title: Exposure to depleted uranium during development affects neuronal differentiation in the hippocampal dentate gyrus and induces depressive-like behavior in offspring.
abstract: The developing brain is known to be sensitive to uranium (U) and exposure to this element during postnatal brain development results in behavioral disorders in adulthood. Moreover, we have previously shown that U exposure during gestation and lactation affects neurogenesis, in particular neural cell proliferation and cell death. In this study, we investigated whether exposure to depleted U (DU) affects neuronal differentiation during prenatal and postnatal brain development. We assessed in situ expression of specific genes involved in neuronal differentiation and expression of neuronal protein markers. The effects of DU on neurobehavioral function were investigated in parallel. Neuronal differentiation involves many signaling pathways that regulate the balance between cell proliferation and the transition to neuronal differentiation. In the present study pregnant rats were exposed from gestational day (GD) 1 throughout lactation to postnatal day (PND) 21. Using in situ hybridization, our results show decreased expression of Wnt3a in the hippocampal neuroepithelium in GD 13 embryos from DU exposed dams and decreased expression of Notch1 and increased expression of Mash1 in the hippocampal and dentate neuroepithelia of GD 18 fetuses from DU exposed dams. Expression of the NeuroD and NeuroD2 genes was not modified in the hippocampal neuroepithelium of GD18 fetuses from DU exposed dams. There was no change in the expression of any of these genes in the dentate gyrus of PND 5 pups from DU exposed dams. No change in nestin or doublecortin immunestaining was observed in the prenatal or early postnatal stages. However, the number of doublecortin-positive cells increased in the granular cell layer of PND 21 pups from DU exposed dams. Finally, depressive-like behavior was induced in PND21 rats, without modification of locomotor and exploratory activities or of spatial memory. In conclusion, these results showed that exposure of pregnant and lactating rats to DU affects brain development by causing disturbed cell proliferation and neuronal differentiation at the prenatal stage. Moreover, this exposure increased the pool of immature neurons in the dentate gyrus and induced depressive-like behavior in neonatal rats. Therefore, these data strongly suggest that exposure to DU during gestation and lactation affects brain development in embryos, fetuses and neonates with behavioral consequences in the offspring.
authors.affiliation: Laboratoire de RadioToxicologie Expérimentale, Service de Radiobiologie et d'Epidémiologie, Institut de Radioprotection et Sûreté Nucléaire, B.P. 17, 92262 Fontenay aux Roses Cedex, France. Electronic address: legmarie@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Legrand
authors.affiliation: Laboratoire de RadioToxicologie Expérimentale, Service de Radiobiologie et d'Epidémiologie, Institut de Radioprotection et Sûreté Nucléaire, B.P. 17, 92262 Fontenay aux Roses Cedex, France. Electronic address: suzanne.lam92@gmail.com.
authors.forename: S
authors.initials: S
authors.lastname: Lam
authors.affiliation: Sorbonne Universités, UPMC Univ Paris 06, UMR7622, CNRS, Institut de Biologie Paris Seine (IBPS)-Developmental Biology Laboratory, UMR7622, INSERM, 7 quai Saint Bernard, 75 252 Paris Cedex, France. Electronic address: isabelle.anselme@upmc.fr.
authors.forename: I
authors.initials: I
authors.lastname: Anselme
authors.affiliation: Laboratoire de RadioToxicologie Expérimentale, Service de Radiobiologie et d'Epidémiologie, Institut de Radioprotection et Sûreté Nucléaire, B.P. 17, 92262 Fontenay aux Roses Cedex, France. Electronic address: celine.gloaguen@irsn.fr.
authors.forename: C
authors.initials: C
authors.lastname: Gloaguen
authors.affiliation: Laboratoire de RadioToxicologie Expérimentale, Service de Radiobiologie et d'Epidémiologie, Institut de Radioprotection et Sûreté Nucléaire, B.P. 17, 92262 Fontenay aux Roses Cedex, France. Electronic address: chrystelle.ibanez@irsn.fr.
authors.forename: C
authors.initials: C
authors.lastname: Ibanez
authors.affiliation: Department of Environmental Toxicology, Uppsala University, Norbyvägen 18 A, 752 36 Uppsala, Sweden. Electronic address: per.eriksson@ebc.uu.se.
authors.forename: P
authors.initials: P
authors.lastname: Eriksson
authors.affiliation: Laboratoire de RadioToxicologie Expérimentale, Service de Radiobiologie et d'Epidémiologie, Institut de Radioprotection et Sûreté Nucléaire, B.P. 17, 92262 Fontenay aux Roses Cedex, France. Electronic address: philippe.lestaevel@irsn.fr.
authors.forename: P
authors.initials: P
authors.lastname: Lestaevel
authors.affiliation: Laboratoire de RadioToxicologie Expérimentale, Service de Radiobiologie et d'Epidémiologie, Institut de Radioprotection et Sûreté Nucléaire, B.P. 17, 92262 Fontenay aux Roses Cedex, France. Electronic address: celine.dinocourt@irsn.fr.
authors.forename: C
authors.initials: C
authors.lastname: Dinocourt
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000187:drug effects*; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D003863:Depression / Q000209:etiology*; D000089662:Doublecortin Protein; D004622:Embryo, Mammalian; D005106:Exploratory Behavior / Q000187:drug effects; D005260:Female; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000503:physiopathology; D012333:RNA, Messenger; D051381:Rats; D017207:Rats, Sprague-Dawley; D013550:Swimming / Q000523:psychology; D014501:Uranium / Q000633:toxicity*
chemical_list: C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D014501:Uranium
keywords: Behavior; Heavy metal; Neurogenesis; Ontogenesis