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Biomedical subjects

W S Webster

Publications and source records attributed to W S Webster.

At least 73 records · Page 4Linked to original sources
PubMed1981

The toxic effects of cadmium on the neonatal mouse CNS.

Mice (QS outbred strain) received a single subcutaneous injection of cadmium chloride in saline on postnatal day 1, 8, 15, or 22. Histological examination, 24 hours after cadmium exposure on day 1, revealed petechial hemorrhages, edema, and cellular pycnosis throughout much of the immature brain. Treatment on days 8 or 15 produced similar damage, particularly edema and pycnosis, but affected progressively less of the brain until, by day 22, the brain was apparently unaffected by cadmium. Some animals, allowed to survive six to eight weeks after cadmium injection, showed behavioral anomalies and persistent brain deficits. Electron microscopic examination of parietal cortex from animals exposed to cadmium on day 1 revealed that petechial hemorrhages first occurred tow hours after treatment. The hemorrhages increased during the next six hours, and were accompanied by thinning and vacuolization of the capillary walls and widening of interendothelial gaps. In general, such changes were restricted to the partially differentiated capillaries. Degenerative changes in the brain cells were first seen about six hours after cadmium exposure.

Animals↗
PubMed1980

Changes in the mouse neuroepithelium associated with cadmium-induced neural tube defects.

The aim of this study was to investigate the teratogenic action of cadmium (Cd) on the developing mouse CNS. Pregnant mice were injected with 4 mg/kg CdCl2 on day 7, 8, 9, or 10 of gestation. These animals and saline injected controls were sacrificed either on the day before birth or at various times up to 48 hours after injection and the embryos examined grossly and histologically. Exencephaly occurred after Cd treatment on day 7 or 8 and its development was examined in day 8 embryos. Eight hours after Cd injection many cells of the closing neural plate contained dense-staining inclusions, thought to be autophagic vacuoles. After 24 hours this damage had almost disappeared, but the anterior neural folds, although looking histologically normal, were more open than in controls. Forty-eight hours after injection it was apparent that this part of the neural tube was not going to close and would result in exencephaly. Cd exposure on day 9 or 10 did not cause gross CNS defects such as exencephaly. On both days, twelve hours after Cd injection, similar dark-staining inclusions were seen in many cells throughout the CNS. After twenty-four hours there were variable amounts of cell death, resulting in some embryos in breakdown of parts of the wall of the neural tube. Forty-eight hours after treatment all inclusions and cellular debris had disappeared, indicating repair had taken place, but in some embryos, treated on day 9, severe lasting damage was seen as dorsal openings in the previously closed neural tube.

Animals↗
PubMed1979

Iron deficiency and its role in cadmium-induced fetal growth retardation.

The aim of this investigation was to establish the relationship of cadmium-induced fetal growth retardation in the mouse to iron deficiency. Pregnant mice were either fed a low iron diet or given 40 ppm cadmium in their drinking water. The effects of these factors on fetal weight and hematological values of the fetuses and dams were established and compared, both with each other and with appropriate controls. Both treatments caused maternal and fetal anemia, the fetuses being more severely affected. The anemic fetuses were also severely growth retarded. These changes, when caused by the iron deficient diet, could be completely prevented by either parenterally or orally administered iron supplements. When the changes were caused by cadmium in the drinking water they were only partially prevented by oral supplements. From these results it was concluded that iron deficiency in pregnancy causes not only anemia but also fetal growth retardation. Cadmium exposure in pregnancy, presumably by blocking intestinal absorption of iron, also causes anemia and hence fetal growth retardation.

Anemia↗
PubMed1979

Cadmium-induced fetal growth retardation in mice and the effects of dietary supplements of zinc, copper, iron and selenium.

Many of the toxic effects of cadmium can be prevented by prior or simultaneous administration of either zinc, copper, iron or selenium. The aim of this investigation was to determine whether cadmium-induced fetal growth retardation in the mouse could be prevented, or reduced, by dietary supplementation with salts of these elements. Pregnant mice, receiving either distilled water to drink or distilled water containing 40 ppm cadmium, were fed, throughout pregnancy, a normal stock mouse diet supplemented with either zinc (200, 400 or 800 ppm), copper (30, 100 or 400 ppm), iron (200 or 1,000 ppm) or selenium (0.05, 2, 20 or 200 ppm). Also included was a control group which did not receive cadmium or dietary supplements. The animals were killed on the 19th day of pregnancy and the fetuses removed and weighed. The results showed that the iron supplemented diets gave partial protection against the cadmium-induced growth retardation; the other diets were ineffective.

