bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diazepam‐induced cleft palate in the mouse and lack of correlation with the H‐2 locus
Authors: Tocco Donald R. , Renskers Kevin , Zimmerman Ernest F. 
Published: June 2005

AbstractCleft palate frequencies were studied in AJ and SW mice following either 1‐ or 2‐day dosing schedules with the anxiolytic drug diazepam (DAZ). In all cases, mice were food and water deprived for 24 and 48 hours in the 1‐ and 2‐day dosing schedules, respectively. High cleft palate frequencies in control mice of both strains resulting from 48‐hour food and water deprivation (on days 13.5 and 14.5 of gestation) were reduced in mice deprived for 24 hours, indicating a stress related effect. Two‐day dosing with DAZ (400 mg/kg) produced a net increase in cleft palate frequency in SW (33%) and AJ (18%) mice. Mice treated only on day 13.5 had reduced control and DAZ cleft palate frequencies, neither of which were significant. Clefting was significant but reduced following 1‐day dosing on day 13/20 of gestation (13 days 20 hours) in SW mice (18%), whereas no clefting was seen in the AJ strain. This strain difference was shown not to be related to differences in developmental timing. Production of cleft palate seen in AJ mice after 2 days of dosing may be indicative of an interaction of DAZ with the stresses resulting from food and water deprivation. Genes of the major histocompatibility locus, H‐2, have been shown to regulate cleft palate formation following glucocorticoid and phenytoin administration to mice. Despite pharmacological similarities between DAZ and phenytoin, comparison of cleft palate frequencies following administration of DAZ to various strains of mice of different H‐2 haplotypes indicated that genes associated with the H‐2 locus do not regulate DAZ‐induced cleft palate in these strains.
Influence of β‐D‐xyloside on growth and histological aspect of long bones in chicken embryos
Authors: Groot C. G. , Thesingh C. W. , te Pas M. , Moskalewski S. 
Published: June 2005

AbstractIt is known that β‐D‐xylosides interfere with the proteoglycan synthesis in several tissues. A possible influence of this disturbed synthesis on the matrix formation of bone and cartilage has not been described light microscopically. In the present study we used 10‐day‐old chicken embryos which were exposed in ovo to a final concentration of 0.5 β‐D‐xyloside. After 3, 6, 9, 20, 25, 31, 35 and 40 days, lengths of several skeletal elements were determined and the middle metatarsal bones were processed for light microscopical demonstration of acidic groups.The results demonstrate that β‐D‐xyloside inhibits growth of long bones and induces synthesis of a cartilage matrix with a very low concentration of chondroitin sulphate. It has no noticeable influence on the amount of acidic groups in the organic bone matrix. Despite the absence of chondroitin sulphate, the cartilage matrix becomes mineralized normally.
6.5‐mm human embryo with a single nasal placode: Cyclopia or hypotelorism?
Authors: Vermeij‐Keers Christl , Poelmann Rob E. , Smits‐Van Prooije Annette E. 
Published: June 2005

AbstractA macroscopic study on the missing elements in cyclopia (a single eye or closely approximated eyes with all intergrades in a single orbit) with or without proboscis and hypotelorism was performed on 12 human fetuses and 2 human fetal skulls. In addition, microscopic investigations were carried out on the orbital contents of the cyclops with a single eye without proboscis, crown–heel length (C–HL) 37 cm, and on the 6.5‐mm‐crown–rump length (C–RL) human embryo with a single nasal placode localized in front of two eye cups. In the embryo and in all 14 fetal cases the midfacial region was more‐or‐less deficient. In the two cyclopia cases without proboscis the nasal placode(s) had not developed at all during the embryonic period. In cases with proboscis, consisting of a single tube localized above both eyes, and in the hypotelorismic specimens, there could only have been a single nasal placode during development: a situation evident in the 6.5‐mm‐C–RL human embryo. In this holoprosencephalic embryo the single nasal placode was undulated, as if formed from two fused nasal placodes, and flanked by the prospective areas for the lateral nasal processes. Caudally, it was bordered by the maxillary processes. In view of the position of the single placode in this embryonic face, as described above, it is most likely that this is a preliminary stage of hypotelorism. Moreover, both medial nasal processes with the internasal groove in between, i.e., the interplacodal area, were missing. In the fetal cyclopic skulls this missing area is indicated by the agenesis of, for example, the ethmoid, nasal, and lacrimal bones; the nasal septum; and two premaxillae. All specimens under study, including the microscopically investigated cyclops with a single eye, showed elements of two eye primordia. It can be concluded, therefore, that cyclopses with or without proboscis and hypotelorismic specimens have the same abnormal stages of development of the prosencephalon in relation to the eye primordia. In cyclopia cases with proboscis, the single nasal placode develops out of the range of the maxillary processes.
Developmental effects of isotretinoin and 4‐oxo‐isotretinoin: The role of metabolism in teratogenicity
Authors: Kochhar D. M. , Penner John D. 
Published: June 2005

