{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:56:24Z","timestamp":1785405384656,"version":"3.56.0"},"reference-count":47,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,3,7]],"date-time":"2023-03-07T00:00:00Z","timestamp":1678147200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01NS099178"],"award-info":[{"award-number":["R01NS099178"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["R01HD29421"],"award-info":[{"award-number":["R01HD29421"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Fetal-neonatal iron deficiency (ID) causes long-term neurocognitive and affective dysfunctions. Clinical and preclinical studies have shown that early-life ID produces sex-specific effects. However, little is known about the molecular mechanisms underlying these early-life ID-induced sex-specific effects on neural gene regulation. Objective: To illustrate sex-specific transcriptome alterations in adult rat hippocampus induced by fetal-neonatal ID and prenatal choline treatment. Methods: Pregnant rats were fed an iron-deficient (4 mg\/kg Fe) or iron-sufficient (200 mg\/kg Fe) diet from gestational day (G) 2 to postnatal day (P) 7 with or without choline supplementation (5 g\/kg choline) from G11\u201318. Hippocampi were collected from P65 offspring of both sexes and analyzed for changes in gene expression. Results: Both early-life ID and choline treatment induced transcriptional changes in adult female and male rat hippocampi. Both sexes showed ID-induced alterations in gene networks leading to enhanced neuroinflammation. In females, ID-induced changes indicated enhanced activity of oxidative phosphorylation and fatty acid metabolism, which were contrary to the ID effects in males. Prenatal choline supplementation induced the most robust changes in gene expression, particularly in iron-deficient animals where it partially rescued ID-induced dysregulation. Choline supplementation also altered hippocampal transcriptome in iron-sufficient rats with indications for both beneficial and adverse effects. Conclusions: This study provided unbiased global assessments of gene expression regulated by iron and choline in a sex-specific manner, with greater effects in female than male rats. Our new findings highlight potential sex-specific gene networks regulated by iron and choline for further investigation.<\/jats:p>","DOI":"10.3390\/nu15061316","type":"journal-article","created":{"date-parts":[[2023,3,8]],"date-time":"2023-03-08T01:58:22Z","timestamp":1678240702000},"page":"1316","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Sex-Specific Effects of Early-Life Iron Deficiency and Prenatal Choline Treatment on Adult Rat Hippocampal Transcriptome"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2550-008X","authenticated-orcid":false,"given":"Shirelle X.","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tenille K.","family":"Fredrickson","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2558-1126","authenticated-orcid":false,"given":"Natalia","family":"Calixto Mancipe","sequence":"additional","affiliation":[{"name":"Research Informatic Solutions, Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael K.","family":"Georgieff","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4301-941X","authenticated-orcid":false,"given":"Phu V.","family":"Tran","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"516","DOI":"10.1016\/j.ajog.2020.03.006","article-title":"Iron deficiency in pregnancy","volume":"223","author":"Georgieff","year":"2020","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1001\/archpsyc.65.10.1136","article-title":"Maternal iron deficiency and the risk of schizophrenia in offspring","volume":"65","author":"Insel","year":"2008","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1294","DOI":"10.1001\/jamapsychiatry.2019.2309","article-title":"Association of Prenatal Maternal Anemia with Neurodevelopmental Disorders","volume":"76","author":"Wiegersma","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/BF03033574","article-title":"Brain iron deficiency and excess; cognitive impairment and neurodegeneration with involvement of striatum and hippocampus","volume":"14","author":"Youdim","year":"2008","journal-title":"Neurotox. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1093\/ajcn\/nqy249","article-title":"Anemia in infancy is associated with alterations in systemic metabolism and microbial structure and function in a sex-specific manner: An observational study","volume":"108","author":"McClorry","year":"2018","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1001\/archpediatrics.2010.269","article-title":"Long-term outcome of brain structure in premature infants: Effects of liberal vs. restricted red blood cell transfusions","volume":"165","author":"Nopoulos","year":"2011","journal-title":"Arch. Pediatr. Adolesc. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1080\/87565641.2013.874428","article-title":"The relationship between brain structure and cognition in transfused preterm children at school age","volume":"39","author":"McCoy","year":"2014","journal-title":"Dev. Neuropsychol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/s41390-021-01832-9","article-title":"Dose- and sex-dependent effects of phlebotomy-induced anemia on the neonatal mouse hippocampal transcriptome","volume":"92","author":"Singh","year":"2021","journal-title":"Pediatr. