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Biomedical subjects

W S Webster

Publications and source records attributed to W S Webster.

At least 37 records · Page 2Linked to original sources
PubMed1992

The warfarin embryopathy: a rat model showing maxillonasal hypoplasia and other skeletal disturbances.

Sprague-Dawley rats were given daily subcutaneous doses of sodium warfarin (100 mg/kg) and vitamin K1 (10 mg/kg) for up to 12 weeks, starting on the day after birth. This dosing regimen creates an extrahepatic vitamin K deficiency while preserving the vitamin K-dependent processes of the liver. Control rats received either vitamin K1 only or were untreated. All rats survived without any signs of hemorrhage. The warfarin-treated rats developed a marked maxillonasal hypoplasia associated with a 11-13% reduction in the length of the nasal bones compared with controls. The length of the posterior part of the skull was not significantly different from controls. In the warfarin-treated rats, the septal cartilage of the nasal septum showed large areas of calcification, not present in controls, and abnormal calcium bridges in the epiphyseal cartilages of the vertebrae and long bones. The ectopic calcification in the septal cartilage may have been the cause of the reduced longitudinal growth of the nasal septum and the associated maxillonasal hypoplasia. It is proposed that (1) the facial features of the human warfarin embryopathy are caused by reduced growth of the embryonic nasal septum, and (2) the septal growth retardation occurs because the warfarin-induced extrahepatic vitamin K deficiency prevents the normal formation of the vitamin K-dependent matrix gla protein in the embryo.

Animals↗
PubMed1992

Binder's syndrome due to prenatal vitamin K deficiency: a theory of pathogenesis.

There is evidence that vitamin K-deficiency during human pregnancy can be caused by the therapeutic use of warfarin or phenytoin. The pregnancy histories of three cases of Binder's syndrome are reported. One was associated with warfarin exposure, one with phenytoin exposure and one with alcohol abuse. It is proposed that Binder's syndrome can be caused by prenatal exposure to agents that cause vitamin K-deficiency. Sprague-Dawley rats were treated from postnatal day 1 to 12 weeks with daily doses of warfarin (100 mg/kg) and concurrent vitamin K1 (10 mg/kg). This regimen creates a net extra-hepatic vitamin K-deficiency. The treated rats developed with a distinct facial appearance characterized by a markedly reduced snout. Histological examination showed that the normally non-calcified septal cartilage was extensively calcified. It is proposed that normal growth of the septal cartilage is necessary for the development of the profile of the nose and midface and that normal growth will only take place while the septal cartilage is uncalcified.

Adolescent↗
PubMed1991

Parameters determining isotretinoin teratogenicity in rat embryo culture.

At the in vitro threshold serum concentration of 500 ng/ml, isotretinoin induces defects of visceral arch development in 9.5-day rat embryos grown in culture for 48 h. Experiments were performed to determine the minimum period of exposure necessary to induce these arch defects and whether an increase in concentration of isotretinoin could compensate for reduced exposure time. The results showed that a minimum 6-h exposure to 500 ng/ml immediately prior to cranial neural crest migration was necessary to induce severe defects of the second visceral arch in a majority of embryos. Maximal increase in isotretinoin concentration to 16,000 ng/ml did not compensate for shorter exposure periods. These results suggest that to cause malformations of the visceral arches, the embryo must be exposed to isotretinoin for a minimum period of time regardless of the concentration of isotretinoin above the threshold.

Abnormalities, Drug-Induced↗
PubMed1991

Embryotoxicity of xylene and toluene: an in vitro study.

Exposure to aromatic hydrocarbon solvents during pregnancy has been reported to adversely affect human embryonic development. This exposure may be due to deliberate abuse or may occur in the workplace. Xylene and toluene are the most common solvents encountered in the workplace and toluene is a constituent of commonly abused substances. This study was performed in an endeavour to fulfil two requirements for proof of teratogenicity of a substance, namely development of an animal model and demonstration of a dose-response relationship of teratogenicity. To fulfil these aims, the possible teratogenic and embryotoxic effects of xylene and toluene on rat embryos during the organogenic period was investigated in vitro. Rat embryos were explanted on day 9.5 of gestation and cultured in heat-inactivated rat serum to which xylene or toluene (0.1, 0.5 or 1.0 microL/mL) had been added, dispersed in 0.1% DMSO. The amount of solvent in the culture medium was quantitated using gas chromatography. Neither xylene nor toluene had any observable teratogenic effect on the embryos in terms of increased malformations. However, both solvents were embryotoxic and caused a dose-dependent retardation of growth and development. A no-effect level was not established for either xylene or toluene, however, the lowest levels used for each of these compounds caused only a slight retardation of growth. Although there was no indication that exposure to these solvents caused a teratogenic effect, there was clear evidence of embryotoxicity. The embryotoxic levels of these solvents needed in culture were higher than blood levels likely to occur in the human following industrial exposure or recreational abuse.

