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.
Cooperative Division of Veterinary Sciences, Graduate School of Agriculture, Tokyo University of Agriculture and Technology, 3-5-8 Saiwai-cho, Fuchu-shi, Tokyo, 183-8509, Japan.
Neurotox Res. 2022 Dec;40(6):2203-2220. doi: 10.1007/s12640-022-00577-5. Epub 2022 Sep 13.
Lead (Pb) causes developmental neurotoxicity. Developmental exposure to Pb acetate (PbAc) induces aberrant hippocampal neurogenesis by increasing or decreasing neural progenitor cell (NPC) subpopulations in the dentate gyrus (DG) of rats. To investigate whether hippocampal neurogenesis is similarly affected by PbAc exposure in a general toxicity study, 5-week-old Sprague-Dawley rats were orally administered PbAc at 0, 4000, and 8000 ppm (w/v) in drinking water for 28 days. After exposure to 4000 or 8000 ppm PbAc, Pb had accumulated in the brains. Neurogenesis was suppressed by 8000 ppm PbAc, which was related to decreased number of type-2b NPCs, although number of mature granule cells were increased by both PbAc doses. Gene expression in the 8000 ppm PbAc group suggested suppressed NPC proliferation and increased apoptosis resulting in suppressed neurogenesis. PbAc exposure increased numbers of metallothionein-I/II cells and GFAP astrocytes in the DG hilus, and upregulated Mt1, antioxidant genes (Hmox1 and Gsta5), and Il6 in the DG, suggesting the induction of oxidative stress and neuroinflammation related to Pb accumulation resulting in suppressed neurogenesis. PbAc at 8000 ppm also upregulated Ntrk2 and increased the number of CALB2 interneurons, suggesting the activation of BDNF-TrkB signaling and CALB2 interneuron-mediated signals to ameliorate suppressed neurogenesis resulting in increased number of newborn granule cells. PbAc at both doses increased the number of ARC granule cells, suggesting the facilitation of synaptic plasticity of newborn granule cells through the activation of BDNF-TrkB signaling. These results suggest that PbAc exposure during the young-adult stage disrupted hippocampal neurogenesis, which had a different pattern from developmental exposure to PbAc. However, the induction of oxidative stress/neuroinflammation and activation of identical cellular signals occurred irrespective of the life stage at PbAc exposure.
铅（Pb）可导致发育神经毒性。发育过程中醋酸铅（PbAc）暴露通过增加或减少大鼠齿状回（DG）中的神经祖细胞（NPC）亚群，诱导异常的海马神经发生。为了研究在一般毒性研究中 PbAc 暴露是否同样影响海马神经发生，将 5 周龄的 Sprague-Dawley 大鼠用饮用水中的 0、4000 和 8000ppm（w/v）PbAc 进行口服处理 28 天。暴露于 4000 或 8000ppm PbAc 后，Pb 在大脑中积累。8000ppm PbAc 抑制神经发生，这与 NPC 数量减少有关，尽管两种 PbAc 剂量都增加了成熟颗粒细胞的数量。8000ppm PbAc 组的基因表达表明，NPC 增殖受到抑制，凋亡增加，导致神经发生受到抑制。PbAc 暴露增加了 DG 门区的金属硫蛋白-I/II 细胞和 GFAP 星形胶质细胞的数量，并上调了 DG 中的 Mt1、抗氧化基因（Hmox1 和 Gsta5）和 Il6，表明与 Pb 积累相关的氧化应激和神经炎症的诱导导致神经发生受到抑制。8000ppm PbAc 还上调了 Ntrk2，并增加了 CALB2 中间神经元的数量，表明 BDNF-TrkB 信号的激活和 CALB2 中间神经元介导的信号改善了受抑制的神经发生，导致新生颗粒细胞数量增加。两种剂量的 PbAc 均增加了 ARC 颗粒细胞的数量，表明通过 BDNF-TrkB 信号的激活促进了新生颗粒细胞的突触可塑性。这些结果表明，成年早期的 PbAc 暴露破坏了海马神经发生，其模式与发育过程中暴露于 PbAc 不同。然而，氧化应激/神经炎症的诱导和相同的细胞信号的激活发生在 PbAc 暴露的生命阶段无关。
