bluuebunny/crossref_metadata_2025_split huggingface dataset:
Teratogenic and cytogenetic effects of some plant‐derived antitumor agents (vincristine, colchicine, maytansine, VP‐16‐213 and VM‐26) in mice
Authors: Sieber S. M. , Whang‐Peng J. , Botkin C. , Knutsen T. 
Published: June 2005

AbstractThe teratogenic effects of three new plant‐derived antitumor agents, maytansine, VP‐16‐213 and VM‐26, were compared to the effects of vincristine and colchicine in pregnant Swiss albino mice that received a single ip injection of drug on day 6, 7 or 8 of gestation. Cytogenetic studies were also performed using maternal bone marrow and embryos obtained 48 hours after injection of maytansine, vincristine, VP‐16‐213, VM‐26 and colchicine on day 6, 7 or 8 of gestation. A close correlation between teratogenic and cytogenetic effects was not noted among the compounds tested. Vincristine had greater embryotoxic and teratogenic activity than maytansine at equimolar doses (0.36 μmoles/kg), with the peak effects appearing after injection on day 7 of gestation. Colchicine, VP‐16‐213 and VM‐26 were comparatively less potent than maytansine and vincristine, since doses of 2.5 μmoles/kg (colchicine and VP‐16‐213) and 1.5 μzmoles/kg (VM‐26) were required to elicit embryotoxic effects. At their teratogenic doses, all compounds induced various cranial abnormalities including exencephaly, hydrocephalus, anophthalmia and microtia, as well as major skeletal malformations. The teratogenic dose of vincristine is comparable to its effective antitumor dose in transplantable rodent tumor systems; in contrast, the teratogenic dose of maytansine is approximately 10‐fold higher than its antitumor dose. Of the compounds studied, VP‐16‐213 and VM‐26 exerted the most consistent cytogenetic effects in embryonic tissue. A large proportion of the structural chromosome aberrations induced in embryonic cells by VM‐26 were stable and are most likely capable of surviving at least one cell division.
A selection experiment for distinct types of 6‐aminonicotinamide‐induced cleft lip in mice
Authors: Trasler D. G. , Rearden C.‐A. , Rajchgot H. 
Published: June 2005

AbstractThe face shape hypothesis (Trasler, '68) suggests that the face shape of the embryo at the time of lip formation plays a role in the genetic predisposition to lateral cleft lip (LCL). Predisposed strains like A/J and CL/Fr have narrower inter‐nasal‐pit distances than those not predisposed such as C57BL/6 and C3H. The present paper reports a test of the hypothesis by deriving two new lines of mice from the same heterogeneous stock, selecting for differences in type of response on day 9.5 of gestation to the teratogen 6‐aminonicotinamide (6AN). The M line responds with a high frequency of induced median cleft lip (MCL) and the L line with a low frequency of MCL. The M line has a wider inter‐pit‐distance than the L line. The L line has a 3 to 9% spontaneous LCL frequency and has the same narrow inter‐pit‐distance component of embryonic face shape found in A/J and CL/Fr. The face measurements have already been reported (Juriloff and Trasler, '76). The present paper outlines the selection experiment and discusses the differences obtained between lines for induced CL and for spontaneous LCL. These findings have provided independent support for the face shape hypothesis.
Limb anomalies produced by 2,2′‐dipyridyl in rats
Authors: Oohira Atsuhiko , Nogami Hiroshi 
Published: June 2005

AbstractThe teratogenicity of 2,2′‐dipyridyl (DIP), a chelator for ferrous iron, was investigated by administration of single dose of 60 or 75 mg/kg intraperitoneally to pregnant SD rats on days 11.5‐14.5. Fetuses examined on day 21 were decreased in weight, and had defects chiefly in the limb. The type and incidence of limb defects differed according to day of treatment. Digital malformations in the forelimb and long‐bone defects in the hindlimb were produced with high incidence by treatment on day 12.5, and the frequency of digital malformations in the hindlimb was increased by treatment on day 13.5. Light and electron microscopic examinations revealed the delay of mesenchymal condensation and destruction of mesenchymal cells in the forelimb bud in the early stage after day 12.5 treatment. The normal increase of DNA, protein, collagen and glycosaminoglycan contents in the forelimb bud was markedly inhibited by the treatment. The incorporation activities for [14C] proline and [14C] glucosamine of the forelimb bud were reduced to 50–60% of the control. These results indicate that DIP has potent teratogenic and cytotoxic effects on the development of the rat limb bud.
Embryonic development and mitochondrial function. III. Inhibition of respiration and ATP generation in rat embryos by thiamphenicol
Authors: Bass Rolf , Oerter Detlef , Krowke Ralf , Spielmann Horst 
Published: June 2005