Animals↗
PubMed1976

The ultrastructural localisation of cadmium.

A modified technique for the ultrastructural localisation of heavy metals is described in this paper. The method involves precipitation of heavy metals as sulphides in the tissue by using (NH4)2 S after brief fixation in glutaraldehyde. The sulphides are, in the presence of a physical developer, then used to catalyse the reduction of silver ions into visible molecular silver. This latter step of physical development has been normally carried out after embedding and sectioning. However, when we followed this method we found that the dark metal sulphide was lost from the tissue during the embedding in epoxy resin. Hence the method was unsuitable for our proposed experiment on the ultrastructural localisation of cadmium. We subsequently modified the technique primarily by treating very thin tissue slices with the developer before dehydration and embedding, thus eliminating any problem from sulphide loss. This modified technique was used to investigate the ultrastructural localisation of cadmium in the kidneys of mice which had been exposed to 50 ppm cadmium in their drinking water for up to eight months. The molecular silver was found to be located mainly in the proximal tubule cells, either as dense clumps in apical vesicles and lysosomes or diffuse grains throughout the cytoplasm of the cells particularly in the basal region. We interpret these results as indicating that cadmium is found in the apical vesicles, lysosomes and cytoplasm of proximal tubule cells.

Animals↗
PubMed1974

Experimental aortic intimal thickening. I. Morphology and source of intimal cells.

Repair to injury of the rabbit aorta was studied with special attention to the source of new intimal cells. Two types of injury, suture placement and electrocautery, were used to ascertain whether the type of injury significantly modifies the reparative response of the artery. Cell morphology and DNA synthesis, as determined by autoradiographic localization of tritiated thymidine uptake, were studied sequentially during the course of the repair reaction. Suture injury was the more reliable model for these studies because the magnitude of injury was quite comparable between animals, while with cauterization there was considerable variation in the magnitude of injury. The overall reparative response with the two types of injury was, however, similar. Cell division was first seen in the media adjacent to the injured focus and was followed by migration of medial cells into the intima. In the intima, medial cells continued to divide for a few days and then gradually matured from undifferentiated ovoid cells resembling monocytes to morphologically differentiated smooth muscle cells. Medial cells exhibiting DNA synthesis were both differentiated and undifferentiated smooth muscle cells, supporting previous reports that mature as well as undifferentiated smooth muscle cells are capable of mitosis. However, with injury and repair, the migrating cells appeared to be mainly undifferentiated since there was a predominance of these cells early in the repair reaction in the intima.

Animals↗
PubMed1974

Experimental aortic intimal thickening. II. Endothelialization and permeability.

Experimental aortic intimal thickening has been induced in rabbits by two types of injury, suture placement and electrocautery. Scanning electron microscopy showed that endothelialization of the suture plaque was completed at about 10 days following injury. New endothelial cells had no particular orientation or were oriented at right angles to the adjacent normal aortic endothelium. Realignment parallel with the aortic axis had occurred by 21 days after induction of the lesion. Orientation patterns of new endothelial cells over irregularly shaped cautery-induced intimal thickening were difficult to ascertain. Aortic permeability studies were accomplished by using the tracers horseradish peroxidase (HRP) and ferritin. Several naturally occurring intimal thickenings in normal aortas had greater permeability for HRP than did adjacent normal intima. An enhanced penetration of both tracers was observed in mature intimal lesions produced by both experimental procedures compared to adjacent morphologically normal aortic intima. HRP molecules entered the thickened aortic intima in increased amounts through interendothelial junctions and by endothelial pinocytotic vesicles; ferritin molecules were seen only in pinocytotic vesicles. Increased penetration of HRP was observed for as long as 27 weeks after injury, while that of ferritin was observed only for 3 weeks. The enhanced permeability of the thickened intima as compared to normal for these two tracers of considerably different sizes strongly suggests an increased permeability of endothelium overlying intimal thickening for naturally circulating macromolecules.

Animals↗
PubMedDate not supplied

Model predicting the teratogenic potential of retinyl palmitate, using a combined in vivo/in vitro approach.

