title: Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study.
abstract: Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600mg/kg body weight/day for 28days. In the subgranular zone (SGZ), 600mg/kg CPZ increased the number of cleaved caspase-3(+) apoptotic cells. At ≥120mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥120mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥120mg/kg decreased phosphorylated TRKB(+) interneurons, although the number of reelin(+) interneurons was unchanged. At 600mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells.
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.
authors.forename: Hajime
authors.initials: H
authors.lastname: Abe
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.
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.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kimura
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.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Mizukami
authors.affiliation: Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004, Japan.
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.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Imatanaka
authors.affiliation: Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Akahori
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan.
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: D000284:Administration, Oral; D000367:Age Factors; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D019070:Cell Lineage; D003471:Cuprizone / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D000089662:Doublecortin Protein; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009186:Myelin Sheath / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects*; D017207:Rats, Sprague-Dawley; D000091042:Reelin Protein; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D000091042:Reelin Protein; C000717129:Reln protein, rat; D003471:Cuprizone
keywords: 28-day oral toxicity study; Adult neurogenesis; Cholinergic signaling; Cuprizone (CPZ); Hippocampal dentate gyrus; Myelin toxicant