This research proposes to study the effects of methylmercury on the growth and development of fetal brain. A genetically defined inbred strain of mouse, and orgnano-typic and dissociated cultures of mouse fetal brain and human fetal brain (obtained from hysterotomy and hysterectomy) will be used. Pregnant mice will be given predetermined doses of methylmercury at specific stages of pregnancy. Offspring sacrificed at specified times will be studied with various morphologic techniques including light and electron microscopy, immunohistochemistry, Golgi methods, radioautography and enzyme histochemistry. Primary and secondary cultures of human and mouse fetal cerebrum and cerebellum as well as specifically cloned cells of fetal brain will be exposed to various concentrations of methylmercury and the short and long term effects on growth and development of brain in-vitro will be analyzed. Various modifying factors such as Vitamin E, selenium, dimercaptosuccinic acid, dimercaptopropanol, colchicine, cytochalasin B will be used to delineate the specific action of each factor and their influence on the effects of methylmercury will be investigated. The overall objectives of this proposal are to assess in detail the changes in development of fetal brain brought about by maternal intoxication of methylmercury, particularly the changes in the pattern of cell proliferation, neuronal migration, selective aggregation, programmed cell death during embryogenesis, elongation of axons and establishment of connections, differentiation and maturation of growing brain; to ascertain as fully as possible the mechanisms whereby these changes are brought about; and to correlate the findings with alterations observed in some of the developmental disorders of the nervous system encountered in man.
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