Neurons are more sensitive than astrocytes to lead toxicity in vivo. In order to understand the b... more Neurons are more sensitive than astrocytes to lead toxicity in vivo. In order to understand the bases for the differences in brain cell responses to lead, the effects of lead acetate on cell morphology and on aerobic energy metabolism were studied in rat primary cultured neurons and astrocytes. By transmission electron microscopy, neuronal cell damage was seen with exposure to lead concentrations which were much lower than those required for similar changes in the astrocyte. As previously described in our studies of in vivo lead exposure, astrocytes in primary culture concentrated lead in nuclear, cytoplasmic, and lysosomal inclusions while neurons showed lead densities only in lysosomes. With acute lead exposures, inhibition of maximal respiratory capacity was greater and occurred at lower lead concentrations in neurons than in astrocytes. Similarly, respiratory rates were inhibited at lower lead concentrations in cerebral cortical slices from 8-day-old rat pups compared to those from adults. We conclude that primary cultured brain cells are appropriate in vitro systems for studying the in vivo cellular responses to lead. As in vivo, neurons are more sensitive than astrocytes to lead toxicity. In both cells, inhibition of aerobic energy metabolism appears to be closely associated with cell damage. The capacity of the astrocyte to sequester lead in nonmitochondrial intracellular sites may be critical in resistance to lead toxicity in vitro and in the mature brain.
Although it is well established that respiratory uptake of lead-containing particles plays a subs... more Although it is well established that respiratory uptake of lead-containing particles plays a substantial role in the epidemiology of plumbism, relatively little is known about the role of the pulmonary alveolar macrophage in lead poisoning. An in vitro system was designed to investigate the effects of lead oxide particles of respirable size on the rabbit alveolar macrophage. The studies were concerned with the intracellular solubility of PbO and Pb3O4 and changes in fine structure attributable to lead toxicity. The distribution of phagocytosed lead and its intracellular reprecipitation complexes was established by electron microprobe analysis and secondary ion mass spectroscopy in conjunction with transmission electron microscopy, scanning electron microscopy, scanning transmission electron microscopy, and backscatter imaging. It was found that Pb3O4, PbO and PbO-coated particles were ingested by the rabbit alveolar macrophages and that each of these lead oxide compounds produced similar damage to the fine structure of the cell. Swelling of the mitochondria, nuclear membrane, and endoplasmic reticulum was common, as well as were characteristic reprecipitation complexes of lead, phosphorous, and calcium within the nuclear heterochromatin and cytoplasm of the cell. The precipitation complexes were not seen in cells incubated with the particles if phagocytosis was blocked by 0.22-microns, membrane filters. It was concluded that phagocytosis of these lead oxide particles was necessary to produce the cytopathic changes. It is suggested that solubilization of lead from the ingested particles in phagosomes of macrophages results in the liberation of intracellular lead with the resultant formation of reprecipitation complexes.
The rat pup fed inorganic lead has been studied extensively as an animal model of human lead ence... more 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)
ABSTRACT Filarial disease, transmitted from person-to-person by mosquitoes, principally affects p... more ABSTRACT Filarial disease, transmitted from person-to-person by mosquitoes, principally affects people in tropical and sub-tropical areas. One hundred and twenty million people in at least 80 nations of the world have lymphatic filariasis. One billion people are at risk of getting infected. Ninety percent of these infections are caused by Wuchereria bancrofti , and most of the remainder by Brugia malayi. For W. bancrofti , humans are the exclusive host. The major vectors for W. bancrofti are culicine mosquitoes in most urban and semiurban areas, anophelines in the more rural areas. Larvae in the blood of human hosts are ingested when the insect vectors feed. Within the vector, the microfilarias migrate to specific sites and develop from first-stage larvae into infective third-stage larvae. The vector transmits the infective larvae into a human host when feeding. Mosquitoes deposit the larvae on the host skin adjacent to the puncture site and the third stage larval (L3) parasites migrate through the venous system and lungs to eventually take up residence in the lymphatics. There they form nests occupied by male and female worms, and produce the first stage larvae or microfilariae by viviparous reproduction These larvae migrate from the lymphatics to the peripheral blood where mosquitoes ingest them. The filarial disease has protean manifestaions in the form of chronic, acute and ′asymptomatic′ presentations as well as a number of syndromes associated with these infections that may or may or not be caused by the parasites.
