[Ability of the neurotoxic effects of lead to regress].
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Child↗
Biomedical subjects
H Lilienthal
Publications and source records attributed to H Lilienthal.
Persistence of retention deficit in rats after neonatal lead exposure.
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Animals↗
Neurobehavioral effects of lead and cadmium.
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Age Factors↗
Task dependent neurobehavioral effects of lead in rats.
In order to test neurobehavioral effects of low-level lead exposure during early development, Wistar-rats were given pre- and postnatal dietary lead as lead acetate in four concentrations: 0, 80, 250, and 750 ppm. These diets, known to give rise to blood lead-levels (PbB) of less than 5, 11, 18, and 31 micrograms/dl, resulted in erythrocyte ALAD-inhibition of 40, 73, and 83%, respectively. The animals were tested first at 70 to 100 days postnatal (PN 70-100) in a 2-way active avoidance-task, and then at PN 190-250 in a visual discrimination-task. Lead-exposure was associated with performance-disruption in the discrimination-task, significant (p less than 0.001) already for the 250 ppm-exposure, but with significant (p less than 0.05) performance-facilitation in the avoidance-task. If learning and retention in animals is taken as a measure of cognitive performance neurobehavioral lead-toxicity cannot easily be explained in terms of cognitive deficit. An interpretation in terms of emotional reactivity or behavioral disinhibition would seem more convincing, which covers the results from activity-studies as well. 70% ALAD-inhibition corresponds to PbBs of about 20 micrograms/dl in rats, and to about 40 micrograms/dl in children. Some implications of animal studies for neuropsychological results from Pb-exposed children are discussed.
Animals↗
Alteration of the visual evoked potential and the electroretinogram in lead-treated monkeys.
Rhesus monkeys were pre- and postnatally exposed to either 0, 350, or 600 ppm lead acetate in lab chow. At the age of 7-7 1/4 years visual evoked potentials (VEP) and electroretinograms (ERG) were recorded. Flashes were used as stimuli. The VEP was taken under two background illuminance conditions. Lead-related decreases in amplitudes and increases in latencies were observed. Effects on amplitudes were more pronounced under the dark condition while latencies were more affected at the bright background level. The ERG was studied during the course of dark adaptation. The increase in amplitudes of the b-wave during the adaptation period was more prominent in lead-exposed subjects than in controls. Oscillatory potentials were not altered by lead. The findings are discussed in terms of the physiological mechanisms underlying these different potentials.
Aging↗
Significance of hippocampal dysfunction in low level lead exposure of rats.
Previous reports have suggested a relationship between the neurotoxicity of lead and hippocampal dysfunction. Therefore, a comparison between the behavioral changes induced by lead exposure and by selective destruction of hippocampal neurons should help to clarify whether the intrinsic neurons of the hippocampus are directly influenced by lead. Rats maternally and permanently exposed to lead (750 ppm in the diet as lead acetate) were tested in a radial arm maze and compared with controls and rats with ibotenic acid-induced neuronal depletion in the dorsal hippocampus. Lead-exposed groups showed an impairment in the acquisition performance of the spatial task while hippocampally damaged animals did not. When they were retested 4 weeks after the end of the original acquisition, both groups of lead-exposed and ibotenic acid-treated rats showed a significant deficit in retention. These results suggest that this deficit produced by lead can be due to the damage of the hippocampal neurons but not the impairment observed in the acquisition. We propose that the neurotoxicity of lead is not entirely due to the dysfunction of the dorsal hippocampus and that other areas of the brain should be considered. Both maternally and permanently lead-exposed rats showed a similar degree of deficit in acquisition and retention, suggesting a long-lasting effect of early lead exposure.
Animals↗
Neuronal depletion of the amygdala resembles the learning deficits induced by low level lead exposure in rats.
The behavioral deficits observed after lead exposure have been related to limbic system dysfunction. In a previous study it was shown that the neurotoxicity of lead could not be explained by the damage of the hippocampus alone. The purpose of the present investigation was to use behavioral comparisons to test the hypothesis that the intrinsic neurons of several nuclei of the amygdala, where lead has been found to accumulate, can be a target of the effects of the metal as well. A group of rats were maternally and permanently exposed to lead (750 ppm in the diet as lead acetate). Another group of equally aged and housed rats, never experimentally exposed to lead, were injected ibotenic acid into the amygdala. All groups plus sham-operated and unoperated controls were tested in the open field, the radial arm maze, and a passive avoidance task. The results showed that lead exposure (both permanent and maternal) and amygdalectomy produced a) no effect on locomotor activity, b) impairments in the acquisition phase of the radial maze, and c) impairments in passive avoidance. These results suggest an involvement of the amygdala in the neurotoxic action of lead, but not as the only brain structure. The deficits in permanently lead-exposed rats are more pronounced than in only maternally-exposed animals suggesting a longlasting, but not totally irreversible effect of early lead exposure.
