bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular alterations in rabbit embryos in situ after a teratogenic dose of hydroxyurea: An in vivo microscopic study
Authors: Millicovsky Guillermo , DeSesso John M. 
Published: June 2005

AbstractThe early cardiovascular (CV) responses of New Zealand white rabbit embryos in situ subsequent to maternal SC injection with hydroxyurea (HU) were analyzed by in vivo microscopic methods. Laparotomies were performed on gestational day 12, and the gravid uteri were exteriorized. The embryos were exposed by careful incisions of the uterine wall and reflection of the extraembryonic membranes. Temperature, water, and electrolyte homeostasis were maintained throughout all procedures. Maternal injection with HU at a teratogenic level (750 mg HU/kg) caused alterations in the embryonic CV system as early as 2 minutes post‐treatment. Typically, within 4 minutes the embryonic craniofacial region responded with dilations of the anterior cardinal vein (ACV) and its tributaries. The ensuing pathological events included petechial hemorrhages and hematomas in the forebrain, postocular region, mandibular and nasal processes, and apparent collapse of the vasculature in the forelimb bud. Many embryos exhibited pericardial hemorrhage within 9 minutes. The most severly affected embryos displayed cardiac tamponade and stasis of blood flow through the cardiac chambers. In contrast, control embryos, which received either no drug treatment or SC injection of saline at various osmolarities and pH's, demonstrated none of the CV changes reported above, even after 120 minutes. Low doses of HU (500 mg/kg) produced only ACV dilations in some embryos by 30 minutes. Histologic analysis of HU embryos confirmed the in vivo microscopic observations. The drastic CV derangements exhibited by many embryos may be one of the causes for the high resorption rates associated with the treatment. Furthermore, since teratogenic doses of HU produce immediate hemorrhages and hematomas in the embryos in the same craniofacial areas which are later deformed in the term fetus, it is possible that the teratogenic action of this drug may be related to the initial vascular embryopathies.
Differential embryonic cardiovascular responses to acute maternal uterine ischemia: An in vivo microscopic study of rabbit embryos with either intact or clamped umbilical cords
Authors: Millicovsky Guillermo , DeSesso John M. 
Published: June 2005

AbstractThe effects of acute episodes of maternal uterine ischemia on the cardiovascular system of New Zealand white rabbit embryos were studied by in vivo microscopic methods. On gestational day 12, gravid uteri were surgically externalized, and the walls of the implantation sites were carefully incised and reflected to reveal the embryos. Throughout all procedures, temperature, water, and electrolyte homeostasis were preserved. The embryos within each litter were divided into two groups: 1) two randomly selected embryos whose umbilical cords were clamped, and 2) the remaining embryos of the litter whose umbilical cords were uncompromised. Uterine ischemia was induced by clamping all uterine arterial and venous channels. Occlusion of the maternal uterine vessels produced severe uterine cyanosis within 1–2 min. The embryos whose umbilical cords were not clamped exhibited severe cardiovascular derangements beginning within 3–4 min. In contrast, the embryos whose umbilical cords were clamped (thereby interrupting both umbilical and vitelline circulations) had no observable cardiovascular alterations. The absence of effects in embryos with clamped umbilical cords suggests that acute episodes of hypoxia are well tolerated by young embryos. In contrast, the rapid appearance of cardiovascular derangements after interruption of maternal uterine circulation in embryos with undamped umbilical cords emphasizes the idea that even brief intervals of uterine ischemia are deleterious to the rabbit embryo.
Investigations on cyclophosphamide treatment during the preimplantation period. II. In vitro studies on the effects of cyclophosphamide and its metabolites 4‐OH‐cyclophosphamide, phosphoramide mustard, and acrolein on blastulation of four‐cell and eight‐cell mouse embryos and on their subsequent development during implantation
Authors: Spielmann Horst , Jacob‐müller Ursula 
Published: June 2005

