Search PubMed⌕ Search

Biomedical subjects

W J Scott

Publications and source records attributed to W J Scott.

At least 109 records · Page 6Linked to original sources
PubMed1984

Determination of the proximate teratogen of the mouse fetal alcohol syndrome. 1. Teratogenicity of ethanol and acetaldehyde.

The proximate teratogen of the fetal alcohol syndrome is unknown. CD-1 mice were treated ip on Day 10 of gestation with 2, 4, 6, or 7 g/kg ethanol. The percentage of resorptions and malformed fetuses was increased and mean fetal weight was decreased in a dose-related manner. Treatment with 7 g/kg ethanol ip on one of gestational Days 7, 8, 9, 10, or 11 significantly increased the percentage of malformed fetuses and decreased fetal weight. In addition, treatment on Days 10 or 11 significantly increased the percentage of resorptions. Coadministration of 100 mg/kg of 4-methylpyrazole, an inhibitor of alcohol dehydrogenase, orally with 6 g/kg ethanol ip on Day 10 of gestation dramatically increased the embryotoxicity of ethanol. Five ip treatments of 200 mg/kg acetaldehyde at 2-hr intervals on Day 10 of gestation did not significantly increase the percentage of resorptions and malformed fetuses or decrease fetal weight. These data suggest that ethanol is the proximate teratogen of the fetal alcohol syndrome in CD-1 mice.

Abnormalities, Drug-Induced↗
PubMed1984

Determination of the proximate teratogen of the mouse fetal alcohol syndrome. 2. Pharmacokinetics of the placental transfer of ethanol and acetaldehyde.

CD-1 mice were treated ip on Day 10 of gestation with 4, 6, or 7 g/kg ethanol. Maternal and embryonic tissues were analyzed for ethanol and acetaldehyde levels by head-space gas chromatography 5 min to 24 hr after treatment. Dose-dependent ethanol concentrations were observed in maternal blood and liver. Ethanol rapidly crossed the placenta and appeared in the embryo 5 min after treatment. Acetaldehyde was detectable in maternal blood following all treatments and in maternal liver and embryos following treatment with 7 g/kg ethanol. Coadministration of 100 mg/kg 4-methylpyrazole, an alcohol dehydrogenase inhibitor, with 4 or 6 g/kg ethanol on Day 10 of gestation significantly reduced the rate of ethanol elimination in all tissues examined. This reduction was manifested as a prolongation in the half-life of ethanol detectable in maternal and embryonic tissues but not in an increase in maximum ethanol concentrations. Within 5 min of maternal ip treatment with 200 mg/kg acetaldehyde on Day 10 of gestation, acetaldehyde was detectable in the embryo. These data suggest that both ethanol and acetaldehyde are accessible to the embryo during a critical period of development.

Acetaldehyde↗
PubMed1984

Prostaglandin synthesis in rat embryo tissue: the effect of non-steroidal anti-inflammatory drugs in vivo and ex vivo.

Aspirin and salicylate are well-known but poorly understood teratogens in laboratory animals. Because aspirin inhibits PG synthesis, we systematically examined PG synthesis in rat embryo homogenates, the inhibition of PG synthesis in vivo and ex vivo by various non-steroidal anti-inflammatory drugs, and tested the hypothesis that the inhibition of PG synthesis is responsible for aspirin-induced limb defects in rats. We report that embryonic rat homogenates synthesize 6-keto-PGF1alpha, PGE, and PGF in large amounts from endogenous substrate, that aspirin and other non-steroidal anti-inflammatory drugs inhibit PG synthesis in vitro but not necessarily in vivo, and that contrary to our original hypothesis, the inhibition of PG synthesis is likely not responsible for aspirin-induced limb defects in rats.

6-Ketoprostaglandin F1 alpha↗
PubMed1984

Effects of residual liquid junction potential in direct potentiometry of potassium.