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1759091417746521","DOI":"10.1177\/1759091417746521","article-title":"Iron Deficiency Affects Seizure Susceptibility in a Time- and Sex-Specific Manner","volume":"9","author":"Rudy","year":"2017","journal-title":"ASN Neuro"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e01780","DOI":"10.1002\/brb3.1780","article-title":"Sex differences in adult social, cognitive, and affective behavioral deficits following neonatal phlebotomy-induced anemia in mice","volume":"11","author":"Matveeva","year":"2021","journal-title":"Brain Behav."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4715","DOI":"10.1113\/JP278223","article-title":"Perinatal iron deficiency combined with a high salt diet in adulthood causes sex-dependent vascular dysfunction in rats","volume":"597","author":"Woodman","year":"2019","journal-title":"J. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1093\/jn\/nxab005","article-title":"Maternal Iron Deficiency Modulates Placental Transcriptome and Proteome in Mid-Gestation of Mouse Pregnancy","volume":"151","author":"Cao","year":"2021","journal-title":"J. Nutr."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Marell, P.S., Blohowiak, S.E., Evans, M.D., Georgieff, M.K., Kling, P.J., and Tran, P.V. (2019). Cord Blood-Derived Exosomal CNTN2 and BDNF: Potential Molecular Markers for Brain Health of Neonates at Risk for Iron Deficiency. Nutrients, 11.","DOI":"10.3390\/nu11102478"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.yhbeh.2015.05.024","article-title":"Hippocampal learning, memory, and neurogenesis: Effects of sex and estrogens across the lifespan in adults","volume":"74","author":"Yagi","year":"2015","journal-title":"Horm. Behav."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1159\/000499661","article-title":"Sex differences in Hippocampal Memory and Learning following Neonatal Brain Injury: Is There a Role for Estrogen Receptor-\u03b1?","volume":"109","author":"Zafer","year":"2019","journal-title":"Neuroendocrinology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/s41390-018-0204-8","article-title":"Iron as a model nutrient for understanding the nutritional origins of neuropsychiatric disease","volume":"85","author":"Barks","year":"2019","journal-title":"Pediatr. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1159\/000354178","article-title":"Early-life iron deficiency anemia alters the development and long-term expression of parvalbumin and perineuronal nets in the rat hippocampus","volume":"35","author":"Callahan","year":"2013","journal-title":"Dev. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1159\/000073507","article-title":"Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats","volume":"25","author":"Beard","year":"2003","journal-title":"Dev. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1179\/147683008X344219","article-title":"Early iron deficiency produces persistent damage to visual tracts in Wistar rats","volume":"11","author":"DeMaman","year":"2008","journal-title":"Nutr. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1038\/sj.jcbfm.9600376","article-title":"Perinatal iron deficiency predisposes the developing rat hippocampus to greater injury from mild to moderate hypoxia-ischemia","volume":"27","author":"Rao","year":"2007","journal-title":"J. Cereb. Blood Flow. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Liu, S.X., Barks, A.K., Lunos, S., Gewirtz, J.C., Georgieff, M.K., and Tran, P.V. (2021). Prenatal Iron Deficiency and Choline Supplementation Interact to Epigenetically Regulate Jarid1b and Bdnf in the Rat Hippocampus into Adulthood. Nutrients, 13.","DOI":"10.3390\/nu13124527"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1093\/bioinformatics\/btt703","article-title":"Causal analysis approaches in Ingenuity Pathway Analysis","volume":"30","author":"Green","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/75556","article-title":"Gene ontology: Tool for the unification of biology. The Gene Ontology Consortium","volume":"25","author":"Ashburner","year":"2000","journal-title":"Nat. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1093\/bioinformatics\/btr260","article-title":"Molecular signatures database (MSigDB) 3.0","volume":"27","author":"Liberzon","year":"2011","journal-title":"Bioinformatics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1858","DOI":"10.3945\/jn.114.198739","article-title":"Prenatal choline supplementation ameliorates the long-term neurobehavioral effects of fetal-neonatal iron deficiency in rats","volume":"144","author":"Kennedy","year":"2014","journal-title":"J. Nutr."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"484","DOI":"10.3945\/jn.115.227561","article-title":"Prenatal Choline Supplementation Diminishes Early-Life Iron Deficiency-Induced Reprogramming of Molecular Networks Associated with Behavioral Abnormalities in the Adult Rat Hippocampus","volume":"146","author":"Tran","year":"2016","journal-title":"J. Nutr."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Hoffman, G.E., and Schadt, E.E. (2016). variancePartition: Interpreting drivers of variation in complex gene expression studies. BMC Bioinform., 17.","DOI":"10.1186\/s12859-016-1323-z"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"100739","DOI":"10.1016\/j.yfrne.2019.02.003","article-title":"Giving a good start to a new life via maternal brain allostatic adaptations in pregnancy","volume":"53","author":"Russell","year":"2019","journal-title":"Front. Neuroendocr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1016\/j.bbi.2004.09.006","article-title":"The potential influence of maternal stress hormones on development and mental health of the offspring","volume":"19","author":"Weinstock","year":"2005","journal-title":"Brain Behav. Immun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1488S","DOI":"10.3945\/ajcn.2009.27113B","article-title":"Epigenetic mechanisms for nutrition