AbstractPreimplantation mouse embryos were cultured for 48 hours from the four‐cell and eight‐cell stage to the blastocyst stage in the presence of Cyclophosphamide (CPA) or one of its metabolites–4‐hydroperoxy‐CPA (4‐HP‐CPA), phosphoramide mustard (PAM), and acrolein (Acr)‐to identify the metabolite which is embryotoxic after CPA treatment of pregnant mice during the preimplantation period. The dose‐response relations for the inhibition of blas‐tulation revealed identical inhibition curves for PAM and 4‐HP‐CPA (in solution 4‐HP‐CPA immediately decomposes to 4‐hydroxy‐CPA (4‐OH‐CPA)). These two metabolites are inhibiting blastulation in vitro at concentrations that are 10,000 times lower than CPA and 100 times lower than acrolein. When blastocysts which had developed in the presence of CPA and its metabolites in vitro were subsequently cultured in inhibitor‐free medium NCTC‐109, the same dose‐response relationship pattern was obtained. Since 4‐OH‐CPA decomposes into acrolein and PAM in vivo and in vitro and since PAM and 4‐OH‐CPA exhibit identical embryotoxicity towards preimplantation embryos in vitro, PAM probably also is an active embryotoxic CPA metabolite in vivo before implantation. This result is discussed in relation to the importance of alkylating CPA metab‐olites in cancer treatment and in teratological studies during organogenesis.
Teratogenesis of retinoic acid in rats: Susceptible stages and suppression of retinoic acid‐induced limb malformations by cycloheximide
Authors: Kistler Andreas 
Published: June 2005

AbstractThe susceptible stages and the malformation pattern produced by excess retinoic acid were investigated in rat fetuses. Retinoic acid (120 mg/kg body weight, suspended in rape oil) was administered orally to pregnant females on one of the first 20 days of gestation. Fetuses were examined for external and, after visualization of the skeleton with alizarin red, for skeletal malformations on the 21st day of gestation. Retinoic acid was highly embryolethal when administered on days 9 and 10 of gestation (96.2 and 100% resorptions). The earliest teratogenic effect of retinoic acid was noted on the 9th day of gestation. Severe multiple defects were produced by retinoic acid administration on days 9 and 11 of gestation, but more specific malformations involving the axial skeleton, the fore‐ and hindlimbs, and cleft palate resulted from treatment on days 12–18 of gestation.Cycloheximide, an inhibitor of protein synthesis, reduced the incidence of limb defects induced by retinoic acid. This result indicates that the teratogenic effect of retinoic acid on limb morphogenesis may be dependent upon continuous protein synthesis and is compatible with the view that vitamin A may act like a hormone.
Prevention of congenital malformations
Authors: Warkany Josef 
Published: June 2005

AbstractPrevention of congenital malformations is recognized as the ultimate goal of teratology, a goal that has not yet been reached despite much progress in the description, experimental production, and treatment of birth defects. In addition to quests for the causes of congenital malformations and the removal of these causes, indirect preventive methods must be sought that could aid in eliminating these malformations as sources of children's morbidity and mortality.
Neuromuscular blocking agents and axial teratogenesis in the avian embryo. Can axial morphogenetic disorders be explained by pharmacological action upon muscle tissue?
Authors: Meiniel Robert 
Published: June 2005

AbstractA comparative qualitative and quantitative study of the embryotoxic and teratogenic activities of various chemical agents known to have neuromuscular blocking properties was done on the quail embryo. Intrinsic embryotoxic activity and teratogenicity were evaluated for each agent, and the qualitative nature of the teratogenic effects was correlated with the pharmacologic properties of the different effectors. Gross malformations (contorted posture) were found only with agents which directly (cholinergic agonists) or indirectly (cholinesterase inhibitors) favor muscle membrane depolarization, suggesting that such malformations may be due to muscle contraction following depolarization. All of the agents studied produced variable degrees of vertebral fusion, apparently due to paralysis resulting either from sustained depolarization (cholinesterase inhibitors and cholinergic agonists) or directly from cholinergic blockade (cholinergic antagonists and neurotoxins).
Teratogenic effect of lambda‐carrageenan on the chick embryo
Authors: Monis Benito , Rovasio Roberto A. 
Published: June 2005

