Kawashima Masashi, Watanabe Yousuke, Nakajima Kota, Murayama Hirotada, Nagahara Rei, Jin Meilan, 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.
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.
Exp Toxicol Pathol. 2017 Sep 5;69(7):517-526. doi: 10.1016/j.etp.2017.04.008. Epub 2017 May 8.
Developmental exposure to glycidol of rats causes axonal injury targeting axon terminals in dams and transient disruption of late-stage differentiation of hippocampal neurogenesis, accompanying sustained increase in the number of reelin-producing or calretinin-expressing interneurons in offspring. The molecular mechanism of disruptive neurogenesis probably targets the newly generating nerve terminals. We previously found differences between mice and rats in the effects on hippocampal neurogenesis after developmental exposure to the same neurotoxic substances. In the present study, we examined the effects and underlying mechanisms of developmental exposure to glycidol on hippocampal neurogenesis in mice. Glycidol (800 or 1600ppm) was administered in drinking water to mated female mice from gestational day 6 to postnatal day 21. Compared to mice drinking water without glycidol (control), the exposed dams showed axon terminal injury at both concentrations of glycidol. The offspring of the dams that had received 1600ppm glycidol had fewer parvalbumin (PVALB) γ-aminobutyric acid (GABA)-ergic interneurons and neuron-specific nuclear protein postmitotic neurons in the hilus of the hippocampal dentate gyrus. Thus, exposure of glycidol to adult mice induced axonal degeneration equivalent to that seen in the rat; however, the target mechanism for the disruption of hippocampal neurogenesis by developmental exposure was different from that in rats, with the hilar neuronal population not affected until adulthood. Considering the role of PVALB GABAergic interneurons in the brain, developmental glycidol exposure in mice may cause a decline in cognitive function in later life, and involve a different mechanism from that targeting axon terminals in rats.
大鼠发育过程中接触缩水甘油会导致轴突损伤，损伤靶点为母鼠的轴突终末，并会短暂干扰海马神经发生的晚期分化，同时伴随子代中产生Reelin或表达钙视网膜蛋白的中间神经元数量持续增加。神经发生受到干扰的分子机制可能以新生成的神经终末为靶点。我们之前发现，发育过程中接触相同神经毒性物质后，小鼠和大鼠在海马神经发生方面的影响存在差异。在本研究中，我们检测了发育过程中接触缩水甘油对小鼠海马神经发生的影响及其潜在机制。从妊娠第6天到出生后第21天，给交配后的雌性小鼠饮用含800或1600ppm缩水甘油的水。与饮用不含缩水甘油的水的小鼠（对照组）相比，在两种缩水甘油浓度下，接触过的母鼠均出现了轴突终末损伤。接受1600ppm缩水甘油的母鼠所产子代在海马齿状回门区的小白蛋白（PVALB）γ-氨基丁酸（GABA）能中间神经元和有丝分裂后神经元特异性核蛋白神经元数量较少。因此，成年小鼠接触缩水甘油会诱导出与大鼠所见相当的轴突变性；然而，发育过程中接触缩水甘油对海马神经发生的干扰的靶点机制与大鼠不同，直到成年期海马门区神经元群体才受到影响。考虑到PVALB GABA能中间神经元在大脑中的作用，小鼠发育过程中接触缩水甘油可能会导致其晚年认知功能下降，并且涉及与大鼠轴突终末靶点不同的机制。
