PMID- 24594278 OWN - NLM STAT- MEDLINE DCOM- 20140611 LR - 20211203 IS - 1879-3169 (Electronic) IS - 0378-4274 (Linking) VI - 226 IP - 3 DP - 2014 May 2 TI - N-methyl-N-nitrosourea during late gestation results in concomitant but reversible progenitor cell reduction and delayed neurogenesis in the hippocampus of rats. PG - 285-93 LID - S0378-4274(14)00105-2 [pii] LID - 10.1016/j.toxlet.2014.02.018 [doi] AB - N-Methyl-N-nitrosourea (MNU) is an alkylating agent having genotoxic potential to cause gene mutations and antiproliferative cytotoxic activity on developing brains to cause microcephaly by mid-gestational exposure in rodents. This study investigated the transient genotoxic and cytocidal effect of MNU at the beginning of the subgranular zone (SGZ) formation in the hippocampal dentate gyrus on neurogenesis in later life using rats. Pregnant rats were injected with MNU at 0 (vehicle controls), 1 or 3mg/kg body weight intraperitoneally from gestational day (GD) 18 to GD 20 once a day. In offspring, effects were observed at 3mg/kg. Fetal brains on GD 21 after the last MNU injection increased TUNEL(+) apoptotic cells in the tertiary germinal matrices. At postnatal day (PND) 21 on weaning, offspring displayed decrease of doublecortin (Dcx)(+) cells and cell proliferation in the SGZ and increase of calbindin (Calb1)(+) interneurons in the dentate hilus. Postnatal single bromodeoxyuridine (BrdU) injection on PND 3 resulted in an increase of BrdU(+)/Dcx(+) cells. On PND 77, Dcx(+) cells recovered in number, but cell proliferation increased in the SGZ. Thus, late-gestational maternal MNU exposure may induce reversible reductions of type-3 progenitor and/or immature granule cells and cell proliferation on weaning in response to progenitor cell apoptosis, as well as delayed neurogenesis due to cell cycle arrest. Increases of Calb1(+) interneurons on weaning and SGZ cell proliferation later on may reflect compensatory mechanism for MNU-induced aberrant neurogenesis. Considering the lack of effects on PND 77, MNU may mainly target transient populations of highly proliferative progenitor cells without affecting their stem cells to undergo progenitor production. Protective and plasticity mechanism may be operated against genotoxic agents on hippocampal neurogenesis. CI - Copyright (c) 2014 Elsevier Ireland Ltd. All rights reserved. FAU - Itahashi, Megu AU - Itahashi M AD - 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: itahashi@cc.tuat.ac.jp. FAU - Wang, Liyun AU - Wang L AD - Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan. Electronic address: waly2009@cc.tuat.ac.jp. FAU - Shiraki, Ayako AU - Shiraki A AD - 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. FAU - Abe, Hajime AU - Abe H AD - 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: abeichi@cc.tuat.ac.jp. FAU - Tanaka, Takeshi AU - Tanaka T AD - 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. FAU - Murakami, Tomoaki AU - Murakami T AD - Laboratory of Veterinary Toxicology, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo 183-8509, Japan. Electronic address: mrkmt@cc.tuat.ac.jp. FAU - Yoshida, Toshinori AU - Yoshida T AD - 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. FAU - Shibutani, Makoto AU - Shibutani M AD - 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. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20140302 PL - Netherlands TA - Toxicol Lett JT - Toxicology letters JID - 7709027 RN - 0 (Calbindins) RN - 0 (Dcx protein, rat) RN - 0 (Doublecortin Domain Proteins) RN - 0 (Doublecortin Protein) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Neuropeptides) RN - 684-93-5 (Methylnitrosourea) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Calbindins/analysis MH - Cell Proliferation/drug effects MH - Doublecortin Domain Proteins MH - Doublecortin Protein MH - Female MH - Fetus/*drug effects MH - Hippocampus/*drug effects/pathology MH - Interneurons/drug effects MH - Male MH - Methylnitrosourea/*toxicity MH - Microtubule-Associated Proteins/analysis MH - Neural Stem Cells/*drug effects MH - Neurogenesis/*drug effects MH - Neuropeptides/analysis MH - Pregnancy MH - Rats OTO - NOTNLM OT - Hippocampal dentate gyrus OT - N-Methyl-N-nitrosourea (MNU) OT - Neurogenesis OT - Subgranular zone (SGZ) OT - gamma-Aminobutyric acid (GABA) ergic interneuron EDAT- 2014/03/07 06:00 MHDA- 2014/06/12 06:00 CRDT- 2014/03/06 06:00 PHST- 2014/01/09 00:00 [received] PHST- 2014/02/21 00:00 [revised] PHST- 2014/02/21 00:00 [accepted] PHST- 2014/03/06 06:00 [entrez] PHST- 2014/03/07 06:00 [pubmed] PHST- 2014/06/12 06:00 [medline] AID - S0378-4274(14)00105-2 [pii] AID - 10.1016/j.toxlet.2014.02.018 [doi] PST - ppublish SO - Toxicol Lett. 2014 May 2;226(3):285-93. doi: 10.1016/j.toxlet.2014.02.018. Epub 2014 Mar 2.