Showing papers on "Lead acetate published in 1996"

Effect of Perinatal Lead Exposure on Rat Behaviour in Open-Field and Two-Wky Avoidance Tasks

Abstract: In view of conflicting results in literature concerning lead exposure associated with behavioural alterations, this study investigated behaviour in the open-field and shuttle avoidance, for as well as tissue lead burdens of pre- and postnatally lead-exposed rats. Rats were exposed to the metal from conception to weaning by giving the dams 0.5, 2.0 or 4.0 mM lead acetate in drinking water. This regimen did not affect body weight gain of dams or offspring development and had no effect on cerebral weights nor on haematological parameters of 23-day-old rats. In 1-day-old rats, lead accumulated in the blood but not in the brain, whereas both in 23-day-old rats and in dams lead accumulated in blood, kidney and cerebral cortex. In the open-field, lead-exposed groups showed higher locomotor activity in the test session as compared to controls and did not show any decrease in rearing responses in the test, indicating less habituation. Lead-treated rats subjected to a shuttle avoidance task showed no significant increase in avoidance responses between sessions as compared to control, indicating less retention. Moreover, only the control group presented a significant reduction of the footshock escape latency along testing session, suggesting a lead effect on footshock escape acquisition. In the shuttle box, intertrial crossing responses were not affected by lead treatment. The behavioural alterations occurred in animals with blood lead levels in the range 11-50.6 micrograms/dl.

The Enhancing Effect of Tumour Necrosis Factor‐α on Oxidative Stress in Endotoxemia

Abstract: The enhancing effect of tumour necrosis factor-alpha (TNF-alpha) on oxidative stress with or without a sublethal dose of endotoxin was examined. The mortality of mice treated with recombinant human TNF-alpha (1 x 10(4) units/mouse, intravenously) and endotoxin (0.01-1 mg/kg, intraperitoneally) was dependent on the dose of endotoxin. The liver lipid peroxide level, superoxide anion generation and serum lactate dehydrogenase activity, especially serum lactate dehydrogenase-5 isozyme leakage, in mice 2-4 hr after administration of recombinant human TNF to endotoxin-pretreated mice (0.5 mg/kg, intraperitoneally) were markedly higher than in those without endotoxin, whereas the administration of recombinant human TNF significantly decreased the non-protein sulfhydryl level, superoxide dismutase and glutathione peroxide activities in the liver of endotoxin-injected mice compared with those in mice treated with recombinant human TNF or endotoxin alone. Furthermore, findings clearly demonstrated that J774A.1 cells stimulated with recombinant human TNF (1 x 10(4) units/ml) can effectively produce nitric oxide in the presence of endotoxin, and the production was dependent on the dose of endotoxin (0.01-10 micrograms/ml). The level of lipid peroxide in mice 4 hr after administration of recombinant human TNF and lead acetate (50 mg/kg, intravenously) was markedly higher than that in the mice treated with recombinant human TNF alone. By contrast, injection of polymyxin-B (20 mg/kg, intraperitoneally, an anti-endotoxin drug) markedly decreased the lipid peroxide level in the liver of the mice treated with recombinant human TNF and lead acetate. These findings suggest that the oxidative stress caused by TNF occurs as a enhancing effect of endotoxin or by bacterial translocation from the intestinal gut under reduction of reticuloendothelial system function in various disease states, and that the effect of TNF may cause a marked increase of toxicity of oxidative stress by endotoxin.

