title: Developmental exposure of aflatoxin B1 reversibly affects hippocampal neurogenesis targeting late-stage neural progenitor cells through suppression of cholinergic signaling in rats.
abstract: To elucidate the maternal exposure effects of aflatoxin B1 (AFB1) and its metabolite aflatoxin M1, which is transferred into milk, on postnatal hippocampal neurogenesis, pregnant Sprague-Dawley rats were provided a diet containing AFB1 at 0, 0.1, 0.3, or 1.0 ppm from gestational day 6 to day 21 after delivery on weaning. Offspring were maintained through postnatal day (PND) 77 without AFB1 exposure. Following exposure to 1.0 ppm AFB1, offspring showed no apparent systemic toxicity at weaning, whereas dams showed increased liver weight and DNA repair gene upregulation in the liver. In the hippocampal dentate gyrus of male PND 21 offspring, the number of doublecortin(+) progenitor cells were decreased, which was associated with decreased proliferative cell population in the subgranular zone at ≥ 0.3 ppm, although T-box brain 2(+) cells, tubulin beta III(+) cells, gamma-H2A histone family, member X(+) cells, and cyclin-dependent kinase inhibitor 1A(+) cells did not fluctuate in number. AFB1 exposure examined at 1.0 ppm also resulted in transcript downregulation of the cholinergic receptor subunit Chrna7 and dopaminergic receptor Drd2 in the dentate gyrus, although there was no change in transcript levels of DNA repair genes. In the hippocampal dentate hilus, interneurons expressing CHRNA7 or phosphorylated tropomyosin receptor kinase B (TRKB) decreased at ≥ 0.3 ppm. On PND 77, there were no changes in neurogenesis-related parameters. These results suggested that maternal AFB1 exposure reversibly affects hippocampal neurogenesis targeting type-3 progenitor cells. This mechanism likely involves suppression of cholinergic signals on hilar GABAergic interneurons and brain-derived neurotrophic factor-TRKB signaling from granule cells. The no-observed-adverse-effect level for offspring neurogenesis was determined to be 0.1 ppm (7.1-13.6 mg/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; 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: 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. Electronic address: nobuhiko_onda@ot.olympus.co.jp.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Onda
authors.affiliation: Laboratory of Food Safety Sciences, Azabu University, 1-17-71, Fuchinobe, Chuo-ku, Sagamihara-shi, Kanagawa 252-0206, Japan. Electronic address: y-konishi@azabu-u.ac.jp.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Sugita-Konishi
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: D016604:Aflatoxin B1 / Q000633:toxicity*; D000818:Animals; D000831:Animals, Newborn / Q000254:growth & development; D059329:Cholinergic Neurons / Q000187:drug effects; D018891:Dentate Gyrus / Q000187:drug effects / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D000089662:Doublecortin Protein; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000254:growth & development; D008297:Male; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction
chemical_list: C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D016604:Aflatoxin B1
keywords: Adult neurogenesis; Aflatoxin B(1); BDNF signaling; Cholinergic signaling; Hippocampal dentate gyrus; Rat