Lead is a ubiquitous toxic pollutant. The most serious manifestation of pediatric lead poisoning is an acute encephalopathy. In addition, the rising burden of environmental lead may be producing significant brain damage, without overt encephalopathy, in young children, in the unborn fetus, and the neonate. Pathologic studies suggest that lead produces edema and capillary changes at a "critical" time in the immature brain of the human and in a rat model of lead encephalopathy. This "critical" period in the rat contains many age-dependent changes in energy metabolism including activities of the electron transport chain (ETC) as described by this investigator and others. Lead does act on the ETC in other tissues. However, there are no studies in immature brain of lead effects on the ETC, a probable basic step in the pathogenesis of lead encephalopathy. Preliminary results are presented on effects of lead on oxidative phosphorylation in immature rat brain mitochondria. Within 2 days of feeding lead to 2-week old animals, respiration with NAD-linked substrates is uncoupled, reflecting an increased state 4 rate. During the subsequent 2-week pre-encephalitic period of lead feedings, both state 3 and 4 rates become increasingly depressed. Cytochrome oxidase activity shows the same changes. These effects are more significant in cerebellar than in cerebral hemisphere mitochondria. Importantly, these effects of lead occur earlier than previously reported changes in brain fluid, electrolytes, and morphology. Considering the preliminary results and observations outlined above, investigations are proposed based on these hypotheses: a) the primary effect of lead in developing brain is on energy metabolism; specifically on sites in the ETC; and b) this effect is basic to the toxic effects of lead. Experiments are designed to delineate the sites and mechanisms of action of lead to learn more of the properties of the ETC in immature brain and of the pathogenesis of lead encephalopathy. Younger animals will be studied to delineate potential effects of lead on the brain of the human fetus and neonate. BIBLIOGRAPHIC REFERENCES: D. Holtzman and J. Shen Hsu. Early effects of inorganic lead on immature rat brain mitochondrial respiration. Pediatric Research 10:70-75, 1976.