The globally used herbicide glufosinate-ammonium (GLA) is structurally analogous to the excitatory neurotransmitter glutamate, and is known to interfere with cellular mechanisms involved in the glutamatergic system. In this report, we used an in vitro model of murine primary neural stem cell culture to investigate the neurotoxicity of GLA and its main metabolite, 4-methylphosphinico-2-oxobutanoic acid (PPO). We demonstrated that GLA and PPO disturb ependymal wall integrity in the ventricular-subventricular zone (V-SVZ) and alter the neuro-glial differentiation of neural stem cells. GLA and PPO impaired the formation of cilia, with reduced Celsr2 expression after PPO exposure. GLA promoted the differentiation of neuronal and oligodendroglial cells while PPO increased B1 cell population and impaired neuronal fate of neural stem cells. These results confirm our previous in vivo report that developmental exposure to GLA alters neurogenesis in the SVZ, and neuroblast migration along the rostral migratory stream. They also highlight the importance of investigating the toxicity of pesticide degradation products. Indeed, not only GLA, but also its metabolite PPO disrupts V-SVZ homeostasis and provides a novel cellular mechanism underlying GLA-induced neurodevelopmental toxicity. Furthermore, we were able to demonstrate a neurotoxic activity of a metabolite of GLA different from that of GLA active substance for the very first time.

全球使用的除草剂草铵膦铵盐（GLA）在结构上与兴奋性神经递质谷氨酸类似，并且已知会干扰参与谷氨酸能系统的细胞机制。在本报告中，我们使用了体外鼠神经原代干细胞培养的模型，以研究GLA及其主要代谢产物4-甲基膦酸-2-氧代丁酸（PPO）的神经毒性。我们证明了GLA和PPO会扰乱心室-室下区（V-SVZ）的室间隔壁完整性，并改变神经干细胞的神经胶质分化。PLA暴露后，GLA和PPO损害了纤毛的形成，并降低了Celsr2表达。GLA促进神经元和少突胶质细胞的分化，而PPO则增加B1细胞数量并损害神经干细胞的神经元命运。这些结果证实了我们以前的体内报告指出，发育性暴露于GLA会改变SVZ中的神经发生，并改变神经母细胞沿鼻端迁徙流的迁移。他们还强调了研究农药降解产物毒性的重要性。实际上，不仅GLA，而且其代谢产物PPO都破坏了V-SVZ的稳态，并提供了GLA诱导的神经发育毒性基础的新型细胞机制。此外，我们首次证明了GLA代谢产物与GLA活性物质不同的神经毒性。