During the development of the nervous system, the temporal and spatial regulation of gene expression is a critical component of neural and glial growth, development, and interactions between cells and may be a major component in the differential susceptibility of the developing organism to environmental insult. This project examines the effects of various environmental agents, e.g. lead acetate, organometals - lead and tin, on the level of nervous system specific genes developmental regulated and associated with specific developmental stages and cell types in the nervous system. For example, early exposure to lead acetate alters the ontological profile of mRNA for proteins specific to either neurons or glial cells. The expression of GAP-43 mRNA, a protein localized in the growth cone of the developing axon and critical for axonal elongation and synapse formation is significantly depressed. Astroglia cells are responsive by elevated expression of glial fibrillary acidic protein mRNA. The hypomyelinating effects of lead acetate may be linked to the early depression of mRNA for myelin specific proteins. The profile of effects at the level of gene expression were dependent upon the specific region the brain examined and the developmental period of exposure. No alterations are seen in the generalized cytoskeletal protein mRNAs suggestion a specificity of effect rather than a generalized effect on the overall development of the brain. During the formation of the intricate neural network, the system undergoes a process of """"""""pruning"""""""" to remove excess neurites and membranes. This may be associated with phagocytosis and various immune-like cytokine responses of microglia and astrocytes. The expression of various pro-inflammatory cytokines as well as growth associated cytokines may be critically involved in this modulatory process of normal development in the nervous system. Examination of the developmental regulation of cytokines in the brain and the response in conditions known to alter development are being studied.
