Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Brain Res Bull. 2010 Aug 30;83(1-2):76-83. doi: 10.1016/j.brainresbull.2010.06.010. Epub 2010 Jun 25.
The developmental neurotoxicity of organophosphates involves mechanisms other than their shared property as cholinesterase inhibitors, among which are excitotoxicity and oxidative stress. We used PC12 cells as a neurodevelopmental model to compare the effects of chlorpyrifos and diazinon on the expression of genes encoding glutamate transporters. Chlorpyrifos had a greater effect in cells undergoing nerve growth factor-induced neurodifferentiation as compared to undifferentiated PC12 cells, with peak sensitivity at the initiation of differentiation, reflecting a global upregulation of all the glutamate transporter genes expressed in this cell line. In differentiating cells, chlorpyrifos had a significantly greater effect than did diazinon and concordance analysis indicated no resemblance in their expression patterns. At the same time, the smaller effects of diazinon were highly concordant with those of an organochlorine pesticide (dieldrin) and a metal (divalent nickel). We also performed similar evaluations for the cystine/glutamate exchanger, which provides protection against oxidative stress by moving cystine into the cell; again, chlorpyrifos had the greatest effect, in this case reducing expression in undifferentiated and differentiating cells. Our results point to excitotoxicity and oxidative stress as major contributors to the noncholinesterase mechanisms that distinguish the neurodevelopmental outcomes between different organophosphates while providing a means whereby apparently unrelated neurotoxicants may produce similar outcomes.
有机磷的发育神经毒性涉及到除了它们作为胆碱酯酶抑制剂的共同特性之外的其他机制，其中包括兴奋性毒性和氧化应激。我们使用 PC12 细胞作为神经发育模型，比较了毒死蜱和二嗪磷对编码谷氨酸转运体的基因表达的影响。与未分化的 PC12 细胞相比，在神经生长因子诱导的神经分化过程中，毒死蜱对细胞的影响更大，在分化开始时达到峰值，反映出该细胞系中表达的所有谷氨酸转运体基因的全面上调。在分化细胞中，毒死蜱的作用明显大于二嗪磷，一致性分析表明它们的表达模式没有相似之处。与此同时，二嗪磷的较小作用与有机氯农药（狄氏剂）和金属（二价镍）非常一致。我们还对胱氨酸/谷氨酸交换器进行了类似的评估，该交换器通过将胱氨酸转移到细胞内提供对氧化应激的保护；同样，毒死蜱的作用最大，在这种情况下，它降低了未分化和分化细胞中的表达。我们的结果表明，兴奋性毒性和氧化应激是区分不同有机磷化合物神经发育结果的非胆碱酯酶机制的主要贡献者，同时为看似不相关的神经毒物产生相似结果提供了一种方法。
