The effect of prenatal and postnatal lead exposure on neonatal synaptogenesis in rat cerebral cortex.

Pregnant rats were exposed to drinking water with lead (Pb) concentrations of 0, 30, or 200 mg/l. The resultant pups were sacrificed at 11, 15, and 21 d of postnatal age for the determination of synapses/mm3 in parietal cortex. Synaptic counts from electron micrographs of ethanol phosphotungstic acid stained cortical slices were counted by four observers who were blinded as to treatment (control or 200 mg Pb/l drinking water). A greater than fourfold increase in synaptic counts was observed in layers I, II, and III of rat pups parietal cortex between 11 and 21 d of age. Pb treatment depressed synaptic counts maximally at 15 d of age. However, Pb-exposed pups displayed essentially the same synaptic counts as controls by 21 d of age. In a cross-fostering design, it was shown that prenatal exposure to Pb completely accounted for the delays in synaptogenesis. No significant depression of synaptic counts was observed in pups exposed only during the postnatal period. Blood lead concentrations (Pb X B) were determined during gestation and suckling in both mother and offspring. A dramatic peripartum (partum plus and minus 4 d) peak in Pb X B was seen in mother and pup. Pup Pb X B peaked at 80 micrograms/dl at exposures of 200 mg Pb/l drinking water. In addition to being dose-dependent, blood Pb levels resulting from the same concentration of Pb in drinking water displayed a significant dependence on litter at time-points between birth and 1 yr of age. These data indicate that the substantially elevated blood Pb concentrations that are evident at partum in pups prenatally exposed to Pb might be responsible for the postnatally observed delay in synaptogenesis.

Specificity of the effects of lead on brain energy metabolism for substrates donating a cytoplasmic reducing equivalent.

Lead chloride, at concentrations of 67 muM in the incubation media, inhibits the potassium-stimulated respiration (3 to 30mM increase in K+) of rat cerebral cortex slices. The inhibition observed was dependent upon the substrate provided. In the presence of 10mM glucose or lactate, 35-50% inhibition of the response was observed, but no evidence of an effect could be observed when 10mM pyruvate served as substrate. In consonance with these observations, spectral measurements during the course of the response revealed an attenuation of the initial NAD(P)H oxidation followed by a substantial accumulation of the intermediate in slices metabolizing glucose, but not those metabolizing pyruvate. In vivo treatment of adult rats with six intrapertoneal injections spaced over a 14-day period gave rise to essentially similar findings at cerebral cortical lead concentrations averaging 0.41 mug/g (range equals 0.34-0.52) and above. No effect was observed at brain lead concentrations averaging 0.17 mug/g. These data suggested that lead interfered with the oxidation of the NAD(P)H produced by the initial oxidations of glucose in the cytoplasm. Inhibition of cytoplasmic NAD(P)H oxidation by brain mitochondria is of peculiar importance in a tissue relying almost exclusively upon the metabolism of glucose in vitro.