title: Maternal exposure to hexachlorophene targets intermediate-stage progenitor cells of the hippocampal neurogenesis in rat offspring via dysfunction of cholinergic inputs by myelin vacuolation.
abstract: Hexachlorophene (HCP) is known to induce myelin vacuolation corresponding to intramyelinic edema of nerve fibers in the central and peripheral nervous system in animals. This study investigated the effect of maternal exposure to HCP on hippocampal neurogenesis in rat offspring using pregnant rats supplemented with 0 (controls), 100, or 300 ppm HCP in the diet from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, the numbers of T box brain 2(+) progenitor cells and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling(+) apoptotic cells in the hippocampal subgranular zone (SGZ) decreased in female offspring at 300 ppm, which was accompanied by myelin vacuolation and punctate tubulin beta-3 chain staining of nerve fibers in the hippocampal fimbria. In addition, transcript levels of the cholinergic receptor, nicotinic beta 2 (Chrnb2) and B-cell CLL/lymphoma 2 (Bcl2) decreased in the dentate gyrus. HCP-exposure did not alter the numbers of SGZ proliferating cells and reelin- or calcium-binding protein-expressing γ-aminobutyric acid (GABA)-ergic interneuron subpopulations in the dentate hilus on PND 21 and PND 77. Although some myelin vacuolation remained, all other changes observed in HCP-exposed offspring on PND 21 disappeared on PND 77. These results suggest that maternal HCP exposure reversibly decreases type-2b intermediate-stage progenitor cells via the mitochondrial apoptotic pathway in offspring hippocampal neurogenesis at 300 ppm HCP. Neurogenesis may be affected by dysfunction of cholinergic inputs into granule cell lineages and/or GABAergic interneurons as indicated by decreased transcript levels of Chrnb2 and numbers of Chrnb2(+) interneurons caused by myelin vacuolation in the septal-hippocampal pathway.
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: itahashi@cc.tuat.ac.jp.
authors.forename: Megu
authors.initials: M
authors.lastname: Itahashi
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: abeichi@cc.tuat.ac.jp.
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. 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: smizuka@cc.tuat.ac.jp.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Mizukami
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: mskimura@cc.tuat.ac.jp.
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. 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: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D019070:Cell Lineage; D002799:Cholinergic Fibers / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D059330:GABAergic Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D006582:Hexachlorophene / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018811:Maternal Exposure / Q000009:adverse effects*; D009186:Myelin Sheath / Q000378:metabolism*; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects*; D010641:Phenotype; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000091042:Reelin Protein; D014404:Tubulin / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
chemical_list: D006582:Hexachlorophene; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D000091042:Reelin Protein; D014404:Tubulin; C000717129:Reln protein, rat; C488416:Tubb3 protein, rat
keywords: Cholinergic receptor; Hexachlorophene; Hippocampal neurogenesis; Myelin vacuolation