title: Maternal exposure to ochratoxin A targets intermediate progenitor cells of hippocampal neurogenesis in rat offspring via cholinergic signal downregulation and oxidative stress responses.
abstract: To elucidate the developmental exposure effects of ochratoxin A (OTA) on postnatal hippocampal neurogenesis, pregnant SD rats were provided a diet containing 0, 0.12, 0.6, or 3.0ppm OTA from gestation day 6 to day 21 on weaning after delivery. Offspring were maintained through postnatal day (PND) 77 without OTA exposure. At 3.0ppm, offspring of both sexes showed a transient body weight decrease after weaning. Changes in hippocampal neurogenesis-related parameters as measured in male PND 21 offspring were observed at 3.0ppm. In the subgranular zone (SGZ) of the dentate gyrus, PAX6+or TBR2+cells were decreased, while GFAP+or DCX+cells did not fluctuate in number, suggesting decreased numbers of type-2 progenitor cells. On the other hand, SGZ cells accumulating malondialdehyde increased. In the hilus of the dentate gyrus, SST+or CHRNB2+γ-aminobutyric acid (GABA)-ergic interneurons decreased, accompanied with transcript downregulation of Chrnb2 in the dentate gyrus. These results suggest that maternal exposure to OTA decreased type-2 progenitor cells by reducing hilar GABAergic interneurons innervating type-2 progenitor cells via cholinergic signal downregulation and also by increasing oxidative stress in the SGZ. Transcript levels of neurotrophin (Bdnf), glutamatergic receptors (Gria1, Gria2, and Grin2a), serotonin-synthesizing enzyme, and serotonergic receptors (Tph2, Htr1a, and Htr4) increased in the dentate gyrus, suggesting multiple neuroprotective actions against OTA-induced aberrant neurogenesis. All observed fluctuations were reversed by PND 77. The no-observed-adverse-effect level for offspring neurogenesis was determined to be 0.6ppm, corresponding to 39.3-76.0μg/kg body weight/day.
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. Electronic address: yhase@cc.tuat.ac.jp.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hasegawa-Baba
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: 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. Electronic address: kangawa_yumi@kaken.co.jp.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Kangawa
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; D000089662:Doublecortin Protein; D015536:Down-Regulation; D005260:Female; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D008297:Male; D008431:Maternal-Fetal Exchange; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D019055:No-Observed-Adverse-Effect Level; D009793:Ochratoxins / Q000633:toxicity*; D018384:Oxidative Stress; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D017207:Rats, Sprague-Dawley
chemical_list: C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D009793:Ochratoxins; C025589:ochratoxin A
keywords: Cholinergic signal; Hippocampal neurogenesis; Ochratoxin A; Oxidative stress; Rat