AbstractPregnant rats were injected s.c. with thiamphenicol (TAP) on days 10 and 11 of gestation. Embryos were removed on day 12 and mitochondrial energy parameters (respiration and ATP content), mitochondrial enzyme characteristics (cytochrome oxidase activity), as well as extramitochondrial growth indicators (dry weight, and DNA content) were measured. All those factors showed a dose‐dependent inhibition by TAP. Concentrations of TAP in the embryos (8 μ/g wet weight two to three hours after application of 100 mg/kg) were in the range necessary for reduction of mitochondrial protein synthesis in vitro, and well below the concentrations required for direct inhibition of mitochondrial (respiration) and extramitochondrial functions (replication). Cytochrome oxidase was most sensitive and inhibited by 50% at a dose of 10 mg TAP/kg/day. ATP was reduced by 50% and respiratory reserve (additional respiration in the presence of DNP) was inhibited by more than 90% at 100 mg TAP/kg/day using DNA as reference. Delayed and complete embryolethality resulted after injection of 125 mg TAP/kg/day, however, no malformations could be observed. When comparing the inhibition of mitochondrial functions induced by TAP with the inhibition of overall embryonic development, it appeared that respiration was the rate‐limiting step for the embryotoxic effects of TAP. Because of the non‐specificity of these effects, prenatal mortality rather than teratogenic effects was seen.
Enhancement of chlorcyclizine teratogenicity in the rat by coadministration of calcium chelating agents
Authors: Wilk Ann L. , King C. T. G. , Pratt Robert M. 
Published: June 2005

AbstractChlorcyclizine and structurally related drugs induce a high incidence of cleft palate and skeletal malformations in fetal rats. We have shown previously that these teratogens bind tightly and reversibly to chondroitin sulfate of cartilage and compete with calcium for binding. Experiments reported here demonstrate that co‐administration of calcium chelating agents with chlorcyclizine significantly increases both the frequency of malformations and retention of [14C] chlorcyclizine by embryos. Retention of radioactive teratogen by embryos is inverse to retention of [45Ca] calcalcium. These findings suggest that drug binding to embryonic glycosaminoglycans is involved in the pathogenesis of malformations produced by chlorcyclizine.
Delay in postnatal growth and development of offspring produced by maternal restraint stress during pregnancy in the rat
Authors: Barlow S. M. , Knight A. F. , Sullivan F. M. 
Published: June 2005

AbstractRats were subjected to restraint stress for nine hours daily, on three consecutive days, at various stages of pregnancy from days 9–20, and the postnatal development and behaviour of the offspring assessed on a wide‐ranging battery of tests. Stress at any of the stages of pregnancy investigated caused a significant decrease in offspring body weight persisting up to 6 weeks of age, and delayed the appearance of certain developmental landmarks such as ear opening, auditory startle and cliff avoidance responses. Postnatal mortality and impairment of ability to orient to the home cage were also significantly increased in the offspring from rats stressed on days 18–20 of pregnancy. In a second experiment, the effects of restraint stress on days 18–20 were investigated in more detail. At birth, stressed and control offspring were fostered onto mothers from the same treatment group or cross‐fostered onto mothers from the opposite treatment group and assessed as before, to determine whether the adverse effects observed in the first experiment were prenatally or postnatally mediated. The effects were most marked in prenatally stressed pups reared by stressed mothers and least marked in controls reared by controls, with the other two cross‐fostered groups being intermediate; this indicates that the effects were induced partly prenatally at the time of treatment and partly postnatally by the rearing mothers that had been stressed.
Induction of cleft palates: Effects of triamcinolone acetonide on transcription in isolated nuclei
Authors: Anne Lakshmi , Bekhor Isaac 
Published: June 2005

