The Pathogenesis of Lead Encephalopathy in the Rat Pup: Effects of Maternal PbCO3 Feedings from Birth

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Summary: Rat pups received PbCO3 via maternal feedings from the day of birth. Pb-fed pups showed decreased weight gain, decreased activity, and delayed neurologic development compared to controls in the first 2 weeks of life. The highest frequency of spontaneous deaths and of gross hemorrhagic cerebellar encephalopathy occurred in the second week of Pb feedings. Packed red blood cell volumes decreased progressively in Pb-fed animals, compared to controls, during the 4 weeks of Pb feedings. The increase in Pb content, expressed as a function of homogenate protein, was greater in the cerebellum than the cerebrum after 2 and 4 weeks of Pb feedings. In the first 2 weeks of life, respiration was affected more in mitochondria isolated from the cerebrums than from the cerebellums of Pb-fed animals. Respiratory control ratios with NAD-linked substrates were depressed due to inhibition of state 3 respiration. With succinate as substrate, both state 3 and state 4 respirations were inhibited. In cerebral mitochondria from animals surviving the first 2 weeks of Pb feedings, control ratios and respiratory rates returned toward normal values. Cerebellar mitochondria from Pb-fed animals showed no significant changes in respiration in the first 2 weeks. After 3 and 4 weeks of Pb feedings, control ratios in cerebellar mitochondria were decreased due to a marked increase in state 4 rates with the NAD-linked substrates. Similar but smaller changes occurred with succinate as substrate. Cytochrome oxidase (EC 1.9.3.1) activity showed a progressive increase in both cerebellar and cerebral mitochondria from Pb-fed animals throughout the 4 weeks of lead feedings. Speculation: The age-dependent differences in brain regional mitochondrial sensitivity to Pb effects may be due to regional differences in the time course of maturation. The cerebral mitochondrial effects of early Pb feedings may be important in the changes in learning performance and behavior attributed to early Pb feedings in the neonatal rat and the human infant or fetus.