Abnormalities, Drug-Induced↗
PubMed1990

Cocaine as a cause of congenital malformations of vascular origin: experimental evidence in the rat.

Cocaine hydrochloride was administered to pregnant Sprague-Dawley rats as a single intraperitoneal dose or as two doses 1-4 hours apart. A single dose administered on day 16 of gestation was teratogenic in a dose-dependent manner, with 40 mg/kg being a no-effect dose and 50 mg/kg the lowest teratogenic dose; 80 mg/kg was lethal to the dam. Forty-eight hours after exposure to a teratogenic dose on day 16 of pregnancy, the fetuses showed severe hemorrhage and edema in the their extremities, particularly the footplates, tail, genital tubercle, and upper lip/nose. When the fetuses were examined on day 21 of gestation, the main externally visible malformations were reduction deformities of the limbs and tail. When two doses of cocaine were administered 1-4 hours apart, the incidence of affected fetuses increased as the time interval between the two doses decreased. Two doses of cocaine administered 2 hours apart were not teratogenic on day 9, 10, 11, 12, 13, or 14 of gestation but did induce reduction deformities on days 15, 16, 17, 18, or 19. The same dose administered 1 hour apart was teratogenic on days 14-19. In general, cocaine administration on gestational days 14, 15, or 16 induced more severe and more widespread hemorrhage and edema than administration on days 17, 18, or 19. In the latter cases, damage was restricted to the distal parts of the hindlimb digits and the tail. The results show that in the rat cocaine is only teratogenic during the late organogenic or postorganogenic period.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1990

Exposure of the pregnant rat to warfarin and vitamin K1: an animal model of intraventricular hemorrhage in the fetus.

Pregnant Sprague-Dawley rats were given daily oral doses of sodium warfarin (100 mg/kg) and concurrent intramuscular injections of vitamin K1 (10 mg/kg). This dosing regimen did not have any apparent deleterious effect on the dams and did not affect the fetuses when administered from day 1 to day 12 of pregnancy. However, similar treatment from day 9 to 20 caused hemorrhage in the fetuses examined on day 21 of gestation. There were no hemorrhages in the control fetuses from dams receiving vitamin K1 only. The lowest effective dose of warfarin, in conjunction with daily doses of vitamin K1, was 3 mg/kg. This dose caused hemorrhage in 28% of fetuses; the incidence of affected fetuses was not further increased by doses of warfarin up to 100 mg/kg. Hemorrhages affected the fetal brain, face, eyes, and ear and occasionally the limbs. Brain hemorrhages were frequently intraventricular and caused various degrees of hydrocephaly. Bony defects were not a feature of prenatal exposure to warfarin. These results show that prenatal exposure of the rat to warfarin and vitamin K duplicates the hemorrhagic abnormalities and pathology associated with prenatal exposure to warfarin in the human. It did not induce bony or facial defects probably because the vitamin K-dependent components of bone development occur postnatally in the rat. This model should allow detailed determination of the role of vitamin K-dependent proteins in development.

Animals↗
PubMed1989

Moebius syndrome: animal model--human correlations and evidence for a brainstem vascular etiology.

The Moebius syndrome consists of congenital seventh nerve palsy associated with other cranial nerve palsies, most often of the sixth, and/or musculoskeletal abnormalities. A retrospective study of the events of pregnancy in 15 cases was undertaken, after a rat animal model showed that abdominal trauma, uterine vessel clamping and handling and hyperthermia caused bilateral brainstem lesions in fetal rats. Eight of the 15 cases surveyed included a possible associated event during pregnancy; hyperthermia, previous uterine surgery, electric shock, failed abortion, prolonged rupture of the membranes, or alcohol abuse. These events can be correlated with animal studies that involve acute uteroplacental vascular insufficiency produced by a variety of methods. The cause of most cases of Moebius syndrome is probably a transient ischemic/hypoxic insult to the fetus.

Abnormalities, Multiple↗
PubMed1989

Retention and distribution of manganese in the mouse brain following acute exposure on postnatal day 0, 7, 14 or 42: an autoradiographic and gamma counting study.