To further the accurate direct potentiometry of plasma electrolyte concentrations, we investigated the effects of solution composition on the residual liquid junction potential (RLJP) during measurement of K+. Assuming that the binding constant between K+ and proteins or bicarbonate is no greater than with Na+, we calculate that the amount of bound K+ can be neglected. A significant RLJP exists between simple solutions containing Na+, K+, and Cl- ions and solutions containing Na+, K+, Cl-, and HCO3- ions. Replacing Cl- with HCO3- leads to an increase in the RLJP, which in turn contributes to a negative error in K+ analysis. A small decrease in RLJP is observed as the ionic strength is increased. The Henderson equation gives a reasonable estimate of the magnitude of the observed RLJP, even though the liquid junction does not meet the conditions under which the equation is rigorously applicable. Errors attributed to RLJP may be substantially minimized by using a calibrator solution that contains an anion with mobility similar to that of HCO3-.

Bicarbonates↗
PubMed1983

Acetazolamide teratology and its association with carbonic anhydrase inhibition in the mouse.

Acetazolamide, an inhibitor of the enzyme carbonic anhydrase (E.C. 4.2.1.1.), causes a unique congenital anomaly characterized by postaxial reduction of the distal portion of the right forelimb. To gain an understanding of the mechanism of teratogenesis, the activity of carbonic anhydrase in sensitive and resistant mouse strains, and its inhibition by acetazolamide, were examined. Differences in teratologic sensitivity were found not to be attributable to differences in maternal or embryonic drug levels. Enzyme inhibition at acetazolamide concentrations ranging between 10(-11) and 10(-5) M did not differ between the mouse strains when adult erythrocytes or day 12 embryos were assayed. However, in day 10 embryos, the period of maximum teratologic susceptibility, a small strain difference was found which suggested that the form of carbonic anhydrase in the susceptible CBA/J strain at this time is somewhat more sensitive to inhibition by acetazolamide than the form found in the resistant SWV strain. The results suggest further that more than one isozyme of carbonic anhydrase may be present in all three samples.

Acetazolamide↗
PubMed1983

Caffeine-induced limb malformations: description of malformations and quantitation of placental transfer.

Caffeine was administered intraperitoneally to CD-1 mice on days 11 and 12 of pregnancy at doses of 80-250 mg/kg. A dose-related pattern of malformations was seen that included mainly cleft palate, limb malformations, and hematomas. Many of the limb malformations were examined in preparations stained for cartilage and bone and a number of unique structural arrangements were found. As in previous studies, an asymmetric response was seen, the left limbs being affected more often than the right. Transplacental passage of caffeine was also studied. Caffeine and many metabolites pass into the embryo and attain concentrations slightly below those in maternal plasma. A peak caffeine concentration of 1 mM is attained after a teratogenic dose, which is at least an order of magnitude greater than that of any of the metabolites.

Abnormalities, Drug-Induced↗
PubMed1982

Aspirin-induced psychoteratogenesis in rats as a function of embryonic age.

Gravid Wistar rats were treated with either 625 mg/kg of aspirin (acetylsalicylic acid) or vehicle alone on either gestational Day 11 or 12, and their progeny were evaluated postnatally using a standardized series of neurobehavioral tests and physical measurements. The results showed that aspirin given on Day 11 produced maternal and offspring growth deficits not seen when given on Day 12. In addition, aspirin on Day 11 reduced behavioral performance in the progeny on tests of pivoting locomotion, negative geotaxis orientation, home scent (olfactory) orientation, and swimming performance. Further analysis revealed that some of the behavioral effects of aspirin on Day 11 significantly covaried with the body weight reductions noted in this group, such as negative geotaxis, whereas other results showed only minor associations with weight, such as pivoting and swimming. Interestingly, the olfactory orientation results were more apparent after body weight differences were factored out. These data demonstrate that (1) aspirin causes marked differences both in behavior and postnatal growth with only a 24-hr difference in embryonic age at the time of treatment; (2) behavioral tests are differentially affected by differences in body weight; and (3) behavioral tests appear to be measuring phenomena not reflected by growth, survival, or physical landmarks of development and, as such, add significant information about the toxicological effects of aspirin.