AbstractThe effect of triamcinolone acetonide on the transcriptional activity in nuclei isolated from maternal A/J mouse livers and embryonic maxillary processes (EMP) has been studied. Triamcinolone acetonide (TAC, 13 mg/kg body weight) was administered to A/J mice on day 12.5 of gestation, and the mice were sacrificed at different time periods following injection. We find a significant increase in transcription in liver nuclei, and a decrease in this activity in nuclei from embryonic maxillary processes in response to TAC at 16 to 20 hours following injection. With the drug α‐amanitin we show that the effect of TAC on transcription in EMP cannot be due to fluctuations in the concentration of endogenous RNA polymerase B. This is further substantiated by studies on the transcription of EMP‐nuclei in the presence of exogenous DNA template. Relative to controls, the data demonstrates that the concentrations of RNA polymerases A and B in EMP‐nuclei remain unchanged in response to TAC. Conversely, stimulated liver nuclei result in significant increases in the concentrations of RNA polymerases A and B. We therefore propose that in embryonic maxillary processes TAC induces changes in the chromatin template which may interfere with normal development.
Developmental staging and thalidomide teratogenicity in the green monkey (Cercopithecus aethiops)
Authors: Hendrickx Andrew G. , Sawyer Roger H. 
Published: June 2005

AbstractThe developmental stages of 11 Cercopithecus aethiops embryos, 24 to 45 days post‐mating, are described. The onset of organogenesis in this species is approximately five to seven days later than that reported for macaques and baboons. This temporal difference in the embryonic period is an important factor in the analysis of the subsequent teratogenic study. Oral administration of thalidomide in single or multiple (3‐day) treatment periods to pregnant green monkeys between days 28 and 33 resulted in defects of the limbs which resemble those observed in macaques and baboons. However, the sensitive period occurs approximately four days later than that reported for another nonhuman primates. These results indicate that the sensitive period of the limbs to thalidomide coincides with their earliest development.
Lectin teratogenesis: Defects produced by Concanavalin a in fetal rabbits
Authors: Desesso John M. 
Published: June 2005

AbstractConcanavalin A (con A) is teratogenic to rabbit embryos during gestational days 12–15. Intracoelomic injections of 40 μl con A solution (4 μg/μl) were performed on rabbit embryos during gestational days 10–15. Control embryos received either 40 μl of saline, sham injection or no treatment. Con A caused increased fetal resorptions on days 10 and 11, but malformation levels did not differ from controls. On days 12–15, con A produced craniofacial, trunk and limb anomalies. The highest percentage of malformations occurred on day 14. The defects were classified into four groups: (1) malformations of limbs including paw and digital dysplasias as well as fusions of the limbs to the head or body wall; (2) “closure” defects such as umbilical hernia, encephalocoele, exencephaly or ectopia cordis; (3) “contracture” defects such as club paws, extended knees, or clenched digits, which exhibited normal osseous and cartilaginous skeletons; and (4) miscellaneous, non‐specific anomalies including fused or dysplastic sternebrae or ribs. Histologic analysis of selected 12‐day embryos 4 to 18 hours post‐injection was performed to ascertain potential sites of teratogenic action. At 12 hours ectodermal necrosis was observed in the limb buds adjacent to the apical ectodermal ridge. By 18 hours, the ectoderm had eroded, exposing the basal lamina to the amniotic fluid. Focal areas of mesenchymal necrosis were observed in association with the ectodermal erosion. The potential roles of amniocentesis and limb bud repair in the genesis of the malformations are discussed.
Comparative distribution and embryotoxicity of methotrexate in pregnant rats and rhesus monkeys
Authors: Wilson James G. , Scott William J. , Ritter Edmond J. , Fradkin Rochelle 
Published: June 2005

