ENVIRONMENTALLY INDUCED ALTERATIONS IN NEURON AND GLIA DEVELOPMENT

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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. These critically timed events are assummed to 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, triethyltin, trimethyltin, methyl mercury, mercury vapors, and electromagnetic fields, and AIDs therapeutics), on the development of the nervous system as indicated by alterations in the spatio-temporal expression of mRNA for various developmentally regulated proteins associated with distinct processes of development (e.g., neuronal migration, neurite extension, synapse formation, and myelination). We have shown that lead acetate alters developmentally regulated structural proteins. Ongoing studies are examining the mRNA for neurotrophins and proteins associated with axonal elongation and synapse formation to further understand the subtle lead induced alteration in the formation of the neural network. Using RNase protection assays we have demonstrated a ontological profile for pro-inflammatory cytokines and neurotrophins in various brain regions. Lead acetate decreased mRNA levels for tumor necrosis factor alpha (TNFa) and interleukin-1 alpha (IL-1a) in the cerebellum while leaving the neurotrophins unchanged. Developmental mercury vapor exposure decreased TNFa, TNFbeta, and IL-6 in the cerebellum at postnatal day 14 with no alterations in the neurotrophins. This technique is being expanded with the establishment of new probe sets to detect mRNA levels for proteins associated with the various cell types and stages of brain development. In vitro experiments have shown glial cell cultures to demonstrate a maturation pattern of susceptibility to ischemic injury similar to that seen in vivo with a hypoxia-induced up-regulation of mRNA for neurotrophins in young cells that is gradually lost during maturation. Future Research: We will continue to generate developmental profiles for the neurotrophins, pro-inflammatory cytokines, and structural related proteins in brain regions following exposure to known developmental neurotoxicants to assess the feasibility of using this approach to determine developmental neurotoxic potential of a chemical and to further understand the nature of the interdependency of these critically timed events in the formation of the neural network.