AbstractPrevious observations have indicated that isotretinoin (IT), a drug in common use for therapy of cystic acne, is teratogenic in humans but possesses low embryotoxicity in pregnant mice, probably because of its shorter half‐life and limited placental transfer in rodents. In human volunteers and patients, one major blood metabolite of IT is 4‐oxo‐isotretinoin (4‐oxo‐IT) which undergoes slower elimination than IT and may itself be a participant in teratogenesis. To investigate the problem of species differences displayed by IT and the role of its metabolism, embryotoxic effects of 4‐oxo‐IT were examined after its single or repeated intubations into pregnant ICR mice and compared with the effects of a similar regimen of IT. The two compounds were also tested for their relative ability to suppress chrondrogenesis in the in vitro cell and organ culture assays. We found that a single dose of 4‐oxo‐IT, 100 mg/kg, given on day 11 of gestation (plug day = day 0 of gestation) produced a moderate incidence of limb reduction defects and cleft palate (39% and 27% of surviving fetuses, respectively), while a dose of 150 mg/kg affected virtually every fetus. IT, on the other hand, produced no defects in fetuses exposed to similar dose levels. Repeated intubations with IT, however, resulted in increasing the frequencies of limb reduction defects and cleft palate to levels obtained after 4‐oxo‐IT administration. We found that a 3‐hour interval between IT intubations was more effective in this regard than an 8‐hour interval. Repeated IT intubations also uncovered sharper stage‐dependency of limb and palatal defects than obtained otherwise. IT and 4‐oxo‐IT were equally effective in suppressing chondrogenesis in vitro. We conclude that 4‐oxo‐IT is a potent teratogen in the mouse and that the extent or rate of IT metabolism by the mother may determine the apparent embryotoxic activity of IT in a given species.
Evaluation of the embryotoxic potential of ten chemicals in the whole mouse embryo culture
Authors: Van Maele‐Fabry G. , Picard J. J. 
Published: June 2005

AbstractTen widely different chemicals, actinomycin D, mithramycin, podophyllotoxin, vincristine sulfate, triaziquone, chlorambucil, mercaptopurine riboside, methyl‐mercaptopurine riboside, dimethylsulfoxide, and L‐lysine were tested in the whole mouse embryo culture system. The highest concentration was always the concentration that induced 100% lethality (ELC100). The lowest concentration varied from 1/2 to 1/10 of the ELC100.The chemicals that had the most noxious effect on embryonic growth and differentiation were actinomycin D, triaziquone, and mercaptopurine riboside. Podophyllotoxin, methyl‐mercaptopurine riboside, and L‐lysine were the less embryotoxic. As a whole, no significant discrepancies were observed between the results and the teratological data obtained from the literature. These observations support the assumption that the whole murine embryo culture system can give valuable information on the teratogenicity of chemicals.
Soft tissue anomalies in a patient with congenital tibial aplasia and talo‐calcaneal synchrondrosis
Authors: Hootnick David R. , Packard David S. , Levinsohn E. Mark , Cady Robert B. 
Published: June 2005