AbstractDosages of methotrexate of roughly comparable embryotoxicity were determined to be 0.3 mg/kg on gestation day 10 in rats and 3.0 mg/kg/d on days 29 through 32 of gestation in rhesus monkeys. These times represented similar periods in development. This regimen in rats was moderately embryolethal, slightly teratogenic, and caused some intrauterine growth retardation; in monkeys it was mildly embryolethal, not teratogenic, and caused only transitory growth retardation.Methotrexate was largely cleared from maternal plasma of both species within 8 hours, and in spite of a higher administered dose and initial concentration in monkey, the rate of fall was faster than in rat. The fraction of total drug concentration remaining unbound in plasma was approximately 30‐40% during the first 4 hours after treatment in both species. Embryo concentrations, however, were strikingly different during the first 8 hours, ranging between 108 and 209 ng/g in monkey but between 3.4 and 7.7 ng/g in rat. A slow rate of fall in embryo concentrations in both species was estimated to be inversely proportioned to the rate of growth of embryos, which was in accord with the fact that the absolute amount per embryo was little changed in 24 hours.Thus, the degree and type of embryotoxicity was not closely correlated with the level or duration of concentration in the embryos: a small maternal dosage in rat produced moderate embryotoxicity and very low embryo concentrations; a large maternal dosage in monkey produced slight embryotoxicity despite high embryo concentrations.
The effect of the time of administration of chromium trioxide on the embryotoxic response in hamsters
Authors: Gale Thomas F. , Bunch John D. 
Published: June 2005

AbstractPrior work has demonstrated that chromium trioxide is embryotoxic in hamsters if administered to pregnant animals early on the eighth gestation day. The major manifestations are cleft palate and an increased frequency of resorptions. In the present study a single iv dose (8 mg/kg) of chromium trioxide was injected into pregnant hamsters at 8 A.M. on either day 7, 8, 9, 10 or 11 of gestation in order to determine the effect of altering the time of treatment on embryotoxicity. Fetuses from females treated with chromium or demineralized‐distilled water were collected on day 15 of gestation and were examined for the types and frequency of external and internal malformations. The number of resorption sites was recorded. Cleft palate, the major malformation detected, was produced only when chromium was administered on days 7, 8 or 9 of gestation. Since the frequency of resorptions and the incidence of cleft palate varied with the time of treatment it is concluded that the time at which chromium trioxide is injected into the pregnant hamster does influence embryotoxicity. The results suggest that an interference with embryonic growth may be an important factor in chromium‐induced cleft palate in hamsters.
Newborn and adult face shapes related to mouse cleft lip predisposition
Authors: Trasler Daphne G. , Machado Marie 
Published: June 2005

AbstractEmbryonic face shape was postulated to be a factor in the multifactorial basis for susceptibility to cleft lip (CL) in A/J mice, since A/J differed from C57BL/6 (resistant embryos). To test this hypothesis new lines were created by selection and the embryos measured (Juriloff and Trasler, 1976). The L line with 9% CL had the predicted narrow internasal pit distance like A/J (12% CL) compared to the M line (0% CL) like the resistant C57BL/6 (0% CL). Newborns and adults of these four lines and CL/Fr (23% CL) were measured to find whether they, like embryos, have face shapes related to their CL predisposition. Measurements were made on newborn and 2 1/2 month old mouse skulls and on heads fixed for soft tissue. Premaxilla length (PL, distance from incisive foramen to anterior edge of anterior palatine foramen) was significantly shorter in newborns and adults in CL lines CL/Fr, A/J and L than non‐CL lines M and C57BL/6. Premaxilla width (PW) tended to be narrower in adults (except A/J) and gum (i.e. filtrum) length (GL) in newborns and adults tended to be shorter in CL lines. Discriminant analysis of adult skeletal data involving four variables PL, PW, Interorbital distance (ID) and length of nasal bones (LN) discriminated A/J and L from M and C57BL/6 lines. Discriminant analysis with ID omitted discriminated CL lines A/J, L and CL/Fr from non‐CL lines M and C57. For variables PL, LN and ID in newborn skulls discriminant analysis had less discriminating ability, but showed a strong tendency to separate A/J and L from C57 and M. Thus a particular facial complex associated with CL predisposition has been found.
Fetal and placental weight relationships in the albino rat near term
Authors: Norman Neroli A. , Bruce Neville W. 
Published: June 2005

AbstractThe relationship of fetal weight to placental weight was examined in 34 albino rats on day 22 of gestation. The influence of maternal weight, fetal position and the number of fetuses in the litter and each uterine horn were assessed also. There was no indication that rats with heavier placentas had heavier or lighter fetuses. However, within each litter, placental weight was weakly correlated (r = 0.297, p < 0.01) with fetal weight. Maternal weight at mating, although positively related to the number of corpora lutea, was not related to mean fetal or placental weight. The number of fetuses in the Jitter was negatively related to placental weight but there was no apparent relation to fetal weight. Fetuses and placentas at the ovarian end of the horn were significantly lighter than those at the vaginal end. The strength of the fetal weight:placental weight correlation in the rat is compared to those in other species.
Fetal and placental responses to artificially induced hyperthermia in rats
Authors: Arora K. L. , Cohen B. J. , Beaudoin A. R. 
Published: June 2005

