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. 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. The major structural protein for astrocytes in the brain, GFAP showed a temporal shift and elevation in mRNA levels during development and a slight elevation in the final protein produced in the mature CNS. mRNA levels for proteins required for the formation of myelin was depressed yet the signalling proteins for myelination remained unchanged. No alterations are seen in the generalized cytoskeletal protein mRNAs suggesting a specificity of effect rather than a generalized effect on the overall development of the elongation and synapse formation to further understand the subtle lead induced alteration in the formation of the neural network. 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 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.
