title: Developmental exposure to manganese chloride induces sustained aberration of neurogenesis in the hippocampal dentate gyrus of mice.
abstract: The effect of exogenously administered manganese (Mn) on developmental neurogenesis in the hippocampal dentate gyrus was examined in male mice after maternal exposure to MnCl(2) (0, 32, 160, or 800 ppm as Mn in diet) from gestational day 10 to day 21 after delivery on weaning. Immunohistochemistry was performed to monitor neurogenesis and interneuron subpopulations on postnatal days (PNDs) 21 and 77 (adult stage). Reelin-synthesizing γ-aminobutyric acid (GABA)ergic interneurons increased in the hilus with ≥ 160 ppm on weaning to sustain to PND 77 at 800 ppm. Apoptosis in the neuroblast-producing subgranular zone increased with 800 ppm and TUC4-expressing immature granule cells decreased with 800 ppm on weaning, whereas at the adult stage, immature granule cells increased. On PND 21, transcript levels increased with Reln and its receptor gene Lrp8 and decreased with Dpysl3 coding TUC4 in the dentate gyrus, confirming immunohistochemical results. Double immunohistochemistry revealed a sustained increase of reelin-expressing and NeuN-lacking or weakly positive immature interneurons and NeuN-expressing mature neurons in the hilus through to the adult stage as examined at 800 ppm. Brain Mn concentrations increased at both PNDs 21 and 77 in all MnCl(2)-exposed groups. These results suggest that Mn targets immature granule cells causing apoptosis and neuronal mismigration. Sustained increases in immature reelin-synthesizing GABAergic interneurons may represent continued aberration in neurogenesis and following migration to cause an excessive response for overproduction of immature granule cells through to the adult stage. Sustained high concentration of Mn in the brain may be responsible for these changes.
authors.affiliation: Laboratory of Veterinary Pathology, Tokyo University of Agriculture and Technology, Fuchu-shi, Tokyo 183-8509, Japan.
authors.forename: Liyun
authors.initials: L
authors.lastname: Wang
authors.forename: Takumi
authors.initials: T
authors.lastname: Ohishi
authors.forename: Ayako
authors.initials: A
authors.lastname: Shiraki
authors.forename: Reiko
authors.initials: R
authors.lastname: Morita
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Akane
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ikarashi
authors.forename: Kunitoshi
authors.initials: K
authors.lastname: Mitsumori
authors.forename: Makoto
authors.initials: M
authors.lastname: Shibutani
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002712:Chlorides / Q000378:metabolism / Q000633:toxicity*; D004268:DNA-Binding Proteins; D018891:Dentate Gyrus / Q000187:drug effects* / Q000196:embryology / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D005865:Gestational Age; D007150:Immunohistochemistry; D007501:Iron / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D017895:Manganese Compounds / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D055495:Neurogenesis / Q000187:drug effects*; D009687:Nuclear Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D000091042:Reelin Protein; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000097:blood; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D002712:Chlorides; C526904:Dpysl3 protein, mouse; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D026502:LDL-Receptor Related Proteins; D017895:Manganese Compounds; D009419:Nerve Tissue Proteins; C492380:NeuN protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D000091042:Reelin Protein; D013963:Thyroid Hormones; C098773:low density lipoprotein receptor-related protein 8; D005680:gamma-Aminobutyric Acid; D007501:Iron; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases; C025340:manganese chloride