ADHESION AND REPULSION MOLECULES IN DEVELOPMENTAL NEUROTOXIC INJURY

DESCRIPTION (provided by applicant) The appropriate temporal and spatial expression of neural adhesion and repulsion molecules, membrane proteins which provide instructive guidance and support for neuron and neurite movement, is critical to normal brain develop disturbance of the synchronous expression and function of these molecules has adverse consequences ranging fro subtle learning disabilities to severe malformations. Exposure to toxic metals, particularly methylmercury known to result in behavioral disabilities in development and in deficient learning and processes in adults-possibly by the shared mechanism of disturbing brain morphogenesis. It is hypothesized that neurotoxic metals perturb brain development/morphogenesis by disrupting the co-regulated expression and function of critical morphoregulatory adhesion and repulsion molecules. To elucidate the neurotoxic roles of these metals, four questions will be examined in hippocampus and cerebellum: 1) Does exposure to neurotoxic metals alter the expression of adhesion and repulsion molecules during stages of brain development, and thereby compromise morphogenesis? 2) Do selective transcriptional, translational or posttranslational processes mediate metal-induced changes adhesion and repulsion molecules? 3) What are the behavioral consequences of toxicant-disturbed adhesion and repulsion molecules? 4)Can the deleterious effects of toxic metals on morphoregulatory molecules be modified or ameliorated by intervention strategies? Complementary morphological, biochemical and behavioral assessments will be used to characterize the adverse of methylmercury or lead exposure on the adhesion molecules, NCAM L1, N-cadherin, and the Eph family of repulsion molecules in hippocampus (which remain plastic throughout life)and cerebellum (in which plasticity fades maturation). Consequences to both structural and behavioral development will be addressed in vivo, using ex vivo and in vitro models. Current clinical interventions for metal toxicity will be assessed for effects on molecules. As data are developed by the Exposure Assessment and Intervention and Clinical Science Projects, other candidate neurotoxic agents will similarly be studied for their effects on the adhesion and repulsion critical for normal develop. The long-term objective is to elucidate the mechanisms by which toxic metals an other xenobiotics alter neural pathway formation and synaptic regulation and how consequences of such exposures might be minimized.