AbstractCarrageenans are widely used as food additives. Thus, it seemed of interest to test their possible teratogenic action. For this purpose, 530 chick eggs were injected in the yolk sac with 0.1 ml of a solution of 0.1% lambda‐carra‐geenan in 0.9% sodium chloride. As controls, 286 eggs were injected with 0.1 ml of 9.0% sodium chloride. In addition, 284 eggs received no treatment. After incubation for 48–50 hours at 39°C, embryos were fixed, cleared, and observed with a stereoscopic microscope.The frequency of abnormal embryos in the group receiving lambda‐carrageenan was higher than in the controls (p<0.04). Partial duplication of the body, abnormal flexures of the trunk, anencephaly, a severely malformed brain, thickening of the neural tube wall, an irregular neural tube lumen with segmentary occlusion and a reduction in crown‐rump length and number of somites were distinctly seen in the lambda‐carrageenan‐injected group. Moreover, the average number of anomalies per embryo in the lambda‐carrageenan‐injected group was nearly twice that in the controls. Present data indicate that lambda‐carrageenan has teratogenic effects on early stages of the development of the chick embryo.
Pathogenesis of bromodeoxyuridine‐induced polydactyly
Authors: Scott William J. 
Published: June 2005

AbstractIntraperitoneal 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 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.
Vascular hypervolemia and hematoma formation in chick embryos treated with trypan blue
Authors: Weaver T. E. , Kaplan S. , Rajala G. M. 
Published: June 2005

AbstractThe relationship between cardiovascular disturbances and the formation of hematomas in trypan blue‐treated chick embryos was investigated. Hematocrits from Hamburger‐Hamilton stage 15 and 16 embryos (8–10 hours after treatment at stage 13) were obtained. The hematocrit value from the treated embryos was significantly lower (P < 0.001) than the values from controls. Unopened and saline‐injected control values were not significantly different (P > 0.05). We interpret this to mean that there is excess circulating fluid volume in the treated embryos. The results of direct injection of measured volumes of fluid into the cardiovascular system of normally developing embryos (stages 15 and 16) provided evidence to suggest that the caudal dorsal aortae are susceptible to fluid‐induced distension and rupture.
Modification of the mutagenicity and teratogenicity of cyclophosphamide in rats with inducers of the cytochromes P‐450
Authors: Hales Barbara F. 
Published: June 2005

AbstractCyclophosphamide must be enzymatically activated to be either mutagenic or teratogenic. This activation is thought to be catalyzed by the cytochrome P‐450 monooxygenase system. To study the relationship between the mutagenic and teratogenic metabolites of Cyclophosphamide, the mutagenicity and teratogenicity of this drug were compared after activation by rats pretreated with chemicals (phenobarbital and β‐naphthoflavone) inducing different cytochromes P‐450. Activation of Cyclophosphamide to mutagenic metabolites by enzyme fractions from rats on day 13 of gestation was measured with the Ames test using Salmonella typhimurium TA1535. Teratogenicity was assessed in vivo by treatment of rats with Cyclophosphamide on day 13 of gestation. Cyclophosphamide was activated to mutagenic metabolites to the same extent (on a tissue wet weight basis) by enzyme fractions from maternal liver, kidney and placenta, despite differences in cytochrome P‐450 content. Fetal homogenates did not activate Cyclophosphamide. Phenobarbital pretreatment increased the activation of Cyclophosphamide to mutagenic metabolites by maternal liver microsomes 10‐fold and liver cytochrome P‐450 content 1.8 fold; however, this drug did not alter the activation of Cyclophosphamide by maternal kidney, by placenta or by the fetus. Phenobarbital pretreatment increased the teratogenicity of cyclophosphamide in rats on day 13 of gestation (increased incidence of malformed embryos, decreased fetal weight). Pretreatment with β‐naphthoflavone did not induce liver cytochrome P‐450 in the pregnant rat and did not change the activation of cyclophosphamide to mutagenic metabolites by liver, kidney, placenta or the fetus. Pretreatment with this polycyclic aromatic hydrocarbon had no effect or decreased the teratogenicity of cyclophosphamide. Thus, these experiments suggest that the mother, rather than the fetus, is the site of activation of cyclophosphamide; after phenobarbital pretreatment the predominant site of cyclophosphamide activation is the maternal liver. There appears to be a correlation between the teratogenicity and mutagenicity of cyclophosphamide after induction of the cytochromes P‐450. We can speculate that the “proximate teratogen” of cyclophosphamide may also be the “proximate mutagen”.
Immunohistochemical localization of cyclic AMP during normal and abnormal chick and mouse limb development
Authors: Elmer William A. , Smith Mary Alice , Ede Donald A. 
Published: June 2005

