title: Immunohistochemistry of aberrant neuronal development induced by 6-propyl-2-thiouracil in rats.
abstract: 6-Propyl-2-thiouracil (PTU)-induced hypothyroidism disrupts neuronal/glial development. This study sought to identify the sensitive immunohistochemical parameters of developmental neurotoxicity (DNT) following PTU-exposure, as well as their responses in a 28-day toxicity study in adults. In the developmental exposure study, pregnant rats were treated with 0, 1, 3, and 10ppm PTU in drinking water from gestational day 6 to postnatal day (PND) 21 and pups were examined on PNDs 21 and 77. In the adult-stage exposure study, 5-week-old male rats were treated with 0, 0.1 and 10mg PTU/kg by oral gavage for 28 days. In the developmental exposure study on PND 21, there were fewer GFAP+, PAX6+, and DCX+cells in the subgranular zone (SGZ) of the hippocampal dentate gyrus at ≥3 or 10ppm. Regarding synaptic plasticity-related molecules, there were fewer EPHA4+and ARC+cells in the dentate granule cell layer. Regarding GABAergic interneuron subpopulations, there were more RELN+, CALB2+, and SST+cells and fewer PVALB+cells in the dentate hilus. There were also differences in the numbers of RELN+, PVALB+, CALB2+, and NPY+cells in the cerebral cortex, and RELN+, PVALB+, and SST+cells in the cerebellar cortex. Most of these changes were sustained until PND 77. Following adult-stage exposure (10mg/kg), there were fewer SGZ DCX+cells, but more RELN+and SST+cells in the dentate hilus. Results suggest that GABAergic interneuron populations in cortical tissues, hippocampal neurogenesis, and synaptic plasticity are sensitive to PTU-induced DNT during development. In contrast, only hippocampal neurogenesis was sensitive to adult-stage exposure.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. Electronic address: shirakia@cc.tuat.ac.jp.
authors.forename: Ayako
authors.initials: A
authors.lastname: Shiraki
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. Electronic address: tatanaka@cc.tuat.ac.jp.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan; Pathogenetic Veterinary Science, United Graduate School of Veterinary Sciences, Gifu University, 1-1 Yanagido, Gifu-shi, Gifu 501-1193, Japan. Electronic address: ywatana@cc.tuat.ac.jp.
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Watanabe
authors.affiliation: Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004, Japan. Electronic address: saito-fumiyo@ceri.jp.
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Saito
authors.affiliation: Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004, Japan. Electronic address: akahori-yumi@ceri.jp.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Akahori
authors.affiliation: Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004, Japan. Electronic address: imatanaka-nobuya@ceri.jp.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Imatanaka
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan. Electronic address: yoshida7@cc.tuat.ac.jp.
authors.forename: Toshinori
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan. Electronic address: mshibuta@cc.tuat.ac.jp.
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000818:Animals; D015415:Biomarkers; D000089662:Doublecortin Protein; D005260:Female; D007037:Hypothyroidism; D008297:Male; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011441:Propylthiouracil / Q000633:toxicity*; D051381:Rats; D000091042:Reelin Protein
chemical_list: D015415:Biomarkers; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D000091042:Reelin Protein; C000717129:Reln protein, rat; D011441:Propylthiouracil
keywords: Developmental neurotoxicity; GABAergic interneuron; Hippocampal neurogenesis; Hypothyroidism; Rat; Toxicity study