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Reprod Toxicol. 2016 Oct;65:113-122. doi: 10.1016/j.reprotox.2016.06.018. Epub 2016 Jun 23.

Maternal exposure to ochratoxin A targets intermediate progenitor cells of hippocampal neurogenesis in rat offspring via cholinergic signal downregulation and oxidative stress responses.

Author information

1
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.
2
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.
3
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.
4
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.
5
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.
6
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.
7
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.

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.

KEYWORDS:

Cholinergic signal; Hippocampal neurogenesis; Ochratoxin A; Oxidative stress; Rat

PMID:
27346841
DOI:
10.1016/j.reprotox.2016.06.018
[Indexed for MEDLINE]

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