Analysis of Variance↗
PubMed1982

Potentiative interactions between caffeine and various teratogenic agents.

Acetazolamide and inhibitors of DNA synthesis (hydroxyurea, 5-fluoro-2'-deoxyuridine), RNA synthesis (actinomycin D), and protein synthesis (cycloheximide, emetine) were each administered to pregnant rats together with caffeine at doses where each agent alone caused minimal embryotoxicity. Caffeine co-administered with any of the other agents induced a powerful potentiative response. It is not clear from the present experiments whether much lower caffeine dosage, as normally encountered in humans, would potentiate embryotoxicity due to other agents.

Abnormalities, Drug-Induced↗
PubMed1982

Incorporation of 5-bromo-2'-deoxyuridine into mesenchymal limb-bud cells destined to die: relationship to polydactyly induction in rats.

The thymidine analogue, 5-bromo-2'-deoxyuridine (BUdR), given at the proper dose and time to pregnant rats produces preaxial hindlimb polydactyly in a high proportion of near term foetuses. The lack of physiological cell death in an area of preaxial mesenchyme known as the foyer primaire preaxial (fpp) is thought to be important in the pathogenesis of this defect. This study addresses the question of whether BUdR's well-known antidifferentiative effects, which are due in some way to drug incorporation into DNA, are operative in this in vivo system. The dose and temporal response of BUdR for the induction of preaxial polydactyly inversely parallels the frequency of embryonic hindlimbs with an fpp. Incorporation of BUdR into degenerative fragments within the fpp of these treated limbs is demonstrated with indirect immunofluorescence using an antibody to bromouridine. Hindlimbs exposed to a threshold dose of BUdR at the optimal time for producing polydactyly have incorporated the drug into degenerative fragments within the fpp. This suggests that a higher, teratogenic dose of BUdR might likewise be incorporated. The resulting higher level of incorporation presumably alters the normal course of terminal differentiation for these cells originally destined to die. Teratogenic doses of BUdR injected at later than the optimal time are also incorporated into dead cell fragments within the fpp, suggesting that presumptive dead cells have additional rounds of DNA synthesis which are BUdR-insensitive. Approximately 12 h prior to overt death presumptive fpp cells no longer incorporate the drug. Results reported support the hypothesis that incorporation of teratogenic levels of BUdR prevent cell death in the fpp. The extra cells are thought to contribute directly or indirectly to the added digit. Contrary to other views, it is suggested that BUdR-induced teratogenesis can be a result of the drug's antidifferentiative effects on specific, 'sensitive', populations of cells.

Abnormalities, Drug-Induced↗
PubMed1981

Indomethacin--placental transfer, cytotoxicity, and teratology in the rat.

Aspirin is a well-known teratogen in laboratory animals and is an inhibitor of prostaglandin synthesis. To further investigate the inhibition of prostaglandin synthesis as a mechanism of teratogenesis, we examined the teratologic potential, cytotoxic potential, and placental transfer of indomethacin in the rat. Indomethacin was not teratologic, not cytotoxic to cells in the embryonic hindlimb bud, and did not cross the placenta in physiologically significant amounts on days 11 to 12 of gestation. Near parturition, however, indomethacin crossed the placenta in pharmacologically significant amounts. The pharmacokinetics of placental drug transfer are discussed.

Abnormalities, Drug-Induced↗
PubMed1981

Aspirin-induced teratogenesis: a unique pattern of cell death and subsequent polydactyly in the rat.

Offspring of pregnant rats treated with a high dose of aspirin on day 11 of gestation frequently had predominantly right-sided polydactyly of the hindlimbs at term. Aspirin-treated embryos removed on day 12 exhibited a unique pattern of preaxial mesodermal cell death in the hindlimb buds. In addition, these embryos had a delay of the normal episode of cells death in the preaxial apical ectodermal ridge and an absence of cell death in a zone of physiological necrosis in the preaxial mesoderm thought to be instrumental in controlling preaxial digit formation. The role of cell death in the pathogenesis of polydactyly is discussed.

