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; 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.
Toxicology. 2021 May 30;456:152782. doi: 10.1016/j.tox.2021.152782. Epub 2021 Apr 20.
Lead (Pb) exposure causes cognitive deficits in children. The present study investigated the effect of developmental exposure to Pb acetate (PbAc) on postnatal hippocampal neurogenesis. Pregnant rats were administered drinking water containing 0, 2000, or 4000 ppm PbAc from gestational day 6 until day 21 post-delivery (weaning), and offspring were maintained without PbAc exposure until adulthood on postnatal day (PND) 77. There was a dose-related accumulation of Pb in the offspring brain at weaning, while Pb was mainly excreted in adulthood. In the hippocampus, metallothionein I/II immunoreactive glia were increased through adulthood as a neuroprotective response to accumulated Pb, accompanied by increased astrocyte and microglia numbers in adulthood, suggesting sustained neural damage. Gene expression changes suggested elevated oxidative stress at weaning and suppression of the antioxidant system in adulthood, as well as continued neuroinflammatory responses. At weaning, granule cell apoptosis was increased and numbers of type-3 neural progenitor cells (NPCs) were decreased. By contrast, type-2a and type-2b NPCs were increased, suggesting suppressed differentiation to type-3 NPCs. In adulthood, there were increased numbers of immature granule cells. In the hilus of the dentate gyrus, somatostatin interneurons were increased at weaning, while calbindin-D-29K interneurons were increased throughout adulthood, suggesting a strengthened interneuron regulatory system against the suppressed differentiation at weaning. In the dentate gyrus, Bdnf, Ntrk2, and Chrna7 gene expression were upregulated and numbers of hilar TrkB interneurons increased at weaning. These findings suggest activation of BDNF-TrkB signaling to increase somatostatin interneurons and promote cholinergic signaling, thus increasing later production of immature granule cells. In adulthood, Pcna and Apex1 gene expression were downregulated and Chek1 and cyclin-dependent kinase inhibitor expression were upregulated. Furthermore, there was an increase in γ-H2AX SGZ cells, suggesting induction of cellular senescence of SGZ cells due to Pb genotoxicity.
铅（Pb）暴露会导致儿童认知能力受损。本研究探讨了发育过程中接触醋酸铅（PbAc）对产后海马神经发生的影响。从妊娠第 6 天到产后第 21 天（断奶），给怀孕的老鼠喂食含有 0、2000 或 4000ppm PbAc 的饮用水，并且在产后第 77 天（PND）之前，让后代不再接触 PbAc。在断奶时，后代大脑中的 Pb 呈剂量相关的积累，而 Pb 主要在成年时排出。在海马体中，金属硫蛋白 I/II 免疫反应性胶质细胞通过成年期增加，作为对积累的 Pb 的神经保护反应，伴随着成年期星形胶质细胞和小胶质细胞数量的增加，表明持续的神经损伤。基因表达变化表明在断奶时氧化应激升高，成年时抗氧化系统受到抑制，以及持续的神经炎症反应。在断奶时，颗粒细胞凋亡增加，第 3 型神经前体细胞（NPCs）数量减少。相比之下，第 2a 和第 2b NPCs 增加，表明对第 3 型 NPCs 的分化受到抑制。在成年期，未成熟颗粒细胞数量增加。在齿状回的颗粒细胞层，生长抑素中间神经元在断奶时增加，而在整个成年期，钙结合蛋白-D-29K 中间神经元增加，表明抑制分化时中间神经元调节系统增强。在齿状回中，Bdnf、Ntrk2 和 Chrna7 基因表达上调，齿状回的 hilar TrkB 中间神经元数量增加。这些发现表明 BDNF-TrkB 信号的激活增加了生长抑素中间神经元并促进了胆碱能信号，从而增加了以后未成熟颗粒细胞的产生。在成年期，Pcna 和 Apex1 基因表达下调，Chek1 和细胞周期蛋白依赖性激酶抑制剂表达上调。此外，SGZ 细胞中的 γ-H2AX 增加，表明由于 Pb 遗传毒性导致 SGZ 细胞发生细胞衰老。