Phosphorylation of membrane proteins in erythrocytes treated with lead

Abstract: In immature rat microvessels, endothelial cells and glioma cells, exposure to lead results in an increase in the level of protein kinase C in membranes. In this paper we have extended these studies to human erythrocytes and, in addition, studied the phosphorylation of membrane proteins. A significant increase in the phosphorylation of membrane cytoskeletal proteins of molecular mass 120, 80, 52 and 45 kDa was observed in human erythrocytes treated for 60 min with lead acetate at concentrations greater than 100 nM. These same proteins were phosphorylated when erythrocytes were treated for 10 min with 50 nM phorbol 12-myristate 13-acetate (PMA). Similarly, protein kinase C activity was elevated and an increase in the amount of protein kinase C-α was observed in membranes from erythrocytes exposed to concentrations of lead acetate above 100 nM. No changes, however, in the activities of cAMP-dependent protein kinase, protein phosphatases I and IIA or casein kinase were observed. Phosphorylation of these membrane proteins stimulated by lead acetate or by PMA was not observed in erythrocytes depleted of protein kinase C by a 72-h treatment with 500 nM phorbol 12,13-dibutyrate. Finally, no changes in the levels of calcium or diacylglycerol were observed in erythrocytes stimulated with 100 nM lead acetate. These results indicate that, in erythrocytes, lead acetate stimulates the phosphorylation of membrane cytoskeletal proteins by a mechanism dependent on protein kinase C. Since levels of calcium or diacylglycerols did not increase, it appears that lead may activate the enzyme by a direct interaction.

Role of heme in cytochrome P450 transcription and function in mice treated with lead acetate.

Abstract: Genetic and acquired heme deficiencies are associated with impaired cytochrome P450 (P450) function in experimental animals and in humans. The hypothetical explanations have been either a decreased supply of heme for saturation of apo-P450 or a requirement of heme for P450 gene transcription. We investigated the effect of heme deficiency on P450 function, mRNA, and transcription in C57BL/6 mice treated with lead acetate (75 mg of Pb2+/kg intraperitoneally). Lead caused an increase in delta-aminolevulinic acid levels in plasma (> 30-fold) and a decrease in the heme saturation of hepatic tryptophan-2,3-dioxygenase (15 +/- 4% versus 33 +/- 6% of heme saturation in controls; p

Lead Cytotoxicity in Primary Cultured Rat Astrocytes and Schwann Cells

Abstract: The cytotoxic effects of lead acetate on primary cultured astrocytes and Schwann cells (SCs) were studied for comparing the sensitivity of the two kinds of cells and exploring the possible mechanism of lead cytotoxicity. The results indicated that the number of astrocytes detached from the culture surfaces were dependent on the concentration and time of lead exposure. Under phase contrast microscopy, increases in the number of vacuoles were observed at doses of 50 and 100 micrograms ml-1 lead after 96 h of lead exposure for astrocytes and 1, 5 and 10 micrograms ml-1 lead after 24 h of lead exposure for SCs. By scanning electron microscopy, the surface changes in astrocytes began to appear at the dose of 10 micrograms ml-1 lead, whereas in SCs it began in 1 microgram ml-1 lead. By transmission electron microscopy, astrocytes exposed to 10, 50 and 100 micrograms ml-1 lead had increased lysosomal densities, the presence of nuclear inclusions and enlargement of rough endoplasmic reticulum, whereas SCs exposed to 1 microgram ml-1 lead began to show swelling of mitochondria and endoplasmic reticulum, cytoplasmic vacuolizations and numerous myelinoid bodies. Increases in the content of lactic dehydrogenase (LDH) leakage from the astrocytes exposed to 100 micrograms ml-1 lead and SCs exposed to 1, 5 and 10 micrograms ml-1 lead were observed, respectively. Decreases in sulphydryl group (SH) levels in astrocytes exposed to 50 and 100 micrograms ml-1 lead and SCs exposed to 1, 5 and 10 micrograms ml-1 lead were also observed. A dose of 1.0 mmol l-1 reduced glutathione (GSH) and 2.0 mmol l-1 dithiothreitol (DTT) could protect astrocytes from lead-induced SH decrease and LDH leakage. Doses of 10-100 mumol l-1 cAMP were shown to have a protective effect on lead-induced SH decrease in SCs. No significant changes of GSH or lipid peroxidation (LPO) were observed in astrocytes. The results indicated that SH was involved in lead-induced cytotoxicity of astrocytes and SCs, and SCs were more sensitive to lead-induced cytotoxicity than astrocytes.

