Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
Toxicol Lett. 2012 Feb 25;209(1):86-93. doi: 10.1016/j.toxlet.2011.11.026. Epub 2011 Dec 3.
Several extensively used organophosphorus ester (OP) insecticides are phosphorothionates. The oxon metabolites of phosphorothionates have long been known to be responsible for the acute cholinergic neurotoxicity associated with OP poisoning. In addition, there is now sufficient evidence to suggest that the oxon metabolites may also be directly responsible for the particular neurotoxicity that phosphorothionate insecticides, and especially chlorpyrifos (CP) and diazinon (DZ), are known to inflict on the developing organism. In vitro data reveal that the oxons, which are present at increased levels in the developing brain, have the ability to directly disrupt, at toxicologically relevant doses, separately a number of neurodevelopmental processes, including those of neuronal proliferation, neuronal differentiation, gliogenesis and apoptosis. In most cases, the effects of the oxons are very potent. Inhibition of neuronal and glial cell differentiation by the oxons in particular is up to 1000-times stronger than that caused by their parent phosphorothionates. The neurodevelopmental toxicity of the oxons is not related to the inhibition of the enzymatic activity of acetylcholinesterase (AChE), but may be due to direct oxon interference with the morphogenic activity that AChE normally shows during neurodevelopment. Other possible direct targets of the oxons include neurodevelopmentally important cell signaling molecules and cytoskeletal proteins which have been found to be affected by the oxons and to which covalent binding of the oxons has been recently shown. Future studies should aim at confirming the developmental neurotoxic capacity of the oxons under in vivo conditions and they must also be extended to include OP parent insecticides with a P=O moiety.
几种广泛使用的有机磷酯（OP）杀虫剂是硫代磷酸酯。硫代磷酸酯的氧代代谢物长期以来一直被认为是与 OP 中毒相关的急性胆碱能神经毒性的原因。此外，现在有足够的证据表明，氧代代谢物也可能直接导致特定的神经毒性，即硫代磷酸酯杀虫剂，尤其是毒死蜱（CP）和二嗪磷（DZ），已知对发育中的生物体造成伤害。体外数据显示，在发育中的大脑中水平升高的氧代物具有在毒理学相关剂量下直接破坏许多神经发育过程的能力，包括神经元增殖、神经元分化、神经胶质发生和细胞凋亡。在大多数情况下，氧代物的作用非常强烈。特别是，氧代物对神经元和神经胶质细胞分化的抑制作用比其母体硫代磷酸酯要强 1000 倍。氧代物的神经发育毒性与乙酰胆碱酯酶（AChE）的酶活性抑制无关，但可能是由于氧代物直接干扰 AChE 在神经发育过程中通常表现出的形态发生活性。氧代物的其他可能直接靶标包括神经发育重要的细胞信号分子和细胞骨架蛋白，这些分子已被发现受到氧代物的影响，并且最近已经证明氧代物与这些分子发生共价结合。未来的研究应旨在在体内条件下确认氧代物的发育神经毒性能力，并且还必须将其扩展到包括具有 P=O 部分的 OP 母体杀虫剂。