Retinyl palmitate (RP) is a known laboratory animal teratogen inducing abnormalities of the second visceral arch when administered on day 9 of gestation in the rat. However, there are significant problems when attempting to extrapolate this result to the human. A combined in vivo/in vitro model was developed to assist in human risk assessment. The in vitro teratogenic threshold concentration of a number of retinyl palmitate metabolites was established. Serum concentrations of retinyl palmitate metabolites following a single teratogenic dose of RP in the pregnant rat were also measured. These dosed sera were also used to culture rat embryos. Our hypothesis was that malformations would only be induced by the dosed sera in vitro if the threshold concentration(s) of one or more metabolites was exceeded. Using this approach, it was determined that the teratogenicity of the sera were best predicted by serum retinol levels, with some indication that all-trans-retinoic acid and 4-oxo-all-trans-retinoic acid could be involved in some cases. The available human data suggest that threshold concentrations of these retinoids were unlikely to be exceeded following vitamin A supplements of 25,000 IU/day. While the proposed model does not take into account species differences, protein binding, and transfer to the embryo, it does have potential for human risk assessment.

Animals↗
PubMedDate not supplied

In vitro assessment of individual and interactive effects of aromatic hydrocarbons on embryonic development of the rat.

There have been reports of disruption of embryonic development following exposure of pregnant women to aromatic hydrocarbons. In the present study, the embryotoxicity of toluene, xylene, benzene, styrene, and its metabolite, styrene oxide, was evaluated using the in vitro culture of postimplantation rat embryos. Possible interactions between toluene, xylene, and benzene were also studied using mixtures of these solvents. The results of the study showed that toluene, xylene, benzene, and styrene all have a concentration-dependent embryotoxic effect on the developing rat embryo in vitro. Styrene was embryotoxic at a lower concentration (1.00 mumol/mL) than benzene (1.56 mumol/mL), toluene (2.25 mumol/mL), or xylene (1.89 mumol/mL). The metabolite of styrene, styrene oxide, was embryotoxic at a concentration (0.038 mumol/mL). more than 20 times less than the parent compound. There was no evidence of a synergistic interaction between toluene, xylene, and benzene in causing embryotoxicity; the solvents interacted in an additive manner. The embryos were exposed to the solvents for 40 h of the organogenic period. When the levels of solvents found to be embryotoxic in the present study are compared to blood levels in the human following industrial exposure or solvent abuse, it appears unlikely that the threshold blood levels for embryotoxicity would be exceeded in the workplace. However, the possibility that exposure to solvents earlier or later or throughout the entire organogenic period might result in a different conclusion cannot be excluded.

Animals↗
PubMedDate not supplied

The contribution of primary and secondary neuronal degeneration to prenatally-induced micrencephaly.

Prenatal exposure of rats to the alkylating agent methylazoxymethanol acetate (MAM Ac) induces severe micrencephaly in the offspring. The aim of the present study was to examine the contribution of primary cell death (due to a direct action of MAM Ac on the neuroepithelium), and secondary (target-dependent) cell death to the subsequent cell deficits in the visual system following prenatal exposure to MAM Ac on embryonic day 11, 12, 13, 14, 15 or 16. The results showed that when primary cell death substantially reduced the neuronal population of a target structure then there was increased target-dependent cell death in the neurons which normally project to that target. This was particularly evident in the dorsal lateral geniculate nucleus following exposure to MAM Ac on E15. Although the MAM Ac caused virtually no primary cell death in the embryonic precursor cells of the dLGN, the nucleus in the adult offspring was reduced by 87% compared with controls. This reduction was shown to be due to increased postnatal target-dependent, or secondary, cell death due to a severe reduction in layers III and IV of the occipital cortex. The cortical damage was due to primary cell death. Hence, primary cell death only partly accounts for the degree of micrencephaly seen in the offspring, consideration of secondary cell death is necessary to understand the total deficit.

Animals↗
PubMedDate not supplied

Fetal brain damage in the rat following prenatal exposure to cocaine.

The aim of this study was to identify fetal brain damage induced by 1) prenatal cocaine exposure or 2) physical procedures causing temporary constriction or occlusion of the uterine vessels in pregnant rats. Brains were examined from rat fetuses killed 48 hours after the dam was given one or more intraperitoneal doses of cocaine (50-70 mg/kg) on day 16 of gestation. Only brains from fetuses with hemorrhage in the extremities were examined, as this indicated they had undergone a circulatory disturbance. Four of the 10 brains examined showed bilateral necrosis and cavitation in the cerebral cortex. There were also hemorrhage and ectopic outgrowths in the corpus striatum, bilateral cavitation in the brainstem and vacuolization in the lens of the eye. A similar type and distribution of damage was seen in rat fetal brains from dams treated by temporary occlusion of the uterine vessels or direct handling of the pregnant uterus on day 16 of gestation and examined 48 hours later. It is proposed that the procedures act through the common mechanism of constriction/occlusion of the uterine vessels. The damage to the fetuses appears to be due to hemorrhage from the fetal vessels and ischemia. These findings are discussed in relation to cocaine use during human pregnancy.

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