GAP-43 mRNA expression in the developing rat brain : Alterations following lead-acetate exposure

Abstract: The developmental neurotoxicity of environmental lead exposure manifests as alterations in neural functioning and perturbed axonal and dendritic development. To examine the hypothesis that such lead-induced alterations in the neural network are associated with an altered mRNA expression of a specific neural cell growth associated protein, mRNA levels of GAP-43 (growth associated protein 43) were measured in the cortex and hippocampus of developing Long-Evans hooded rats following various lead exposure paradigms. Postnatal developmental profiles (PND 6, 9, 12, 15, 20, and 25) of mRNA expression were generated following either prenatal (gestational day 13 to birth), postnatal (postnatal day 1 to postnatal day 20), or perinatal (gestational day 13 to postnatal day 20) exposure to lead acetate (0.2% in the drinking water of the dam). In control rats, GAP-43 mRNA levels displayed a distinct developmentally regulated profile of expression in both the cortex and hippocampus, characterized by an elevated level of expression within the first week of life. This peak level of expression was significantly depressed following either postnatal or perinatal exposure to lead acetate, while prenatal lead exposure produced an initial elevation of GAP-43 mRNA on postnatal day 6 followed by a sharp decline. These data suggest that lead exposure results in altered mRNA expression of a specific neural cell growth associated protein critical to the normal process of development. This perturbation in expression may play a role in the previously reported effects of lead acetate on axonal elongation during development of the nervous system and the subsequent alteration in nervous system functioning.

Influence of iron deficiency and lead treatment on behavior and cerebellar and hippocampal polyamine levels in neonatal rats

Abstract: Effect of lead exposure and iron-deficiency on polyamine levels in neuronal and glial cells of cerebellum and hippocampus was investigated in weaned rats. Lactating dams with one day old litters were given 0.2% (w/v) lead acetate in drinking water from postnatal day one to twenty one and maintained on an iron-deficient diet. There was an overall reduction of putrescine, spermidine and spermine in neuronal and glial cells of cerebellum and hippocampus consequent to lead exposure and iron-deficiency alone. Lead exposure and iron-deficiency together did not potentiate the polyamine levels in neuronal and glial cells of cerebellum and hippocampus uniformly. However, the enhanced lowering of putrescine in the hippocampal glia, spermidine in cerebellar neuronal and spermine in both neuronal and glial cells of cerebellum during the critical stage of brain development may result in stunted neuronal growth and sprouting in lead exposed and iron-deficient animals. The behavioral alterations as observed in the present study may be due to impaired neuronal development resulting from a depressed polyamine pathway and which could be attributed to cognitive deficits in growing children.

Lead levels in bone and hair of rats treated with lead acetate.

Abstract: The use of hair and bone as media in evaluation of lead exposure was investigated in this study. For 12–16 wk rats were given tap water containing lead acetate in the following concentrations: 41.7 mg Pb/L, 83.3 mg Pb/L, and 166.6 mg Pb/L. The animals were sacrificed every 4 wk and their tibia bones and hair were collected for determination of lead content. In control animals, the lead level amounted to 1.2 μg/g (range 0.8–1.3 μg/g) and 0.7 μg/g (range 0.4–2.0 μg/g) in bone and hair, respectively. In the treated rats the accumulation of lead in bone and hair occurred in a dose-dependent manner. A positive corelation (r=0.876) was established between the lead levels in bone and hair of the rats. The regression equation was as follows: μg Pb/g bone=0.842×μg Pb/g hair+1.868. After discontinuation of exposure, a significant decrease in the lead content in bone and hair was noticed. About 9 wk after cessation of treatment, the lead content in hair declined to the pre-exposure level, but 64% of the maximal lead concentration did remain in bone. The results of this study indicate that during a continuous exposure the lead level in hair reflects its content in bone. Such phenomena did not occur during the postexposure period.

