Roy Tara Sankar, Seidler Frederic J, Slotkin Theodore A
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 3813 DUMC, Durham, NC 27710, USA.
Brain Res Dev Brain Res. 2004 Feb 20;148(2):197-206. doi: 10.1016/j.devbrainres.2003.12.004.
The widely used organophosphate insecticide, chlorpyrifos (CPF), elicits neurobehavioral teratogenesis with exposure windows ranging from the embryonic neural tube stage through postnatal development. To explore the morphologic changes occurring in late-stage exposure, newborn rats were given 5 mg/kg of CPF s.c. daily on postnatal days (PN) 11-14, a regimen that is devoid of systemic toxicity, but that elicits long-term cognitive impairment. On PN15 and 20, we examined the septal nucleus, striatum and somatosensory cortex. Across all three regions, CPF elicited a significant decrease in the number of glial cells. Superimposed on this basic pattern, there were region-specific alterations in the number and type of neurons, and neuronal perikaryal dimensions. In the septal nucleus, the CPF group exhibited an increase in the number of neurons on PN20, representing a delay in the normal maturational decline; there was a parallel decrease in the glial/neuronal ratio. In the striatum, the number of neurons per unit area was reduced in the CPF group, accompanied by perikaryal hypertrophy, as evidenced by an increase in the average neuronal cell diameter. In the somatosensory cortex, the distribution of cell sizes indicated a decrease in the proportion of small, nonpyramidal cells. Thus, there are subtle morphological changes in the juvenile rat brain after neonatal CPF exposure that are detectable with quantitative analysis and that correlate with later emergence of behavioral alterations. Furthermore, the current findings support the hypothesis that CPF interferes with gliogenesis, a relatively late event in brain development; accordingly, the vulnerable period for adverse effects of CPF is likely to extend into childhood or adolescence.
广泛使用的有机磷杀虫剂毒死蜱（CPF）会引发神经行为致畸作用，其暴露窗口涵盖从胚胎神经管阶段到出生后发育阶段。为探究晚期暴露时发生的形态学变化，对新生大鼠在出生后第11至14天每天皮下注射5 mg/kg的CPF，该方案无全身毒性，但会引发长期认知障碍。在出生后第15天和第20天，我们检查了隔核、纹状体和体感皮层。在所有这三个区域，CPF均导致神经胶质细胞数量显著减少。在此基本模式之上，神经元的数量和类型以及神经元胞体尺寸存在区域特异性改变。在隔核中，CPF组在出生后第20天神经元数量增加，这代表正常成熟衰退延迟；神经胶质细胞/神经元比例平行下降。在纹状体中，CPF组单位面积内的神经元数量减少，同时伴有胞体肥大，平均神经元细胞直径增加即证明了这一点。在体感皮层中，细胞大小分布表明小的非锥体细胞比例下降。因此，新生大鼠暴露于CPF后，幼鼠大脑会出现细微的形态学变化，这些变化可通过定量分析检测到，并且与后期行为改变的出现相关。此外，当前研究结果支持CPF干扰神经胶质生成这一假说，神经胶质生成是大脑发育中相对较晚的事件；因此，CPF产生不良反应的敏感期可能会延伸至儿童期或青春期。
