EFFECTS OF ORGANOPHOSPHATE INSECTICIDE ON DEVELOPMENTAL NEUROTROPHIN PRODUCTION

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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.