Laboratory of Veterinary Pathology, Division of Animal Life Science, Institute of Agriculture, 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.
Chemicals Evaluation and Research Institute, Japan, 1-4-25 Koraku, Bunkyo-ku, Tokyo 112-0004, Japan.
Toxicol Lett. 2019 Sep 15;312:195-203. doi: 10.1016/j.toxlet.2019.05.013. Epub 2019 May 11.
Developmental exposure to valproic acid (VPA), a model compound for experimental autism, has shown to primarily target GABAergic interneuron subpopulations in hippocampal neurogenesis of rat offspring. The VPA-exposed animals had revealed late effects on granule cell lineages, involving progenitor cell proliferation and synaptic plasticity. To investigate the possibility whether hippocampal neurogenesis in postpubertal rats in a protocol of 28-day repeated exposure is affected in relation with the property of a developmental neurotoxicant by developmental exposure, VPA was orally administered to 5-week-old male rats at 0, 200, 800 and 900 mg/kg body weight/day for 28 days. At 900 mg/kg, GFAP cells increased in number, but DCX cells decreased in number in the granule cell lineages. Moreover, CHRNB2 cells and NeuN postmitotic neurons decreased in number in the hilus of the dentate gyrus. Transcript level examined at 900 mg/kg in the dentate gyrus was increased with Kit, but decreased with Dpsyl3, Btg2, Pvalb and Chrnb2. These results suggest that VPA increased type-1 stem cells in relation to the activation of SCF-KIT signaling and suppression of BTG2-mediated antiproliferative effect on stem cells. VPA also decreased type-3 progenitor cells and immature granule cells probably in relation with PVALB interneuron hypofunction and reduced CHRNB2 interneuron subpopulation in the hilus, as well as with suppression of BTG2-mediated terminal differentiation of progenitor cells. Thus, the disruption pattern of VPA by postpubertal exposure was different from developmental exposure. However, disruption itself can be detected, suggesting availability of hippocampal neurogenesis in detecting developmental neurotoxicants in a 28-day toxicity study.
发育暴露于丙戊酸（VPA），一种实验性自闭症的模型化合物，主要靶向大鼠后代海马神经发生中的 GABA 能中间神经元亚群。暴露于 VPA 的动物表现出对颗粒细胞谱系的晚期影响，涉及祖细胞增殖和突触可塑性。为了研究在 28 天重复暴露方案中，青春期后大鼠的海马神经发生是否因发育暴露而受到影响，与发育神经毒物的特性有关，将 VPA 以 0、200、800 和 900 mg/kg 体重/天的剂量口服给予 5 周龄雄性大鼠，每天一次，连续 28 天。在 900 mg/kg 时，GFAP 细胞数量增加，但颗粒细胞谱系中的 DCX 细胞数量减少。此外，齿状回门区的 CHRNB2 细胞和 NeuN 后分裂神经元数量减少。在 900 mg/kg 时，齿状回中的转录水平检查显示 Kit 增加，但 Dpsyl3、Btg2、Pvalb 和 Chrnb2 减少。这些结果表明，VPA 通过激活 SCF-KIT 信号和抑制 BTG2 对干细胞的抗增殖作用，增加了 1 型干细胞。VPA 还减少了 3 型祖细胞和未成熟颗粒细胞，可能与 PVALB 中间神经元功能低下以及门区中 CHRNB2 中间神经元亚群减少以及 BTG2 介导的祖细胞终末分化抑制有关。因此，青春期后暴露的 VPA 破坏模式与发育暴露不同。然而，可以检测到破坏本身，表明在 28 天毒性研究中，海马神经发生可用于检测发育神经毒物。