The relationship between postnatal age at time of Mn exposure, and the retention and distribution of Mn in the brain of the mouse was studied using gamma counting and autoradiography. A single intraperitoneal dose of Mn2+ (11 micrograms/kg or 25 mg/kg) containing radioactive 54Mn was administered on postnatal day 0, 7, 14 or 42. Animals were then killed at various times post exposure (1-114 days) and retention and distribution determined. Maximum retention of Mn in the brain (calculated as a percentage of administered dose) occurred 43 days following exposure on day 0. For day 7, 14 or 42 the highest Mn retention was 24 h after exposure. Maximum retention was 2.9%, 3.5%, 2.5% or 0.3% respectively, Mn retention after 114 days was 0.4%, 0.3%, 0.3% or 0.04% respectively. For the carrier-added group maximum retention was lower with corresponding figures of 2.5%, 2.4%, 1.1% or 0.2% and retention after 114 days was also lower 0.1%, 0.06%, 0.05% or 0.01%. The autoradiography studies indicated that Mn was located in areas of the brain which had a high perikaryal density at the time of exposure and in the choroid plexus. High and low doses of Mn were similarly distributed and there was little change in distribution with time.

Aging↗
PubMed1989

The choroid plexus as a target site for cadmium toxicity following chronic exposure in the adult mouse: an ultrastructural study.

The effects on the choroid plexus (CP) of chronic (22 weeks) exposure to 1, 10 or 100 ppm Cd2+ in the drinking water was studied in adult mice. The CP from these mice was examined using scanning and transmission electron microscopy. The mice receiving 10 or 100 ppm Cd2+ showed a dose dependent reduction in fluid intake and weight loss. The CP from animals receiving 100 ppm Cd2+ showed severe degenerative changes characterized by loss of microvilli, rupturing of the apical surface, increased cytoplasmic vacuolation and cellular debris. There was also an increase in cellular blebbing and increased dark/light cell ratio. Cerebrospinal fluid analysis revealed an increased protein content. The mice receiving 10 ppm Cd2+ showed similar but less severe degenerative changes. The 1 ppm Cd2+ group were indistinguishable from controls. These results suggest that it would be appropriate to examine CP function in individuals excessively exposed to Cd.

Animals↗
PubMed1988

Interference with gastrulation during the third week of pregnancy as a cause of some facial abnormalities and CNS defects.

During the third week of pregnancy the human embryo undergoes a major developmental process, gastrulation, during which the two-layered embryo is converted into a three-layered embryo. At the same time, the upper epiblast layer is induced to form the neural plate. Evidence is presented which suggests that interference with this process by genetic, physical, or chemical agents can cause a range of CNS abnormalities and facial abnormalities, including those described as characteristic of the FAS.

Abnormalities, Drug-Induced↗
PubMed1988

Chronic cadmium exposure during pregnancy in the mouse: influence of exposure levels on fetal and maternal uptake.

The uptake and distribution of orally administered cadmium-109 was studied in pregnant mice. Female outbred QS mice were given cadmium (Cd) supplemented drinking water for 1 mo before pregnancy and for the duration of pregnancy. The water contained either 0.0015 ppm Cd, 0.24 ppm Cd, or 40 ppm Cd. For the duration of pregnancy, 1.48 micrograms Cd/l (0.0015 ppm) in each solution was in the form of 109Cd (1 mCi/l). Control mice were given distilled/deionized water. On the day before term the mice were killed and a variety of adult and fetal tissues were examined in a gamma counter to determine their 109Cd concentrations. For each group the 109Cd concentration was highest in the maternal gastrointestinal tract, liver, and kidneys and lowest in the central nervous system (CNS) and blood. In general, the 109Cd concentrations in each organ were similar for each group of mice and were therefore independent of the overall oral Cd dose. A notable exception was the lower level in the duodenum in the 40 ppm group. In the fetal unit the chorioallantoic placenta contained the highest concentration of 109Cd. Concentrations in the fetuses were very low, comparable to those in the adult CNS. The 109Cd levels in the fetuses from group A were about fivefold greater than those of the fetuses from group C. There was no statistically significant evidence of specific localization in the fetal brain, kidney, or liver.

Administration, Oral↗
PubMed1988

Teratogens and craniofacial malformations: relationships to cell death.

