EFFECTS OF ORGANOPHOSPHATE INSECTICIDE ON DEVELOPMENTAL NEUROTROPHIN PRODUCTION

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。目前的文献表明，由于发育中的神经系统的脆弱性，儿童在接触毒死蜱期间比成年人面临更大的风险。以往的研究表明，毒死蜱对幼虫的毒理作用可能是通过影响细胞发育来实现的。由于神经营养因子是神经元生存和分化所必需的，毒死蜱对神经营养因子途径的干扰可能导致脑发育的缺陷，导致神经元发育所需的适当的营养和神经发生信号的改变。我们的实验室最近证实，出生后早期接触毒死蜱会降低前脑中神经生长因子(NGF)蛋白的水平。在海马体中没有观察到类似的变化。然而，在断奶后期暴露，最初会增加海马区BDNF蛋白水平，但不会改变NGF蛋白水平。鉴于这些神经营养因子在海马体中的正常产生位置，神经营养因子产生的这种变化模式表明，对不同类型的神经元有不同的影响。这些效应可能是由于刺激了位于海马区和海马区神经元中的M受体(MAChR)。此外，在停止接触后，两种神经营养因子都显著降低，这表明对神经营养因子的产生持续产生影响。该项目旨在进一步研究毒死蜱诱导的BDNF和NGF水平的变化与mAChR介导的信号之间的联系。因此，该项目的假设是--毒死蜱暴露会改变大脑中对胆碱能系统成熟至关重要的神经营养素的产生，从而扰乱或延缓胆碱能神经元的适当发育/维持。正在进行的实验旨在证明，暴露期间神经营养素水平的变化反映了海马区不同神经元亚群的激活和抑制。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Current literature suggests that children are at greater risk during a chlorpyrifos exposure than are adults due to the vulnerability of the developing nervous system. Previous investigations have suggested that the toxicological effects of chlorpyrifos in juveniles may be mediated by affecting cell development. Since the neurotrophins are necessary for neuronal survival and differentiation, disruption of the pathways of the neurotrophins by chlorpyrifos exposure could lead to deficits in brain development resulting in the alteration of the appropriate trophic and neuritogenic signals required for neuron development. Our laboratory recently demonstrated that early postnatal exposure to chlorpyrifos decreases the levels of nerve growth factor (NGF) protein in the forebrain. Similar changes were not observed in the hippocampus. However, exposure during the late preweanling period initially increases hippocampal BDNF protein levels with no change in NGF protein levels. Given the normal location of production of these neurotrophins in the hippocampus, this pattern of changes in neurotrophin production suggests differential effects on different types of neurons. These effects could be due to stimulation of muscarinic receptors (mAChR) located both in the hippocampus and in neurons innervating the hippocampus. In addtion, following cessation of exposure, both neurotrophins were significantly decreased suggesting persistent effects on neurotrophin production. This project is designed to further investigate the links between chlorpyrifos-induced changes in BDNF and NGF levels and signaling mediated through the mAChR. Therefore, the hypothesis of this project is--Chlorpyrifos exposure alters neurotrophin production in brain regions which are important in the maturation of the cholinergic system, thereby disrupting or delaying appropriate development/maintenance of the cholinergic neurons. Ongoing experiments are designed to demonstrate that the change in neurotrophin levels during exposure is reflective of both activation and inhibition of different subsets of neurons in the hippocampus.