AbstractPregnant rats were utilized to study the effect of maternal hyperthermia on fetal development. Eight groups of six to eight rats were exposed to ambient temperatures of 43‐44cC at various stages of pregnancy. All rats were killed on day 20 of gestation. Edema, microencephaly and microph‐thalmia followed heat treatment on day 4, 6, or 8 and skeletal defects occurred on day 10 of gestation. Apparently heat stress of dams after day 14 of gestation had little or no effect on embryos. Most placentas from day 6‐10 treatment groups were significantly heavier than control and exhibited extensive thickening and necrosis of decidua basalis. Our results suggest that the rat is a useful model for investigating maternal hyperthermia as a possible cause of human placentophathies and fetal retardation.
Gap junctional vesicles in the neural tube of the splotch (Sp) mutant mouse
Authors: Wilson Doris B. , Finta Laurel A. 
Published: June 2005

AbstractThe lumbosacral region of the neural tube was studied by means of transmission electron microscopy in retrospectively confirmed normal ( + /+ Sp/ + ) and abnormal (Sp/Sp) embryos of the splotch mutant mouse early on the ninth day of gestation when the caudal neural groove is normally in the process of closing to form the neural tube. In abnormal embryos, a consistent feature is the presence of gap junctional vesicles, particularly in the region of the neural groove which subsequently fails to close, whereas these structures are rarely observed in similar areas of normal embryos. The possible significance of gap junctional vesicles is discussed in terms of cellular adhesion during early neurogenesis.
The teratogenic activity of a thalidomide analogus EM12 in rats on a low‐zinc diet
Authors: Jackson André J. , Schumacher Herbert J. 
Published: June 2005

AbstractThe relationship between the teratogenicity of EM12, 2‐(2,6‐dioxopiperiden‐3′‐yl) phthalimidine, a stable analogue of thalidomide, and zinc status in the maternal animal was investigated using pregnant rats on a low‐zinc diet (1 ppm zinc, days 0–14 gestation) as the experimental model.Previous studies with this compound in rats fed a commercial diet at oral doses up to 250 mg/kg per day for three days and intravenous doses up to 10 mg/kg per day for three days failed to produce “typical” thalidomide malformations. However, when a dose of 150 mg/kg was given intraperitoneally to rats on a low‐zinc diet, typical thalidomide malformations occurred with an incidence of 57.5%.
Changes in chemical composition of chick embryos treated with a β‐xyloside and a lathyrogen
Authors: Gibson K. D. , Segen H. J. , Doller H. J. 
Published: June 2005

AbstractNine‐day chick embryos were treated with 4‐methylum‐belliferyl β‐D‐xyloside or β‐aminopropionitrile fumarate, and their gross chemical composition was examined one week later. Total DNA was 10–20% less in embryos treated with either drug than it was in control embryos. Xyloside‐treated embryos showed marked increases in percent wet weight and in sodium/DNA and chloride/DNA ratios, and small decreases in protein/DNA, hydroxyproline/DNA and sulfate/DNA. None of these parameters was affected in embryos treated with β‐aminopropionitrile. Approximately 85% of the uronic acid of control embryos was present as chondroitin sulfate, with a degree of sulfation of 80% and charge density of 1.8; all of this chondroitin sulfate was covalently linked to peptide and had a number‐average molecular weight of 29,300. In embryos treated with β‐xyloside, 90% of the uronic acid was present as chondroitin sulfate, with a degree of sulfation of 40% and charge density ranging from 1 to 2; 27% of this chondroitin sulfate, with an average molecular weight of 25,400, was peptide linked, while 73% was linked to 4‐methylum‐belliferone arid had an average molecular weight of 22,900. The chemical differences between embryos treated with the xyloside and embryos treated with the lathyrogen reinforce the conclusion on morphological grounds that these are distinct syndromes involving different aspects of the extracellular matrix.