Environmental agents including ethanol, 13-cis retinoic acid (RA, Accutane), the antimetabolite methotrexate, periods of hypoxia, ionizing radiation or hyperthermic stress, when administered acutely to pregnant experimental animals, induce stage-dependent craniofacial malformations comparable to those in corresponding human teratogen syndromes. Acute treatment regimens have allowed analysis of cell populations initially affected and subsequent dysmorphogenetic sequences as well as speculation relative to mechanisms of teratogenesis. In rodent models, ethanol and RA appear to affect similar cell populations and comparable malformations can be induced by both agents. When administered during gastrulation they cause a major insult to the anterior neural plate which results in characteristic ocular, brain and facial malformations comparable to those seen in the fetal alcohol syndrome. Exposure to these drugs at a time just prior to and during neural crest cell migration into the craniofacial and cervical regions results in malformations comparable to those seen in the Di-George sequence and/or retinoic acid embryopathy. Slightly later, at the time that the epibranchial placodes are active, insult results in mandibulofacial dysostosis-like syndromes. We propose that the pattern of these malformations is related to the particular vulnerability of cells in the vicinity of normal programmed cell death. Cell death is also associated with ionizing radiation and hyperthermia-induced malformations. Both of these teratogens are particularly damaging to the early development of the eye and central nervous system. Teratogenic temperature elevations result in arrest of mitotic activity and death of cells in mitosis. Hypoxia is also associated with cell death in specific regions and subsequent malformation. For example, death of cells in the invaginating olfactory placode has recently been associated with cleft lip formation. The relationship of hypoxia-induced cell death to energy requirements is being explored. Acute treatment with methotrexate results in frontonasal dysplasia (median facial clefts). Combined effects of fluid imbalance, lack of proliferation or death of frontonasal mesenchyme appear to be involved. Although the mechanisms of craniofacial malformation are complex, a common feature for many is excessive cell death for which the embryo may be unable to compensate. Excessive cell death in regions of programmed cell death represents an important, yet little appreciated, mechanism of teratogenesis.

Animals↗
PubMed1987

The choroid plexus and cerebral vasculature as target sites for cadmium following acute exposure in neonatal and adult mice: an autoradiographic and gamma counting study.

The relationship between postnatal age at time of cadmium (Cd) exposure, and the retention and distribution of Cd in the central nervous system (CNS) was studied using gamma counting and autoradiography. A single intraperitoneal dose of Cd2+ (84 micrograms/kg or 750 micrograms/kg) containing radioactive 109Cd, was administered on postnatal day 0, 7, 14, or 42. Animals were then killed at various times post exposure (1-115 days) and retention and distribution determined. Maximum retention of Cd in the brain (calculated as a percentage of administered dose) occurred 1-24 days after exposure. Following exposure on day 0, 7, 14, or 42, maximum retention was 1.2%, 1.6%, 0.4%, or 0.09%, respectively. Cd retention after 114 days was 0.3%, 1.0%, 0.1%, or 0.04% for the respective days of exposure. For the carrier-added group maximum retention was higher with corresponding figures of 2.3%, 1.6%, 1.4%, or 0.07% and retention after 114 days was also elevated 0.6%, 1.1%, 0.4%, or 0.04%. The autoradiographic studies indicated that the choroid plexus was the prime target for Cd uptake in the CNS for all age groups, with the blood vessels a target in the early postnatal period.

Animals↗
PubMed1987

Uterine trauma and limb defects.

The temporary clamping of the uterine blood vessels on one side of the uterus during late pregnancy in the rat (days 14-16) results in hemorrhage and tissue necrosis in the extremities of the fetuses from the experimental side and occasionally from the control side. A further series of experiments showed that similar fetal hemorrhage followed the temporary clamping (45 minutes) of the uterine wall or uterine fat, excluding major uterine vessels; handling the uterus for 5 minutes; and stretching of the uterine blood vessels. A low incidence of fetal hemorrhage was also associated with laparotomy alone, but the fetuses were unaffected by extensive handling of the uterus through the abdominal wall or by intraperitoneal anesthesia. Fetal hemorrhage was also induced by a short episode of severe maternal hyperthermia but not by a high dose of ethanol given by gavage. These results suggest that a range of uterine trauma may result in fetal hemorrhage, perhaps through a common mechanism.

Animals↗
PubMed1987

Vascularity and cytochrome oxidase distribution in the occipital cortex in MAM Ac-induced micrencephaly.

The laminar distributions of cytochrome oxidase activity and vascularization of the occipital cortex of animals made micrencephalic by exposure to MAM Ac on E14 or E16 were examined and compared to control animals. Despite severe disruptions of the normal cytoarchitecture in MAM Ac exposed animals, the laminar distributions of vascular profiles, branch points and cytochrome oxidase activity in micrencephalic animals were similar to those in control animals.

Animals↗