Does lead provoke the peroxidation process in rat brain synaptosomes

Abstract: Up to now there has been no information concerning the effect of lead on the peroxidation process in brain nerve endings. We have examined whether lead acetate (in chronic and acute models of toxicity in vivo and in vitro) affected the levels of free radicals in synaptosomes obtained from rat brain. Simulateneously, we have checked the effect of peroxidation of Pb2+ on brain homogenates and microsomal fraction. Our results indicated that the lead level in synaptosomal fraction obtained from lead-treated rats was much higher than in controls. We did not observe induction of spontaneous and Fe3+-dependent peroxidation either in synaptosomes or in homogenates and brain microsomes after chronic and acute lead administration to the rats. Lead itself also did not enhance both processes when added in vitro to the control brain synaptosomes in micromolar concentrations. The lack of the lead effect on the peroxidation process in subcellular fractions of brain was rather surprising, because lead is known to be the accelerator of Fe3+-dependent peroxidation processes in liver. Additionally, livers from rats under the same toxicity conditions were examined. We have found that lead did not provoke spontaneous peroxidation in liver, but contrary to brain fractions, it drastically increased iron-dependent peroxidation in liver homogenates and microsomes. The lack of the effect of lead on inducing peroxidation processes in brain is probably the consequence of the brain having stronger protective mechanisms against its toxicity than the liver.

Neurotoxic effects of gestational administration of low-dose lead acetate.

Abstract: Lead acetate (300 mg l -1 ) was administered to pregnant Wistar rats from day 1 of pregnancy to day 0 postpartum or day 5 postpartum, via drinking water. On these days, pups were sacrificed, collecting the blood to determine the concentration of lead by graphite furnace atomic absorption spectrophotometry. Brains were used to determine the total content of nucleic acids, DNA/RNA ratio and the total amount of proteins, lipids and monoamines. We found a reduction in protein content on day 0 postpartum, and changes in monoamine concentration on day 0 postpartum and day 5 postpartum. These data suggest that prenatal and early lactational exposure to a relatively low dose of lead could produce alterations in monoaminergic metabolism.

Changes in regional brain GFAP levels and behavioral functioning following subchronic lead acetate exposure in adult rats

Abstract: Adult male WAG/Rij/MBL rats were dosed with lead acetate at 0, 4.0, 8.0 or 12.5 mg/kg, 5 days per week for 4 weeks. Animals were assessed prior to exposure, at the end of the 4-week exposure period and after a 2-week recovery period using a functional observational battery (FOB) and motor activity assessment. Rats were sacrificed two weeks after the last test session and glial fibrillary acidic protein (GFAP) concentrations were measured in eight selected brain regions. A dose-dependent decrease in motor activity was observed immediately following the end of the exposure period with no differences observed 2 weeks after cessation of exposure. Alterations in gait, decreased fore-and hindlimb grip strength, and decreased arousal were also found. Behavioral changes were accompanied by reduced weight gain and decreased body temperature during the course of exposure. GFAP concentrations were elevated in the frontal cortex, occipital cortex, striatum and hippocampus but not in thalamus, cerebellum or brain stem. These results indicate that lead causes functional effects in the adult rat which can be detected by neurobehavioral methods. Furthermore, region-specific alterations in brain GFAP concentrations provided evidence of specificity of lead neurotoxicity in the adult brain.

A Swine Model for Determining the Bioavailability of Lead from Contaminated Media

Abstract: Bioavailability is the portion of a chemical dose that enters the systemic circulation from an administered dosage form. Enteric absorption depends on the physical and chemical properties and associated matrix, e.g., soil, slag, food, water, of the chemical. For our purposes, two separate connotations of the term bioavailability will be clarified. Absolute bioavailability is synonymous with the oral absorption fraction (AF0) for a specific chemical from its associated matrix. For example, if lead (Pb) from lead acetate (PbAc) is 50% absorbed from drinking water and lead from lead sulfide (PbS) is 25% absorbed from soil, the absolute bioavailabilities or AF0s of lead would be 50 and 25%, respectively. Relative bioavailability (RBA) refers to the absorption of one chemical form compared to some other reference form. For example, if lead acetate in drinking water is the reference form of lead, then the RBA of lead from lead sulfide would be 25/50, or 50% compared to lead from lead acetate.

