ETA2024 Oral Presentations Oral Session 2: Thyroid hormone action in the brain (5 abstracts)
Gestational hypothyroxinemia in dehal1ko mice: discordant T3-dependent gene expression in brain regions and autistic-like phenotype in the offspring
Pouya Alikhani 1 , Andrea Bertolini 2 , Eva González 1 , Belinda Domínguez de Pablo 1 , Valentina Vitelli 2 , Mario Them Alvarez 1 , Abraham García López 1 , María Fuentes-Andión 1 , Nerea Díaz Gamero 1 , Elsa Cortés Montero 3 , María De La Fuente Fernández 3 , José Luis Trejo 4 , Alessandro Saba 2 , Manuela García López 3 , Riccardo Zucchi 2 & José C. Moreno 1
1Thyroid Molecular Laboratory. Institute for Medical and Molecular Genetics (Ingemm), La Paz University Hospital Reserach Institute (Idipaz) Autonomous University of Madrid (Uam). Spain.; 2Department of Pathology, Laboratory of Biochemistry. University of Pisa. Italy.; 3Teófilo Hernando Institute for Drug Discovery, Department of Pharmacology, School of Medicine, Uam. Madrid, Spain.; 4Department of Translational Neuroscience, Cajal Institute, Spanish National Research Council, Madrid, Spain.
Gestational hypothyroxinemia (GH) is a common event in human pregnancy generally attributed to iodine deficiency (ID). GH has been associated with the risk of neurodevelopmental defects in the offspring, including autistic traits. However, autistic children are mostly euthyroid, for which the role of thyroid hormones in the phenotype remains under debate.
Aim: To generate a mouse model of maternal hypothyroxinemia using moderate ID (mID) in iodine-recycling defective Dehal 1KO dams, and determine the consequences on thyroid hormone economy, behavior and brain gene expression in the progeny.
Methods: Wild type or Dehal1 KO dams were fed sufficient iodine (NID) or mID during gestation and lactation. From weaning, pups were switched to standard iodine diet (SD). Plasma T4 and T3 were measured by LC-MS-MS in dams at midgestation (G10), in F1-pups at postnatal-day 20 (PN20) and in F1-adults at PN150. Brain hippocampi and cerebella from PN20 and PN150 mice were collected for hormone quantification and gene expression changes of T3-signaling (Thra, Thrb, Hr, Rora) and neurodevelopmental genes (Reln, Nrg, Pvalb, Mag, Klf9) using qRT-PCR. Adult mice fulfilled behavioral tests for social interaction (three-chamber), obsessive-compulsive activity (marble burying), anxiety (elevated plus-maze) and mobility (open field).
Results: Only Dehal1 KO-mID dams developed hypothyroxinemia (T4-G10: 22±4 vs. 36.5±3 ng/ml; P < 0.05). Their pups were hypothyroid at weaning (T4-PN20: 36±3.3 vs. 50.4±3 ng/ml; P < 0.05). Consistently, their hippocampi and cerebella were T4-hypothyroid (Hippocampi: 3.4±1 vs. 7.5±1.8 pmol/g, P < 0.05; Cerebella: 3.2±0.5 vs. 4.8±0.8 pmol/g, P < 0.05) while T3 was normal and elevated, respectively. T3-dependent gene expression was globally reduced by 32-90%. After 4-months SD, KO-mID adults became fully euthyroid. However, strikingly, hippocampi were discordantly T4-hyperthyroid, with 40-170% increased Thrb and Hr expression in males, while females showed 20-50% decreased transcription of Thra, Thrb and Hr. Cerebella normalized T4 and T3, however, T3-dependent gene expression remained low for Thra, Thrb, Rora in females. Behaviorally, such “euthyroid” adults showed 40-78% decrease in sociability index (P < 0.05; greater in females), increased compulsivity (2-7 folds, P < 0.01; major in males), anxiety index (15%; P < 0.05) and reduced locomotion only in males (44%, P < 0.005). Neurodevelopmental genes were abnormally expressed in hippocampi, showing significant 30-40% downregulation of Reln and Nrg and 1.5-26 folds upregulation of Klf9, Pvalb and Mag.
Conclusions: Moderate ID in Dehal1 KO dams leads to GH. The progeny is hypothyroid at weaning, but euthyroid as adults under iodine sufficiency, despite showing abnormal behavior, discordant brain T4 and T3, and dysregulation of T3-dependent neurodevelopmental transcription, suggesting region- and sex-specific epigenetic modulation of low T3 during brain development.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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