MOLECULAR MECHANISMS OF INORGANIC LEAD NEUROTOXICITY

Hugo W. Moser Res Inst Kennedy Krieger, Baltimore MD

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Abstract

This program project resubmission is geared to elucidate mechanisms by which lead exposure can interfere with the function of a child's brain. The present application has been reduced from the original five projects to four projects in the response to the review committee's suggestion. The remaining projects focus on two target sites in the developing brain which are affected by lead exposure. Projects 1 and 2 explore potential mechanisms by which lead light compromise the blood-brain-barrier. Projects 3 and 4 examine molecular events at the synapse that are altered by lead. More specifically, project 1, focuses on changes in the immediate early response gene expression, following leading exposure, particularly c-jun and c-fos. The basis for elevated c-fos mRNA levels are due to transcriptional or post-transcriptional mechanisms. The effects of Pb2+ on c-fos mRNA will also be examine din the glial endothelial cell culture. Each of these will be complemented by assay for alterations in the AP1 activity in the vitro: and lastly, the same effects of Pb2+ on c-fos mRNA and AP1 activity will be examined in the vivo. The goal of project 2 is to determine the effect of Pb2+ exposure in the neonate of rat brain microvessel growth and on the expression of blood- barrier proteins such as v-glutamyl transpeptidase, p-glycoprotein, or endothelial barrier antigen. Aims of this project will also investigate whether Pb2+ exposure affects proteolytic enzyme expression and activities that are associated with rat brain microvessel development, and whether exposure alters the level and distribution of proteins that mediate microvessel interaction with the extracellular matrix in the rat brain. Project 3 and 4 deal with molecular events in the synaptogenesis and potential interference by exposure to lead. In the project 3, the focus will be on the binding characteristics of Pb2+ to synaptotagmin and its biochemical and cell physiological consequences. This will be carried out in the vitro using PC12 cells and rat neurotransmitter releases. Lastly, the investigators will determine whether or not synaptotagmin deficient mice are less susceptible to lead-induce changes in the synaptic transmission than wild type. Project 4 will examine the hypothesis that glutamate receptors are a primary target of lead exposure during brain development. To this end, the investigator will ask whether exposure to Pb2+ alters the temporal or spacial distribution of glutamate receptors and/or their relative levels of expression in the fetal rat brains. The effects of lead exposure on glutamate receptor expression will be examined at different pre- and post-natal times. The effects of Pb2+ exposure of glutamate receptor will be analyzed in the barrel field, hippocampus, and cerebellum.