AbstractThis paper describes the immunohistochemical localization of cAMP during limb chondrogenesis in talpid3 chick, brachypod mouse, and normal embryos. Comparisons were made between chick wing buds at Stages 22, 25, and 30, and mouse hind limb buds at Days 11, 12.5, and 14. At Stage 22, the normal mesenchyme in the chick displayed areas of bright fluorescence compared to a lesser intense and more evenly distributed fluorescence in talpid3. Sections of the central region from normal Stage 25 limb buds exhibited an intense fluorescence that was uniformly distributed, whereas, in talpid3 staining was more, mosaic with some areas fluorescing brightly and others showing little fluorescence. At Stage 30 the staining pattern was similar between normal and talpid3, with the fluorescence being brighter in the cartilage tissue than in the surrounding soft tissue. Differences in the staining patterns of normal and brachypod limb tissue were not detectable. At Days 11 and 12.5, tissue from both genotypes displayed a very bright, uniform fluorescence. In the 14‐day hind limb buds, the staining patterns were comparable to those observed in Stage 30 chick wing buds. However, under in vitro conditions conducive for the expression of the chondrogenic phenotype, differences in the intensity and extensiveness of fluorescent staining were detectable in cultures derived from 12‐day normal and brachypod hind limb mesenchyme. Compared to the control, the uneven distribution of immunofluorescence in the talpid3 limb buds and the differences in intensity and extensiveness of fluorescence in the brachypod cultures support the hypothesis that cAMP is involved in limb cartilage differentiation.
Placental findings in spontaneous abortions and stillbirths
Authors: Ornoy A. , Salamon‐Arnon J. , Ben‐Zur Z. , Kohn G. 
Published: June 2005

AbstractPlacentae and membranes of 360 spontaneous abortions and stillbirths were studied by light microscopy and compared to 100 induced abortions of 2–5 months gestation. The placental findings were correlated with morphological and chromosomal studies of the fetuses. A high incidence of hydatid degeneration was found in early spontaneous abortions (less than 12 weeks of age), especially in “blighted ova.” “Atypical” stromal cells were found in the placental villi of early abortions with trisomy and triploidy. In late spontaneous abortions (13–18 gestational weeks) inflammatory lesions of the placentae were observed in over a third of cases and the incidence of hydatid degeneration was very low. The incidence of inflammatory lesions of the placentae was further raised in cases of early fetal death (18–24 gestational weeks), involving 60% of the placentae of fetuses without malformations. In stillborn infants, over 25 weeks of age, the incidence of inflammatory placental lesions dropped again, and the incidence of vascular lesions was raised to 50%. It seems that inflammatory lesions of the placentae may play an important role in the etiology of midtrimester spontaneous abortions. Isolation of the infectious microorganism and subsequent treatment may therefore reduce the rate of fetal losses in this group.
Teratogenic evaluation of 2‐nitro‐p‐phenylenediamine, 4‐nitro‐o‐phenylenediamine, and 2,5‐toluenediamine sulfate in the mouse
Authors: Marks Thomas A. , Gupta Bhola N. , Ledoux Thomas A. , Staples Robert E. 
Published: June 2005

AbstractPregnant outbred albino (CD‐1) mice were given 2‐nitro‐p‐phenylenediamine (2NPPD; 32–256 mg/kg/day), 4‐nitro‐o‐phenylenediamine (4NOPD; 16–1024 mg/kg/day) or 2,5‐toluenediamine sulfate (2,5TDS; 16–64 mg/kg/day) by subcutaneous injection on Days 6–15 of gestation. The mice were killed on Day 18, the general health and reproductive health of the dams evaluated, and the fetuses examined and processed in order to characterize external, visceral, and skeletal malformations. The 32 and 128 through 256 mg/kg/day dose levels of 2NPPD produced a significant (p < 0.05) reduction in average weight gain by the dam during pregnancy. There was also a significant reduction in average fetal weight at 128 mg/kg/day and above. Although 2NPPD administration led to a significant increase in the average percentage of malformed fetuses at 160 mg/kg/day and above, these effects occurred only at dosages which produced significant maternal toxicity. Teratogenic effects were observed with 4NOPD, as administration of this dye led to a significant increase in the average percent of malformed fetuses at 256 mg/kg/day and above. A significant reduction in average weight gain by the dam during pregnancy also was observed at these dose levels, as well as a significant reduction in average fetal weight. Although 2,5TDS killed 4 of 31 dams at 48 mg/kg/day, and 9 of 11 dams at 64 mg/kg/day, this compound did not cause a significant increase in the average percent of malformed fetuses. There were indications of embryotoxicity, however, as dosages of 32 mg/kg/day and above led to significant reductions in average fetal weight.
Deleterious effects of prenatal prednisolone exposure upon morphological and behavioral development of mice
Authors: Gandelman Ronald , Rosenthal Caren 
Published: June 2005