AbstractWe have carried out the third in a series of anatomical dissections of amputated congenitally deformed human limbs in an attempt to determine the etiological relationship between the bony and soft tissue anomalies. This specimen consisted of a limb with congenital tibial aplasia and an adducted foot with five toes. The arterial and nerve patterns were reminiscent of those seen previously by us. The arteries were characterized by absence of the anterior tibial artery and an incomplete plantar arch. The superficial peroneal nerve terminated at the ankle. Extra branches from the sural, deep peroneal, and medial plantar nerves supplied branches to the dorsum of the foot. There were two extra muscles in the leg. The remaining muscles were normal, with the exception that most muscles normally inserting on the plantar surface of the foot inserted instead into a common tendon sheet. The tibia was replaced by a tendinous band, and the talus and calcaneus were united by a complete synchondrosis. The contralateral limb clinically appeared to have a clubfoot. The combination of an absent anterior tibial artery and an incomplete plantar arch is consistent with our theory that a reduced number of vessels puts the embryonic limb at increased risk of congenital defects due to the reduction in the number of collateral blood routes. Some event, such as extravasation of blood or embolization, may concurrently or subsequently compromise blood flow in the remaining vessels. We have previously observed abnormal arterial patterns similar to that described above in limbs having absence of the tibia and in other patients having clubfeet. The presence of abnormal arterial patterns in a limb with absence of the tibia and a contralateral limb with clubfoot suggests that absent tibia and clubfoot may be etiologically related.
D‐(–)‐beta‐hydroxybutyrate‐induced effects on mouse embryos in vitro
Authors: Hunter E. S. , Sadler T. W. 
Published: June 2005

AbstractThe effects of the “physiologically occurring” D‐isomer of betahydroxybutyrate (D‐BOHB) were evaluated in neurulating mouse embryos by using the technique of whole embryo culture. Following a 24‐hour culture period D‐BOHB induced malformations and growth retardation in a concentration‐dependent manner. At a 48 mM concentration essentially all embryos exhibited neural tube defects, and decreased rates of glucose metabolism by the pentose phosphate pathway (PPP) and Krebs cycle were observed when compared to controls. The relationship between an inhibition of the PPP and induction of malformations by DL‐BOHB has been reported, and thereby suggests a similar mechanism may be operating for the D‐isomer. In contrast, the effect of the D‐isomer on the Krebs cycle may result from a replacement of glucose intermediates by those generated from metabolism of D‐BOHB. Concentrations as high as 20 mM D‐BOHB have been reported in the serum of uncontrolled diabetic patients, and since ketones rapidly equilibrate across extraembryonic membranes, embryos in vivo may be exposed to concentrations equivalent to those which induced malformations in vitro. However, the incidence of malformations induced by D‐BOHB was less than that reported for the DL‐racemic mixture at equivalent concentrations, thereby suggesting that the L‐isomer is also teratogenic. Therefore, until the presence and concentration of L‐BOHB in the serum of diabetics are documented, the assessment of the impact of maternal ketosis on the embryo remains incomplete.
Whole embryo morphometry in teratogen screening
Authors: Lanning John C. 
Published: June 2005

AbstractCurrent methodology in embryo evaluation involves qualitative assessment of razor blade and paraffin serial sections. Presently, no one has applied existing computerized morphometric techniques to examine embryos. A technique has been developed that enables investigators to section embryos at 150μ, thereby greatly reducing the number of sections and making morphometric analysis possible. This type of analysis permits the precise volumetric determination of several developing organ systems. The aim of this study was to evaluate the feasibility and sensitivity of whole embryo morphometry in teratogen screening. Cadmium chloride, a well‐established teratogen, was chosen because of its ability to induce exencephaly in approximately one‐half of offspring while having no observable effects on the remaining exposed embryos. It was found that both exencephalic and normal‐appearing cadmium‐exposed embryos had significantly smaller total cellular, neuroepithelial, otic vesicle, optic assembly, limb bud, and cardiac mesenchyme volumes when compared to controls. Also, the neuroepithelial volume of the exencephalic embryos was significantly smaller than the normal‐appearing cadmium‐exposed embryos. These results suggest that in addition to inducing exencephaly, cadmium chloride has an overall inhibitory effect on embryonic growth. We have shown that whole embryo morphometry is a sensitive means of evaluating embryonic growth that permitted determination of cadmium‐induced aberrations not discernable by currently employed techniques. In light of these results, we feel this technique shows promise for future investigations of known and suspected teratogens.
Predictive value of minor anomalies: II. Use in cohort studies to identify teratogens
Authors: Holmes Lewis B. , Kleiner Beth C. , Leppig Kathleen A. , Cann Cristina I. , Muñoz Alvaro , Polk B. Frank 
Published: June 2005

