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.
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.
Chem Biol Interact. 2024 Aug 25;399:111145. doi: 10.1016/j.cbi.2024.111145. Epub 2024 Jul 11.
Imidacloprid (IMI) is a widely used neonicotinoid insecticide that poses risks for developmental neurotoxicity in mammals. The present study investigated the effects of maternal exposure to IMI on behaviors and adult neurogenesis in the hippocampal dentate gyrus (DG) of rat offspring. Dams were exposed to IMI via diet (83, 250, or 750 ppm in diet) from gestational day 6 until day 21 post-delivery on weaning, and offspring were maintained until adulthood on postnatal day 77. In the neurogenic niche, 750-ppm IMI decreased numbers of late-stage neural progenitor cells (NPCs) and post-mitotic immature granule cells by suppressing NPC proliferation and ERK1/2-FOS-mediated synaptic plasticity of granule cells on weaning. Suppressed reelin signaling might be responsible for the observed reductions of neurogenesis and synaptic plasticity. In adulthood, IMI at ≥ 250 ppm decreased neural stem cells by suppressing their proliferation and increasing apoptosis, and mature granule cells were reduced due to suppressed NPC differentiation. Behavioral tests revealed increased spontaneous activity in adulthood at 750 ppm. IMI decreased hippocampal acetylcholinesterase activity and Chrnb2 transcript levels in the DG on weaning and in adulthood. IMI increased numbers of astrocytes and M1-type microglia in the DG hilus, and upregulated neuroinflammation and oxidative stress-related genes on weaning. In adulthood, IMI increased malondialdehyde level and number of M1-type microglia, and downregulated neuroinflammation and oxidative stress-related genes. These results suggest that IMI persistently affected cholinergic signaling, induced neuroinflammation and oxidative stress during exposure, and increased sensitivity to oxidative stress after exposure in the hippocampus, causing hyperactivity and progressive suppression of neurogenesis in adulthood. The no-observed-adverse-effect level of IMI for offspring behaviors and hippocampal neurogenesis was determined to be 83 ppm (5.5-14.1 mg/kg body weight/day).
吡虫啉（IMI）是一种广泛使用的新烟碱类杀虫剂，对哺乳动物的发育神经毒性构成风险。本研究调查了母体暴露于 IMI 对大鼠后代海马齿状回（DG）行为和成年神经发生的影响。从妊娠第 6 天到产后第 21 天断奶，通过饮食（饮食中的 83、250 或 750ppm）使母体暴露于 IMI，并且后代在产后第 77 天维持到成年。在神经发生龛中，750ppm 的 IMI 通过抑制 NPC 增殖和 ERK1/2-FOS 介导的颗粒细胞突触可塑性，减少晚期神经祖细胞（NPC）和有丝分裂后未成熟颗粒细胞的数量。观察到的神经发生和突触可塑性减少可能是由于 reelin 信号转导受到抑制。在成年期，≥250ppm 的 IMI 通过抑制其增殖和增加凋亡来减少神经干细胞，并且由于 NPC 分化受到抑制，成熟的颗粒细胞减少。行为测试显示，750ppm 时成年期自发活动增加。IMI 在断奶和成年时降低 DG 中的海马乙酰胆碱酯酶活性和 Chrnb2 转录水平。IMI 增加 DG 门区的星形胶质细胞和 M1 型小胶质细胞数量，并在断奶时上调神经炎症和氧化应激相关基因。在成年期，IMI 增加了丙二醛水平和 M1 型小胶质细胞的数量，并下调了神经炎症和氧化应激相关基因。这些结果表明，IMI 持续影响胆碱能信号，在暴露期间诱导神经炎症和氧化应激，并在暴露后增加海马体对氧化应激的敏感性，导致成年期过度活跃和神经发生的进行性抑制。IMI 对后代行为和海马神经发生的无观察到不良效应水平确定为 83ppm（5.5-14.1mg/kg 体重/天）。
