Hasegawa-Baba Yasuko, Tanaka Takeshi, Watanabe Yousuke, Wang Liyun, Itahashi Megu, Yoshida Toshinori, Shibutani Makoto
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.
Neurotox Res. 2017 Jul;32(1):27-40. doi: 10.1007/s12640-017-9703-3. Epub 2017 Feb 6.
The effects of developmental exposure to 3,3'-iminodipropionitrile (IDPN), a neurotoxicant that causes proximal axonopathy, on mouse hippocampal neurogenesis was examined. Pregnant mice were exposed to IDPN at 0, 600, or 1200 ppm in their drinking water from gestational day 6 to postnatal day (PND) 21. On PND 21, male offspring showed increased postmitotic neuron-specific NeuN-immunoreactive granule cell numbers in the dentate subgranular zone (SGZ) and granule cell layer (GCL) and decreased glutamate receptor gene Grin2d levels in the dentate gyrus at 1200 ppm. On PND 77, decreased numbers were observed for TBR2 progenitor cells in the SGZ at ≥600 ppm and GFAP stem cells, DCX progenitor cells and immature granule cells, NeuN immature and mature granule cells, PCNA proliferating cells in the SGZ and/or GCL, and immunoreactive cells for ARC or FOS, immediate-early gene products related to neuronal and synaptic plasticity, in the GCL at 1200 ppm. Additionally, at 1200 ppm of IDPN, downregulation of Kit, the gene encoding the stem cell factor (SCF) receptor, and upregulation of Kitl, encoding SCF, were observed in the dentate gyrus. Therefore, maternal IDPN exposure in mice affects neurogenesis involving glutamatergic signals at the end of developmental exposure, with late effects suppressing SGZ cell proliferation, reducing the broad range of granule cell lineage population, which may be responsible for SCF receptor downregulation. The upregulated SCF was likely a feedback response to the decreased receptor level. These results suggest that reduced SCF signaling may cause suppressed neuronal and synaptic plasticity.
研究了发育过程中暴露于3,3'-亚氨基二丙腈（IDPN）这种导致近端轴突病的神经毒素对小鼠海马神经发生的影响。怀孕小鼠在妊娠第6天至出生后第21天（PND）期间，饮用含0、600或1200 ppm IDPN的水。在PND 21时，1200 ppm组的雄性后代齿状回颗粒下区（SGZ）和颗粒细胞层（GCL）中，有丝分裂后神经元特异性NeuN免疫反应性颗粒细胞数量增加，齿状回中谷氨酸受体基因Grin2d水平降低。在PND 77时，≥600 ppm组的SGZ中TBR2祖细胞数量减少，1200 ppm组的SGZ和/或GCL中GFAP干细胞、DCX祖细胞和未成熟颗粒细胞、NeuN未成熟和成熟颗粒细胞、PCNA增殖细胞数量减少，GCL中ARC或FOS免疫反应性细胞数量减少，ARC或FOS是与神经元和突触可塑性相关的即早基因产物。此外，在1200 ppm的IDPN作用下，齿状回中编码干细胞因子（SCF）受体的Kit基因下调，而编码SCF的Kitl基因上调。因此，小鼠母体暴露于IDPN会在发育暴露结束时影响涉及谷氨酸能信号的神经发生，后期影响会抑制SGZ细胞增殖，减少颗粒细胞谱系群体的范围，这可能是SCF受体下调的原因。上调的SCF可能是对受体水平降低的一种反馈反应。这些结果表明，SCF信号减少可能导致神经元和突触可塑性受到抑制。