AbstractCohort studies of putative human teratogens can identify the full spectrum of phenotypic effects, including both major malformations and minor anomalies. Cohort studies which include the much more common minor anomalies make it possible to use a relatively small number of exposed and unexposed infants to identify an increase in the frequency of malformations. We evaluated this use of minor anomalies in a cohort study of newborn infants who had been exposed in utero to three putative teratogens: insulin‐dependent diabetes mellitus in the mother and the use of the anticonvulsant phenytoin and exogenous sex hormones by the mother. In addition, the reproducibility of identifying minor anomalies was tested by comparing the results of examinations by two independent observers of 444 unexposed infants. The frequency of minor anomalies was increased among infants of diabetic mothers. However, the reproducibility of identifying minor anomalies was poor. We conclude that the examination of teratogen‐exposed infants for minor anomalies cannot be used in epidemiologic studies of putative teratogens unless special efforts are made to maximize consistency in the identification of these features.
Retinoic acid‐induced selective mortality of splotch‐delayed mouse neural tube defect mutants
Authors: Moase Connie E. , Trasler Daphne G. 
Published: June 2005

AbstractThe allelic loci splotch (Sp) and splotch‐delayed (Spd) cause neural tube defects (NTDs) in mice homozygous for either of these genes. The polymorphic enzyme isocitrate dehydrogenase (Idh‐1) in conjunction with a recombination suppressor was used as a genetic marker to identify embryos homozygous for these alleles. A split dose of all‐trans retinoic acid (RA) totalling 5.0 mg/kg administered on gestation day 9/15 and 9/18 (days/h) significantly reduced the frequencies of NTD and of mutant genotypes in marked Spd embryos examined on day 16 without significantly increasing the resorption frequency. There was a nonsignificant decrease in the frequencies of NTD and mutant genotypes in embryos examined on day 11 of gestation. Thus, retinoic acid treatment was associated with selective mortality of the homozygous Spd mutants. No evidence of selective mortality was observed in RA‐treated Sp embryos.
Monitoring for multiple malformations in the detection of epidemics of birth defects
Authors: Khoury Muin J. , Adams Melissa M. , Rhodes Phil , Erickson J. David 
Published: June 2005

AbstractAlthough most known human teratogens often produce a combination of birth defects in an affected infant, surveillance programs aimed at detecting epidemics of birth defects usually only monitor rates of individual defects. A drawback to this approach is that an increase in the rate of infants affected with a specific combination of defects may lead to little or no increase in the rates of component defects. Using the Poisson distribution, we show that, compared with monitoring for individual defects, monitoring for combinations of two and three defects may require fewer numbers of births to detect an epidemic. In general, an increase can be detected more rapidly by monitoring the rates of defect combinations than by monitoring the rates of individual defects if most affected infants have combinations of defects rather than isolated defects. For example, in the case of Congenital rubella syndrome (CRS), monitoring for the combination of cataracts with deafness and/or patent ductus arteriosus could have led to earlier detection of an epidemic than could monitoring for cataracts alone. In contrast, in the case of thalidomide embryopathy, monitoring for reduction defects of upper limbs in combination with reduction defects of lower limbs and/or microtia/anotia would not have led to earlier detection of an epidemic than would monitoring for reduction defects of upper limbs alone. This is due mainly to the low frequency of defect combinations among affected cases. When used with regular monitoring for individual defects, surveillance of defect combinations can enhance the ability of monitoring programs to detect epidemics of birth defects.
The in vitro embryotoxicity of 5‐fluorouracil in rat embryos
Authors: Grafton Thomas F. , Bazare Johnny J. , Hansen Deborah K. , Sheehan Daniel M. 
Published: June 2005