The effect of lead on the bone marrow stem cells of mice infected with Listeria monocytogenes.

Abstract: We investigated the effects of lead exposure on the growth and differentiation of bone marrow hematopoietic cells, the so called colony-forming cells, in normal and Listeria monocytogenes infected mice (resistant and susceptible strains). We also studied the effects of lead on the serum colony-stimulating activity (CSA), as well as on the survival of the mice after the infection. The doses of lead acetate were 13, 130 and 1300 ppm for 10, 30 and 70 d. At the end of this dosing, mice were infected with Listeria monocytogenes and killed 24, 48 or 72 h after inoculation of the bacteria. A dose-response suppressive effect of lead was observed in both strains in the 3 periods studied. However, in the resistant strain of mice the suppressive effects were overcome 48 h after the administration of the bacteria, whereas in the susceptible mice the suppressive effect of the infection was evident in all 3 time periods. The administration of lead caused no changes in serum hematopoietic growth factors, thus suggesting this metal acts by direct action on the myelopoietic cells. A significant decrease in host resistance, as measured by the mortality rate, was found when both strains of mice were challenged with sub-lethal doses of Listeria monocytogenes. Lethality was determined for a period of 10 d after dosing with 1300 ppm lead for 30 d.

The effect of lead on lactate formation, ATP level and membrane ATPase activities in human erythrocytes in vitro.

Abstract: Lead ions inhibit aerobic glycolysis and diminish ATP level in human erythrocytes in vitro. Magnesium partly abolishes this inhibitory effect of lead on lactate formation by stimulation of Mg-dependent enzymes. Lead ions also inhibit the (Na, K) ATPase activity of the erythrocyte membranes. This effect is seen after the direct adding of lead acetate to erythrocyte ghosts, as well as in the ghosts obtained after preincubation of intact erythrocytes with lead acetate, prior to cell membrane isolation (Ca, Mg) ATPase is less sensitive to lead and (Mg) ATPase is practically insensitive. During these studies a protective effect of glucose was found. The inhibition of (Na, K) ATPase by lead ions, observed after incubation of human erythrocytes, as an experimental model, may indicate a similar sensitivity of membrane (Na, K) ATPases from other cells during their in vitro exposure to lead, especially from the nervous cells, where (Na, K) ATPase participates in the process of cell surface repolarization.

Ultrastructural investigation of lead-induced intranuclear inclusion bodies in mice.

Abstract: By means of optical and electron microscopy and by atomic absorption spectrophotometry in a graphite chamber, this study evaluated the effect of temperature (22-35 degrees C) on lesions in the kidney, liver, and brain, and on concentrations of lead caused by the administration of 2 and 5 mg/kg/IP of lead acetate to Swiss mice. The most pronounced effects were observed in the kidney and in groups of animals receiving the highest doses (5 mg/kg at 22 and 35 degrees C). These effects consisted of significantly higher (p < .05) lead concentrations in the tissues, a significant decrease (p < .05) in kidney weights, and progressive kidney atrophy and fibrosis with, at the ultrastructural level, constant intranuclear inclusions, which were also observed in the cytoplasm of renal and endothelial cells.

Combined effects of acute lead acetate exposure and tone exposure of the guinea pig cochlea.

Abstract: Lead acetate exposure to humans can induce various disorders of the cranial nerves. Although vertigo and sensorineural deafness have been reported in lead workers, the dose effects of lead acetate on the cochlea and eighth cranial nerve are not well documented. We investigated the effects of lead acetate on the male albino Hartley guinea pig cochlea by measuring cochlear microphonics (CM), whole nerve action potential (AP), endocochlear potential (EP) and K+ ion concentration of the endolymph. Animals were given lead acetate by intraperitoneal injection as 20 mg/week for 4 consecutive weeks. A total dose < 80 mg did not induce electrophysiological changes in the cochlea. However, the AP output voltage (N1) decreased if the 80 mg lead acetate treatment was followed by an 80 dB tone exposure at 6 kHz during 24 h. A change was observed in CM and EP but not K+ ion concentration in the scala media.