Neurons are more sensitive than astrocytes to lead toxicity in vivo. In order to understand the b... more Neurons are more sensitive than astrocytes to lead toxicity in vivo. In order to understand the bases for the differences in brain cell responses to lead, the effects of lead acetate on cell morphology and on aerobic energy metabolism were studied in rat primary cultured neurons and astrocytes. By transmission electron microscopy, neuronal cell damage was seen with exposure to lead concentrations which were much lower than those required for similar changes in the astrocyte. As previously described in our studies of in vivo lead exposure, astrocytes in primary culture concentrated lead in nuclear, cytoplasmic, and lysosomal inclusions while neurons showed lead densities only in lysosomes. With acute lead exposures, inhibition of maximal respiratory capacity was greater and occurred at lower lead concentrations in neurons than in astrocytes. Similarly, respiratory rates were inhibited at lower lead concentrations in cerebral cortical slices from 8-day-old rat pups compared to those from adults. We conclude that primary cultured brain cells are appropriate in vitro systems for studying the in vivo cellular responses to lead. As in vivo, neurons are more sensitive than astrocytes to lead toxicity. In both cells, inhibition of aerobic energy metabolism appears to be closely associated with cell damage. The capacity of the astrocyte to sequester lead in nonmitochondrial intracellular sites may be critical in resistance to lead toxicity in vitro and in the mature brain.
Although it is well established that respiratory uptake of lead-containing particles plays a subs... more Although it is well established that respiratory uptake of lead-containing particles plays a substantial role in the epidemiology of plumbism, relatively little is known about the role of the pulmonary alveolar macrophage in lead poisoning. An in vitro system was designed to investigate the effects of lead oxide particles of respirable size on the rabbit alveolar macrophage. The studies were concerned with the intracellular solubility of PbO and Pb3O4 and changes in fine structure attributable to lead toxicity. The distribution of phagocytosed lead and its intracellular reprecipitation complexes was established by electron microprobe analysis and secondary ion mass spectroscopy in conjunction with transmission electron microscopy, scanning electron microscopy, scanning transmission electron microscopy, and backscatter imaging. It was found that Pb3O4, PbO and PbO-coated particles were ingested by the rabbit alveolar macrophages and that each of these lead oxide compounds produced similar damage to the fine structure of the cell. Swelling of the mitochondria, nuclear membrane, and endoplasmic reticulum was common, as well as were characteristic reprecipitation complexes of lead, phosphorous, and calcium within the nuclear heterochromatin and cytoplasm of the cell. The precipitation complexes were not seen in cells incubated with the particles if phagocytosis was blocked by 0.22-microns, membrane filters. It was concluded that phagocytosis of these lead oxide particles was necessary to produce the cytopathic changes. It is suggested that solubilization of lead from the ingested particles in phagosomes of macrophages results in the liberation of intracellular lead with the resultant formation of reprecipitation complexes.
The rat pup fed inorganic lead has been studied extensively as an animal model of human lead ence... more 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)
ABSTRACT Filarial disease, transmitted from person-to-person by mosquitoes, principally affects p... more ABSTRACT Filarial disease, transmitted from person-to-person by mosquitoes, principally affects people in tropical and sub-tropical areas. One hundred and twenty million people in at least 80 nations of the world have lymphatic filariasis. One billion people are at risk of getting infected. Ninety percent of these infections are caused by Wuchereria bancrofti , and most of the remainder by Brugia malayi. For W. bancrofti , humans are the exclusive host. The major vectors for W. bancrofti are culicine mosquitoes in most urban and semiurban areas, anophelines in the more rural areas. Larvae in the blood of human hosts are ingested when the insect vectors feed. Within the vector, the microfilarias migrate to specific sites and develop from first-stage larvae into infective third-stage larvae. The vector transmits the infective larvae into a human host when feeding. Mosquitoes deposit the larvae on the host skin adjacent to the puncture site and the third stage larval (L3) parasites migrate through the venous system and lungs to eventually take up residence in the lymphatics. There they form nests occupied by male and female worms, and produce the first stage larvae or microfilariae by viviparous reproduction These larvae migrate from the lymphatics to the peripheral blood where mosquitoes ingest them. The filarial disease has protean manifestaions in the form of chronic, acute and ′asymptomatic′ presentations as well as a number of syndromes associated with these infections that may or may or not be caused by the parasites.
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