Amygdala↗
Lead effects on the brain stem auditory evoked potential in monkeys during and after the treatment phase.
Rhesus monkeys were pre- and postnatally exposed to either 0, 350, or 600 mg lead acetate/kg diet continuously until the age of about 9.75 years. At the age of 8-8.25 years (Experiment 1) and 9.25-9.5 years (Experiment 2) brain stem auditory evoked potentials (BAEPs) were recorded. Blood lead levels at the time of testing were about 5, 35, or 55 micrograms/dl for controls, the 350-mg group and the 600-mg group, respectively. There were no clinical signs of intoxications. Clicks varying in sound pressure level (SPL) and rate were used to elicit BAEPs. In addition, the influence of different levels of masking noise was explored in Experiment 1. Four early prominent waves were detected in accordance with other studies of the monkey BAEP. The most reliable wave was No. II. Latencies in the BAEP exhibited the known dependencies on parametric variation for SPL, stimulus rate, and masking level. The 600-mg group exhibited the longest latencies at all stimulus conditions. Analysis of wave II and IV latencies revealed a significant main effect for lead on wave II. At the rate condition there were also signs of latency decreases in the 350-mg group that did not reach significance. Therefore, repetition rate was varied on all SPLs in Experiment 2 to assess the reliability of this effect because similar observations were reported in lead-exposed children. There was no indication of reduced latencies using this extended design. In contrast, significant lead-induced increases in latencies of waves I, II, and IV were revealed by multivariate ANOVA. The purpose of Experiment 3 was to examine whether these results were dependent on current exposure or persisted after cessation of lead treatment. It started 18 months after the end of lead feeding, when blood lead levels had declined to nearly normal values. The same lead-related effects were detected as in the previous experiments. Taken together, these results indicate consistent prolongations of latencies in the BAEP due to subtoxic lead exposure that are not dependent on current treatment. The results are compared to the effects found in epidemiological studies in lead-exposed children.
Aging↗
Sex-dependent effects of maternal PCB exposure on the electroretinogram in adult rats.
The purpose of the present experiment was to evaluate the effects of developmental exposure to polychlorinated biphenyls (PCBs) on the visual system. Pregnant Long-Evans rats were treated with the ortho-chlorinated 2,2',4,4'-tetrachlorobiphenyl and/or with the coplanar 3,3',4,4'-tetrachlorobiphenyl. Total dose of PCBs was 18 mg/kg in all groups. Measurements of the flash-evoked electroretinogram (ERG) started in the offspring at an age of about 200 days. The scotopic b-wave, the maximum potential, and oscillatory potentials were recorded after dark adaptation. Amplitudes of these potentials were reduced in female rats exposed to the coplanar PCB. No differences from controls were found in females of other groups or male rats. The results indicate long-lasting effects on the scotopic ERG after maternal PCB exposure that are sex dependent and congener specific. To our knowledge, this is the first experimental report of PCB-related influences on visual processes.
Animals↗
Behavioral effects following single and combined maternal exposure to PCB 77 (3,4,3',4'-tetrachlorobiphenyl) and PCB 47 (2,4,2',4'-tetrachlorobiphenyl) in rats.
The present study has compared the neurobehavioral effects of two structurally different PCB congeners or their combination in rats. Time-mated Long-Evans rats received daily injections of the coplanar PCB 77 (3,4 3',4'-TCB: 0.5 or 1.5 mg/kg), the di-ortho-chlorinated PCB 47 (2,4,2',4'-TCB: 1.5 mg/kg) or a congener mixture (0.5 mg/kg PCB 77 + 1.0 mg/kg PCB 47) from day 7 to 18 of gestation. The PCB exposure levels in brain and perirenal fat of dams and offspring were determined by GC/ECD on gestational day 19 (GD 19), postnatal day 21 (PND 21), and PND 45. PCB 77 was accumulated to a smaller degree than PCB 47. On GD 19, PCB 77 was found to a greater extent in the brains of the offspring than in the brains of the dams, whereas the level of PCB 47 was almost the same in dams and offspring. The testing of open-field behavior in male rats on PND 18 and PND 70 revealed an altered distribution of activity with enhanced activity in the inner zone in PCB 77-treated rats compared to all other groups, while the overall activity was not changed. Distance traveled and rearing behavior on PND 340 were elevated relative to controls in all PCB-treated groups, indicating age-related effects of maternal exposure. A step-down passive avoidance task revealed decreased latencies in the PCB 77 and combined exposure groups on PND 80. Only PCB 77-treated animals showed increased latencies on PND 100 on the haloperidol-induced catalepsy test. These results indicate long-term effects of maternal exposure to PCB 77 on emotional and motor functions. At the dose levels used in the present experiments, the two congeners given in combination did not cause additive or synergistic effects. Instead, concurrent exposure to PCB 47 seemed to counteract PCB 77-induced changes in the pattern of activity.