AbstractThe influence of prenatal exposure to the synthetic glucocorticoid prednisolone (PRED) was examined in female offspring of mice administered the drug on Days 13–18 of pregnancy. The offspring weighed significantly less than control animals at birth and weaning. Animals born of mothers given the highest dosage of the drug (400 μg) weighed less than controls in adulthood. Fetal exposure to PRED also resulted in morphological masculinization as evidenced by an increase in anogenital distance. In addition to its marked influence, prenatal PRED exposure retarded the attainment of the developmental milestones of eye opening, lifting, walking, and gripping. The effect of PRED upon the fetus is relatively rapid in that a reduction of fetal weight was observed in 13‐day‐old conceptae 7.5 hr following a maternal injection of PRED. The administration of an antiestrogenic compound (MER‐25) concurrently with PRED prevented the reduction in birth weight, thereby suggesting that PRED acts, in part, by its known attenuation of fetoneonatal estrogen‐binding protein. And finally, fetal exposure to PRED had virtually no effect upon reproductive competence as assessed by proportion of successful pregnancies, lactation performance, and postpartum fighting behavior. It is concluded that prenatal exposure to PRED markedly affects somatic and muscular/motor development and it may be worthwhile to examine the influence of the drug upon levels of gonadal hormones in an attempt to elucidate the mechanism through which its effects are produced.
Indicators of developmental toxicity following prenatal administration of hormonally active compounds in the rat. I. Gestational length
Authors: Rands Peggy L. , White Randy D. , Carter Melvin W. , Allen Stanley D. , Bradshaw William S. 
Published: June 2005

AbstractPrenatal administration of 3,4,3′,4′‐tetrachlorobiphenyl, zeranol, or diethylstilbestrol was observed to delay parturition in the rat and result in a concomitant increase in perinatal mortality. Even among control animals, those litters in which birth occurred after the beginning of day 22 of pregnancy contained significantly fewer survivors one day after birth. Increases in the length of gestation were correlated with increased weight of newborn control pups independent of litter size. The relationship between weight and litter size was anomalous, however, in treated animals. Gestational length is a sensitive indicator of a developmental effect even in the absence of overt teratogenicity.
Facial duplication: Case, review, and embryogenesis
Authors: Barr Mason 
Published: June 2005

AbstractThe craniofacial anatomy of an infant with facial duplication is described. There were four eyes, two noses, two maxillae, and one mandible. Anterior to the single pituitary the brain was duplicated and there was bilateral arhinencephaly. Portions of the brain were extruded into a large frontal encephalocele. Cases of symmetrical facial duplication reported in the literature range from two complete faces on a single head (diprosopus) to simple nasal duplication. The variety of patterns of duplication suggests that the doubling of facial components arises in several different ways: Forking of the notochord, duplication of the prosencephalon, duplication of the olfactory placodes, and duplication of maxillary and/or mandibular growth centers around the margins of the stomatodeal plate. Among reported cases, the female:male ratio is 2:1.
Pathogenesis of congenital tumors and malformations of the sacrococcygeal region
Authors: Lemire Ronald J. , Beckwith J. Bruce 
Published: June 2005

AbstractSkin‐covered lesions in the sacrococcygeal region include an unusual array of congenital tumors and malformations. Excluding the easily recognized meningomyelocele, there are over 50 other conditions that occur, many of which seem to be important in linking the disciplines of teratology and oncology. While it is impossible to precisely determine the manner in which these arise, there is suggestive evidence that early structures incorporated within the caudal cell mass of the embryonic tail may play an important role. The present paper reviews the basis for this speculation from both the literature and a series of 136 cases.