determinants of later health outcomes","volume":"89","author":"Zeisel","year":"2009","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1093\/jn\/nxab429","article-title":"Choline Supplementation Partially Restores Dendrite Structural Complexity in Developing Iron-Deficient Mouse Hippocampal Neurons","volume":"152","author":"Bastian","year":"2022","journal-title":"J. Nutr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1093\/ajcn\/nqac101","article-title":"Gestational weight gain and dietary energy, iron, and choline intake predict severity of fetal alcohol growth restriction in a prospective birth cohort","volume":"116","author":"Carter","year":"2022","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1016\/S0002-9440(10)65408-9","article-title":"Interferon-gamma receptor-mediated but not tumor necrosis factor receptor type 1- or type 2-mediated signaling is crucial for the activation of cerebral blood vessel endothelial cells and microglia in murine Toxoplasma encephalitis","volume":"154","author":"Bluethmann","year":"1999","journal-title":"Am. J. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1233","DOI":"10.1034\/j.1398-9995.1999.00099.x","article-title":"Biologic functions of the IFN-gamma receptors","volume":"54","author":"Tau","year":"1999","journal-title":"Allergy"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Baker, J.A., Breit, K.R., Bodnar, T.S., Weinberg, J., and Thomas, J.D. (2022). Choline Supplementation Modifies the Effects of Developmental Alcohol Exposure on Immune Responses in Adult Rats. Nutrients, 14.","DOI":"10.3390\/nu14142868"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"616920","DOI":"10.3389\/fcvm.2020.616920","article-title":"Iron-Deficiency Anemia Results in Transcriptional and Metabolic Remodeling in the Heart Toward a Glycolytic Phenotype","volume":"7","author":"Chung","year":"2020","journal-title":"Front. Cardiovasc. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2633105520935104","DOI":"10.1177\/2633105520935104","article-title":"The Effects of Early-Life Iron Deficiency on Brain Energy Metabolism","volume":"15","author":"Bastian","year":"2020","journal-title":"Neurosci Insights"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"889","DOI":"10.1007\/s11745-998-0285-8","article-title":"Different degrees of moderate iron deficiency modulate lipid metabolism of rats","volume":"33","author":"Stangl","year":"1998","journal-title":"Lipids"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"260","DOI":"10.3945\/jn.112.168617","article-title":"Neuronal-specific iron deficiency dysregulates mammalian target of rapamycin signaling during hippocampal development in nonanemic genetic mouse models","volume":"143","author":"Fretham","year":"2013","journal-title":"J. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1093\/jn\/nxy125","article-title":"Early-Life Neuronal-Specific Iron Deficiency Alters the Adult Mouse Hippocampal Transcriptome","volume":"148","author":"Barks","year":"2018","journal-title":"J. Nutr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1007\/s11302-018-9635-2","article-title":"Impact of genetic variations in ADORA2A gene on depression and symptoms: A cross-sectional population-based study","volume":"15","author":"Oliveira","year":"2019","journal-title":"Purinergic. Signal."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Siokas, V., Mouliou, D.S., Liampas, I., Aloizou, A.M., Folia, V., Zoupa, E., Papadimitriou, A., Lavdas, E., Bogdanos, D.P., and Dardiotis, E. (2022). Analysis of ADORA2A rs5760423 and CYP1A2 rs762551 Genetic Variants in Patients with Alzheimer\u2019s Disease. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232214400"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3389\/fnbeh.2014.00199","article-title":"Serotonin-prefrontal cortical circuitry in anxiety and depression phenotypes: Pivotal role of pre- and post-synaptic 5-HT1A receptor expression","volume":"8","author":"Albert","year":"2014","journal-title":"Front. Behav. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1007\/s12035-012-8330-5","article-title":"alpha-Synuclein posttranslational modification and alternative splicing as a trigger for neurodegeneration","volume":"47","author":"Beyer","year":"2013","journal-title":"Mol. Neurobiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4895","DOI":"10.1038\/s41598-020-61757-x","article-title":"The expression level of alpha-synuclein in different neuronal populations is the primary determinant of its prion-like seeding","volume":"10","author":"Courte","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1097\/WNR.0b013e328354a1f0","article-title":"alpha-Synuclein expression is modulated at the translational level by iron","volume":"23","author":"Febbraro","year":"2012","journal-title":"Neuroreport"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1186\/s13024-017-0218-4","article-title":"Iron regulatory protein (IRP)-iron responsive element (IRE) signaling pathway in human neurodegenerative diseases","volume":"12","author":"Zhou","year":"2017","journal-title":"Mol. Neurodegener."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/6\/1316\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:50:04Z","timestamp":1760122204000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/15\/6\/1316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,7]]},"references-count":47,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["nu15061316"],"URL":"https:\/\/doi.org\/10.3390\/nu15061316","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2022.06.29.498159","asserted-by":"object"}]},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,3,7]]}}}