Maturation of resistance to lead encephalopathy: cellular and subcellular mechanisms.
The rat pup fed inorganic lead has been studied extensively as an animal model of human lead encephalopathy. As in man, the sensitivity of the brain to lead toxicity is age-dependent. Pups given daily lead feedings for one week beginning in the first week of life show pathologic changes (i.e., hemorrhage, edema, and neuronal necrosis) throughout the brain including the cerebral cortex and cerebellum. Pups begun on daily lead feedings for two weeks between 10-18 days of age show similar pathologic changes almost entirely confined to the cerebellum. Pups receiving very large quantities of lead for two weeks beginning at 20 or 24 days of age develop only minimal edema or no changes by light microscopy. We have proposed that the effects of lead on cellular aerobic energy metabolism are important in the pathogenesis of the encephalopathy in the developing brain. Early in the course of lead feedings begun at 14 days of age, isolated cerebellar mitochondria show a loss of respiratory control. During the second week of lead feedings, respiration with NAD-linked substrates is inhibited in cerebellar mitochondria, but not in cerebral mitochondria, from these animals. Cerebral mitochondrial respiration in pups fed lead from birth also is inhibited while both cerebral and cerebellar mitochondrial respiration in lead-fed adults is not affected. Isolated brain mitochondria exposed to lead in vitro show similar changes; an initial respiratory stimulation (probably reflecting an energy-coupled uptake of lead) and a secondary inhibition of dehydrogenases located in the mitochondrial matrix. Lead also may compete with calcium for brain mitochondrial carrier or binding sites. During maturation, the brain appears to become resistant to lead toxicity by sequestering lead away from the mitochondrial site of action. This hypothesis is based upon the observations that: 1. the in vitro effects of lead are the same in immature and mature cerebellar mitochondria; 2. the cerebral and cerebellar lead concentrations are the same in immature encephalopathic and mature encephalopathy-resistant lead-fed animals and; 3. cerebellar mitochondria from animals fed lead from 14 days of age contain much more lead than cerebral mitochondria from these animals and cerebellar mitochondria from lead-fed adults. This hypothesis is supported further by the results of recent electron microscopic and elemental microprobe studies of lead distribution in the brains of animals fed lead beginning at 14-18 days of age.(ABSTRACT TRUNCATED AT 400 WORDS)
D000367:Age Factors; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D001927:Brain Diseases / Q000139:chemically induced* / Q000378:metabolism; D002478:Cells, Cultured; D004198:Disease Susceptibility; D004734:Energy Metabolism / Q000187:drug effects; D006801:Humans; D007854:Lead / Q000494:pharmacology / Q000633:toxicity*; D007855:Lead Poisoning / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D051381:Rats
D009243:NAD; D007854:Lead