AbstractThe fluorinated pyrimidine 5‐fluorouracil (5‐FU) is an effective chemotherapeutic agent that is teratogenic in a number of species. The mechanism for the embryopathic effect of the drug is unknown. We examined the effects of this compound on gestation day 10.5 rat embryos cultured for 48 hours in a rodent whole embryo culture system. Embryos were exposed for 1–4 hours to various doses of 5‐FU. Embryolethality was minimal in all treatment groups. The malformation frequency increased with higher doses; within a dose, the malformation frequency increased with longer exposure to the drug. The tail and hindlimb bud were the most commonly affected structures in vitro; tail and leg defects are produced in several species by exposure to the, drug in vivo. The embryopathic drug concentration in the culture media (2–8 μg/ml) is similar to the plasma level of 2–17 μg/ml, which is associated with embryopathy in vivo. Results from this study suggest that the whole embryo culture system is an appropriate model for developmental toxicity studies of 5‐FU.
The effect of cadmium on the development of the facial prominences: Surface area measurements of day 10‐8 A.M. hamster embryos
Authors: Gale Thomas F. , Horner Jack A. 
Published: June 2005

AbstractThe environmental contaminant cadmium (Cd) is a proven teratogenic agent in rodents. In hamsters, it causes craniofacial dysmorphogenesis. The underlying mechanism for this damage is unknown. Early facial development in hamsters occurs during gestation days 9–11 and involves the formation and appropriate fusion of several prominences surrounding the stomodeum. The hypothesis for this study is that the occurrence of Cd‐induced facial defects involves a disruption of the normal formation and/or fusion of one or more of the facial prominences. Pregnant hamsters were treated with Cd (2 mg/kg) or water intravenously on gestation day 8 (8 A.M.). On gestation day 10 (8 A.M.) surviving embryos were processed to obtain scanning electron micrographs of the frontal view of the face. Measurements of the surface areas of 15 different portions of the face were obtained using a microcomputer equipped with a digitizer. Both qualitative and quantitative differences in the faces were detected upon comparing the Cd‐exposed and control embryos. The surface areas of the prominences measured were significantly smaller in the Cd‐exposed embryos. However the sizes of the other regions of the Cd‐exposed faces were either little affected (nasal pit areas) or markedly increased (the interval of the face between the medial nasal prominences). Two possible explanations for these data are discussed.
Anesthetic agents
Authors: Friedman J. M. 
Published: June 2005

AbstractAlthough many pregnant women undergo anesthesia and many others are occupationally exposed to anesthetics every year, assessment of the teratogenic risk of anesthetic agents in humans must currently be made on the basis of very limited data. Available studies suggest that administration of an anesthetic to a pregnant woman will usually not have a deleterious effect on embryonic or fetal development. The risk of congenital anomalies does not appear to be substantially increased among children of women who have chronic occupational exposure to anesthetic gases during pregnancy, either, but miscarriages may occur more frequently than expected among such women. There is an urgent need for publication of good human epidemiologic and experimental animal studies on the teratogenicity of anesthetics.
Potential role of somatomedin inhibitors in the production of diabetic embryopathies
Authors: Balkan Wayne , Phillips L. S. , Goldstein Steve , Sadler T. W. 
Published: June 2005

AbstractMouse conceptuses at the 18–21‐somite stage were grown for 2–24 h in vitro in the presence of a serum fraction (Mr = 800–1,080 daltons) possessing somatomedin‐inhibitory activity (SI) isolated from diabetic rats. Following an 8‐h exposure to the SI, DNA and incorporation of 3H‐thymidine were reduced in the embryos while 12 h was required to observe a reduction in total protein and RNA. At the 24‐h time point, the neurectoderm was thinner than in controls, and autoradiograms of this region showed a substantial decrease in grain density with 3H‐thymidine, but not 3H‐leucine or ‐uridine. Effects on the visceral yolk sac (VYS) preceded those on the embryo. The cytoplasm of the VYS endoderm cells from conceptuses exposed to the SI contained many vacuoles by 4 h, which were larger by 24 h. Total protein was greater than in controls from 4 h onward, although 3H‐leucine incorporation, which had increased after 2 h of SI exposure, returned to control levels by 8 h. As seen by SDS‐polyacrylamide gel electrophoresis, VYSs from conceptuses exposed to the SI for 4 or 24 h were enriched (compared to control VYSs) in four protein bands also present in the culture medium (primarily rat serum), suggesting that protein degradation and/or transfer of amino acids and peptides to the embryo was inhibited in these VYSs. Such a conclusion was supported by a quantitative decrease in proteins and amino acids in the exocoelomic fluid of conceptuses exposed to the SI for 24 h. The altered processing of proteins may therefore represent a primary cause of the SI‐induced embryonic abnormalities.