Abnormalities, Drug-Induced↗
PubMed1981

Pathogenesis of bromodeoxyuridine-induced polydactyly.

Intraperitoneal injection of BUdR on day 11 or 12 of rat gestation produced preaxial polydactyly of the hindlimb. The pathogenesis of this deformity differed from that of other polydactyly regimes in that drug-induced mesenchymal necrosis was not an essential feature. Likewise an altered pattern of physiological necrosis was not an essential feature. Likewise an altered pattern of physiological necrosis in the apical ectodermal ridge (AER) was not evident in hindlimbs of BUdR-treated embryos. In keeping with earlier studies, a zone of physiological necrosis within the preaxial mesoderm thought to be instrumental in controlling preaxial digitation was abolished. Speculation has focused on the incorporation of BUdR into these prospectively necrotic cells as the means by which they survive. Support for this idea is gained from the protective effect of concomitant thymidine administration, which presumably prevents BUdR incorporation.

Abnormalities, Drug-Induced↗
PubMed1981

The effect of 6-aminonicotinamide on energy metabolism in rat embryo neural tube.

6-Aminonicotinamide (6-AN) is a potent metabolic inhibitor which produces central nervous system malformations when administered to pregnant rats. Since the antimetabolite interferes with energy yielding pathways, the present study was undertaken to determine the effect of maternally administered 6-AN on energy metabolism of the neural tube in developing embryos. On day 9 of gestation, pregnant rats were injected with 2 mg/kg 6-AN, and embryos removed 12 or 24 hours later. Glucose, glycogen, lactate, ATP, PCr, and GABA were measured in neural tube sections using fluorometric techniques. Only ATP and PCr showed changes as compared to appropriate controls. These two metabolites were increased 29% and 37%, respectively, by 6-AN administration. The mechanism of these alterations in metabolites is unclear, but may be related to decreased metabolic demand.

6-Aminonicotinamide↗
PubMed1981

Comparative studies on acetazolamide teratogenesis in pregnant rats, rabbits, and rhesus monkeys.

Acetazolamide produces a characteristic forelimb reduction deformity when administered to pregnant rodents. Past studies indicated that non-rodent species (rabbit and monkey) are resistant to this effect. The present studies confirmed this fact and demonstrated that transport of acetazolamide into the rabbit embryo was similar to that in sensitive rat embryos. In monkeys, however, the concentrations of acetazolamide within maternal plasma and embryo were much lower than in rats. Carbonic anhydrase activity was also measured since inhibition of this enzyme is the primary pharmacologic effect of acetazolamide. Again the rabbit embryo had carbonic anhydrase specific activity levels similar to that of the rat. Monkey embryos, on the other hand, contained negligible levels of enzyme activity during the presumed sensitive period of development. Thus the resistance of monkey embryos to acetazolamide teratogenesis may be due to low carbonic anhydrase activity and/or the small amount of drug reaching the embryo. No basis for the resistance of rabbit embryos to acetazolamide teratogenesis was uncovered.

Acetazolamide↗
PubMed1981

Measurement of prostaglandins in embryonic tissue using radioimmunoassay.

Although prostaglandins appear to play an important role in numerous physiological processes in the adult, neonate, and fetus, very little is known about the role of these compounds in the embryo. This study demonstrates that rat embryo homogenates synthesized 6-oxo-PGF1 alpha, PGE and PGF in markedly different amounts from endogenous substrate. Synthesis was inhibited by indomethacin (10 microM) in varying degrees (70-89%) depending on the prostaglandin. The metabolite of PGF2 alpha, 13, 14-dihydro-15-keto PGF2 alpha (PGF2 alpha-M), was produced in limited amounts in the absence of exogenous NAD. In the presence of exogenous NAD and PGF however, embryonic homogenates produced PGF2 alpha-M. The potential role of prostaglandins during embryogenesis is discussed.

6-Ketoprostaglandin F1 alpha↗