DOI":"10.1080\/15592294.2019.1614743","article-title":"Epigenome-wide DNA methylation in placentas from preterm infants: Association with maternal socioeconomic status.","volume":"14","author":"Santos","year":"2019","journal-title":"Epigenetics"},{"key":"B43","doi-asserted-by":"crossref","first-page":"960","DOI":"10.1016\/j.cell.2017.02.004","article-title":"mTOR signaling in growth, metabolism, and disease.","volume":"168","author":"Saxton","year":"2017","journal-title":"Cell"},{"key":"B44","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/j.1600-0897.2010.00837.x","article-title":"Placental apoptosis in health and disease.","volume":"64","author":"Sharp","year":"2010","journal-title":"Am. J. Reprod. Immunol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"865","DOI":"10.1016\/j.placenta.2011.08.010","article-title":"Influence of sex and glucocorticoid exposure on preterm placental pro-oxidant-antioxidant balance.","volume":"32","author":"Stark","year":"2011","journal-title":"Placenta"},{"key":"B46","doi-asserted-by":"publisher","first-page":"D447","DOI":"10.1093\/nar\/gku1003","article-title":"STRING v10: Protein-protein interaction networks, integrated over the tree of life.","volume":"43","author":"Szklarczyk","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0193271","article-title":"Placental CpG methylation of infants born extremely preterm predicts cognitive impairment later in life.","volume":"13","author":"Tilley","year":"2018","journal-title":"PLoS One"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1392","DOI":"10.1038\/s41593-021-00896-4","article-title":"Placental endocrine function shapes cerebellar development and social behavior.","volume":"24","author":"Vacher","year":"2021","journal-title":"Nat. Neurosci."},{"key":"B49","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1042\/BST20130284","article-title":"Brain damage of the preterm infant: New insights into the role of inflammation.","volume":"42","author":"Van Steenwinckel","year":"2014","journal-title":"Biochem. Soc. Trans."},{"key":"B50","doi-asserted-by":"crossref","first-page":"115","DOI":"10.3892\/br.2017.930","article-title":"Human placental growth hormone in normal and abnormal fetal growth.","volume":"7","author":"Velegrakis","year":"2017","journal-title":"Biomed. Rep."},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000006696","article-title":"Prenatal, perinatal, and postnatal factors associated with autism: A meta-analysis.","volume":"96","author":"Wang","year":"2017","journal-title":"Medicine"},{"key":"B52","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.immuni.2018.07.017","article-title":"Interferons and proinflammatory cytokines in pregnancy and fetal development.","volume":"49","author":"Yockey","year":"2018","journal-title":"Immunity"}],"container-title":["Frontiers in Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.1017953\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,10,28]],"date-time":"2022-10-28T08:56:58Z","timestamp":1666947418000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnins.2022.1017953\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,10,28]]},"references-count":52,"alternative-id":["10.3389\/fnins.2022.1017953"],"URL":"https:\/\/doi.org\/10.3389\/fnins.2022.1017953","relation":{},"ISSN":["1662-453X"],"issn-type":[{"value":"1662-453X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,10,28]]},"article-number":"1017953"}}