{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T12:46:41Z","timestamp":1780058801074,"version":"3.54.0"},"posted":{"date-parts":[[2023,6,17]]},"group-title":"Neuroscience","reference-count":44,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,6,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Developing neurons have high thyroid hormone and iron requirements to support their metabolism and growth. Early-life iron and thyroid hormone deficiencies are prevalent, often coexist, and increase the risk of permanently impaired neurobehavioral function in children. Early-life dietary iron deficiency reduces thyroid hormone levels and impairs thyroid hormone-responsive gene expression in the neonatal rat brain.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>This study determined whether neuronal-specific iron deficiency alters thyroid hormone-regulated gene expression in developing neurons.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Iron deficiency was induced in primary mouse embryonic hippocampal neuron cultures with the iron chelator deferoxamine (DFO) beginning at 3 days in vitro (DIV). At 11DIV and 18DIV, mRNA levels for thyroid hormone-regulated genes indexing thyroid hormone homeostasis (\n                    <jats:italic>Hr<\/jats:italic>\n                    ,\n                    <jats:italic>Crym<\/jats:italic>\n                    ,\n                    <jats:italic>Dio2<\/jats:italic>\n                    ,\n                    <jats:italic>Slco1c1<\/jats:italic>\n                    ,\n                    <jats:italic>Slc16a2<\/jats:italic>\n                    ) and neurodevelopment (\n                    <jats:italic>Nrgn<\/jats:italic>\n                    ,\n                    <jats:italic>Pvalb<\/jats:italic>\n                    ,\n                    <jats:italic>Klf9<\/jats:italic>\n                    ) were quantified. To assess the effect of iron repletion, DFO was removed at 14DIV from a subset of DFO-treated cultures and gene expression and ATP levels were quantified at 21DIV.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    At 11DIV and 18DIV, neuronal iron deficiency decreased\n                    <jats:italic>Nrgn, Pvalb,<\/jats:italic>\n                    and\n                    <jats:italic>Crym<\/jats:italic>\n                    , and by 18DIV,\n                    <jats:italic>Slc16a2, Slco1c1, Dio2,<\/jats:italic>\n                    and\n                    <jats:italic>Hr<\/jats:italic>\n                    were increased; collectively suggesting cellular sensing of a functionally abnormal thyroid hormone state. Dimensionality reduction with Principal Component Analysis (PCA) reveals that thyroid hormone homeostatic genes strongly correlate with and predict iron status (\n                    <jats:italic>Tfr1<\/jats:italic>\n                    mRNA). Iron repletion from 14\u201321DIV restored neurodevelopmental genes, but not all thyroid hormone homeostatic genes, and ATP concentrations remained significantly altered. PCA clustering suggests that cultures replete with iron maintain a gene expression signature indicative of previous iron deficiency.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These novel findings suggest there is an intracellular mechanism coordinating cellular iron\/thyroid hormone activities. We speculate this is a part of homeostatic response to match neuronal energy production and growth signaling for these important metabolic regulators. However, iron deficiency may cause permanent deficits in thyroid hormone-dependent neurodevelopmental processes even after recovery from iron deficiency.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2023.06.17.545408","type":"posted-content","created":{"date-parts":[[2023,6,18]],"date-time":"2023-06-18T03:25:15Z","timestamp":1687058715000},"source":"Crossref","is-referenced-by-count":1,"title":["Cellular Iron Deficiency Disrupts Thyroid Hormone Regulated Gene Expression in Developing Hippocampal Neurons"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4905-757X","authenticated-orcid":false,"given":"Timothy R.","family":"Monko","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma H.","family":"Tripp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sierra E.","family":"Burr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina N.","family":"Gunderson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorene M.","family":"Lanier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael K.","family":"Georgieff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas W.","family":"Bastian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2023062013550722000_2023.06.17.545408v1.1","first-page":"33","article-title":"Adipose tissue in human infancy and childhood: An evolutionary perspective","volume":"41","year":"1998","journal-title":"YEARBOOK OF PHYSICAL ANTHROPOLOGY"},{"key":"2023062013550722000_2023.06.17.545408v1.2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1323099111"},{"key":"2023062013550722000_2023.06.17.545408v1.3","doi-asserted-by":"publisher","DOI":"10.1210\/er.2009-0007"},{"key":"2023062013550722000_2023.06.17.545408v1.4","doi-asserted-by":"publisher","DOI":"10.1177\/2633105520935104"},{"key":"2023062013550722000_2023.06.17.545408v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2020.03.006"},{"key":"2023062013550722000_2023.06.17.545408v1.6","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2021.772382"},{"key":"2023062013550722000_2023.06.17.545408v1.7","doi-asserted-by":"publisher","DOI":"10.1038\/nrendo.2018.18"},{"key":"2023062013550722000_2023.06.17.545408v1.8","doi-asserted-by":"publisher","DOI":"10.1093\/jn\/124.suppl_8.1479S"},{"key":"2023062013550722000_2023.06.17.545408v1.9","doi-asserted-by":"publisher","DOI":"10.1017\/S1368980008002401"},{"key":"2023062013550722000_2023.06.17.545408v1.10","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.115.110429"},{"key":"2023062013550722000_2023.06.17.545408v1.11","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1093\/jn\/132.7.1951","article-title":"Iron deficiency anemia reduces thyroid peroxidase activity in rats","volume":"132","year":"2002","journal-title":"J Nutr"},{"key":"2023062013550722000_2023.06.17.545408v1.12","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2009.08.012"},{"key":"2023062013550722000_2023.06.17.545408v1.13","first-page":"9","article-title":"Iron Deficiency, a Risk Factor of Thyroid Disorders in Reproductive-Age and Pregnant Women: A Systematic Review and Meta-Analysis","volume":"12","year":"2021","journal-title":"Frontiers in Endocrinology"},{"key":"2023062013550722000_2023.06.17.545408v1.14","doi-asserted-by":"publisher","DOI":"10.1210\/en.2012-1067"},{"key":"2023062013550722000_2023.06.17.545408v1.15","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-0252"},{"key":"2023062013550722000_2023.06.17.545408v1.16","doi-asserted-by":"publisher","DOI":"10.1210\/en.2013-1571"},{"key":"2023062013550722000_2023.06.17.545408v1.17","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2015.0293"},{"key":"2023062013550722000_2023.06.17.545408v1.18","unstructured":"Bernal J . 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