title: Adult hippocampal neurogenesis is impaired by transient and moderate developmental thyroid hormone disruption.
abstract: The hippocampus maintains a capacity for neurogenesis throughout life, a capacity that is reduced in models of adult onset hypothyroidism. The effects of developmental thyroid hormone (TH) insufficiency on neurogenesis in the adult hippocampus, however, has not been examined. Graded degrees of TH insufficiency were induced in pregnant rat dams by administration of 0, 3 or 10ppm of 6-propylthiouracil (PTU) in drinking water from gestational day (GD) 6 until weaning. Body, brain, and hippocampal weight were reduced on postnatal day (PN) 14, 21, 78 and hippocampal volume was smaller at the 10 but not 3ppm dose level. A second experiment examined adult hippocampal neurogenesis following developmental or adult onset hypothyroidism. Two male offspring from 0 and 3ppm exposed dams were either maintained on control water or exposed to 3ppm PTU to create 4 distinct treatment conditions (Control-Control; Control-PTU, PTU-Control, PTU-PTU) based on developmental and adult exposures. Beginning on the 28th day of adult exposure to 0 or 3ppm PTU, bromodeoxyuridine (BrdU, 50mg/kg, ip) was administered twice daily for 5days, and one male from each treatment was sacrificed 24h and 28days after the last BrdU dose and brains processed for immunohistochemistry. Although no volume changes were seen in the hippocampus of the neonate at 3ppm, thinning of the granule cell layer emerged in adulthood. Developmental TH insufficiency produced a reduction in newly born cells, reducing BrdU+ve cells at 1 with no further reduction at 28-days post-BrdU. Similar findings were obtained using the proliferative cell marker Ki67. Neuronal differentiations was also altered with fewer doublecortin (Dcx) expressing cells and a higher proportion of immature Dcx phenotypes seen after developmental but not adult TH insufficiency. An impaired capacity for neurogenesis may contribute to impairments in synaptic plasticity and cognitive deficits previously reported by our laboratory and others following moderate degrees of developmental TH insufficiency induced by this PTU model.
authors.affiliation: Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC, USA. Electronic address: gilbert.mary@epa.gov.
authors.forename: M E
authors.initials: ME
authors.lastname: Gilbert
authors.affiliation: Department of Developmental Neurobiology, NY State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA; Departments of Physiology and Pharmacology and Neurology, SUNY Downstate Medical Center Brooklyn, NY 11203, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Goodman
authors.affiliation: Department of Developmental Neurobiology, NY State Institute for Basic Research in Developmental Disabilities, Staten Island, NY 10314, USA.
authors.forename: J
authors.initials: J
authors.lastname: Gomez
authors.affiliation: Toxicity Assessment Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park, NC, USA.
authors.forename: A F M
authors.initials: AFM
authors.lastname: Johnstone
authors.affiliation: Department of Biomedical Sciences, New York Institute of Technology College of Osteopathic Medicine, Old Westbury, NY 11568, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Ramos
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D000963:Antimetabolites / Q000633:toxicity; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D006624:Hippocampus / Q000196:embryology / Q000254:growth & development / Q000473:pathology*; D007037:Hypothyroidism / Q000097:blood / Q000139:chemically induced / Q000473:pathology*; D019394:Ki-67 Antigen / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced / Q000503:physiopathology*; D011441:Propylthiouracil / Q000633:toxicity; D051381:Rats; D020318:Rats, Long-Evans; D013963:Thyroid Hormones / Q000097:blood
chemical_list: D000963:Antimetabolites; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D013963:Thyroid Hormones; D011441:Propylthiouracil; D001973:Bromodeoxyuridine
keywords: Brain development; Dentate gyrus; Developmental neurotoxicity; Hippocampus; Hypothyroidism; Neurogenesis; Thyroid hormone