Adipose Tissue↗
Pre- and postnatal lead-exposure in monkeys: effects on activity and learning set formation.
Rhesus monkeys were pre- and postnatally exposed to 0, 350, or 600 ppm lead acetate in the diet. Blood lead levels of the mothers were less than 1, 24.4, and 37.4 micrograms/100 g blood, respectively, while those of the offspring were substantially higher, at least in the early stages of development. At the age of 12-15 months the animals were tested for group activity levels in an unfamiliar environment. No substantial lead-related alterations of activity occurred neither for group activity nor for the activity of individual animals. There were, however significant dose-related impairments of pattern discrimination learning set formation, while in simple discrimination learning during the early training phases deficits were seen in the high lead group only. Emotional alterations of these animals may account for this result, whereas true cognitive deficits are likely to underly the impairment of learning set formation seen in the low lead group. It is concluded that the effects of lead in cognitive tasks are not secondary to changes of general activity level.
Animals↗
Immunohistochemical localization of neuronal and glial calcium-binding proteins in hippocampus of chronically low level lead exposed rhesus monkeys.
The purpose of this study was to investigate the distribution of the neuronal calcium-binding proteins parvalbumin, calbindin D28k, calretinin and the glial protein S100 in the hippocampus of lead exposed rhesus monkeys. It has been suggested that lead may exert its toxic effects by perturbing the intracellular calcium homeostasis. Lead is able to increase the intracellular Ca2+ concentration and can serve as a calcium substitute. It has been shown that some calcium-binding proteins are capable of binding lead. We tried to find a putative dose-depending relation between long-term low level lead exposure and the expression of the proteins investigated. Rhesus monkeys were pre- and postnatally exposed to 600 mg-350 mg-0 mg lead-acetate in diet for nine years, as described by Lilienthal et al. (1986). After a lead-free period of 32 months animals were sacrificed. Hippocampal paraffin sections were stained for parvalbumin (PV), calbindin D28k (CB), calretinin (CR), and S100 with immunohistochemical methods. The distribution of the neuronal calcium-binding proteins was almost identical for the different exposure groups. The most striking observation was a marked decrease of S100 immunoreactivity in astrocytes in the high lead group. Considering a protective role against high Ca2+ concentration and Pb2+ accumulation respectively the unchanged expression of PV, CB, and CR remains to be clarified. The apparent difference in S100 expression supports the hypothesis that glial cells are the main target of lead toxicity. The reduced expression may indicate a developmental retardation of astroglia.
Animals↗
Myopathy: a possible effect of chronic low level lead exposure.
Morphological changes in the central nervous system and other organs have been reported in numerous studies investigating low level lead exposure. To date, however, there are no investigations on the effect of low level lead exposure on striated muscles, although varying neuromuscular changes in different species have been known for years. Rhesus monkeys were exposed pre- and postnatally to lead acetate in the diet (350 ppm or 600 ppm) over 9 years, followed by a lead free period of 32 months, while a control-group received regular diet. No signs of muscular dysfunction were evident. To elucidate neuromuscular pathomorphology frozen sections of the vastus medialis muscle were processed for routine and enzymohistological staining (Hematoxilin and Eosin, Sudan Black, Gomori, NADH, ATPase). Resin histology was processed for electron microscopy. Morphometric analysis was made with commercial software. Light microscopy revealed dose-related signs of myopathy in the lead-exposed groups. The scatter of fibre diameters was increased, and split fibers and internal nuclei were more frequent. Fibres became separated from each other by copious endomysial connective tissue. Ultrastructural examination showed hydropic mitochondria and a massively dilated sarcotubular system in the 600 ppm group. Dose-related extracellular collagen deposition increased. A heavy fibrosis was seen in the 600 ppm group. These findings are interpreted as myopathical reaction due to chronic low level lead exposure, as there were no signs of neurogenical lesion. It remains unknown how the fibrosis developed. A primary fibrosis could be based upon a developmental delay of satellite cells (expressing metalloproteases for collagen-catabolism). Lead is known to inhibit regular development in many ways if exposure has started prenatally. As the skeletal muscle is a common target of toxicity, the myotoxic effects of chronic low level lead exposure comes into question.
Animals↗