bluuebunny/crossref_metadata_2025 huggingface dataset:
Cysts in cultured fetal rat kidneys
Authors: Monie I. W. , Morgan J. R.
Published: June 2005

The formation of cysts has been studied in kidneys removed from day‐15 and day‐18 rat fetuses and cultured in a mixture of medium 199 (Morgan et al., '50) for periods of up to 15 days. Gas phases of 95% O2 and 5% CO2, and 95% air and 5% CO2, were employed, the latter being considered more satisfactory. In day‐15 kidneys cysts formed from the ampullary portions of the collecting tubules after 2 days whereas cysts derived from nephrons were not seen until 9 days of culturing. The latter arose from developing juxtamedullary nephrons. In day‐18 kidneys cysts from collecting tubules and nephrons were both present after 3 days of culturing. The latter, in this instance, originated mostly in immature midcortical nephrons, the juxtamedullary nephrons having undergone rapid degeneration. The tubular portion of the nephron seemed to be the primary site of dilatation. Under culture conditions cysts of nephrons thus formed from immature actively developing nephrons and not from those that were mature. Cysts associated with collecting tubules arose from the ampullary (terminal) portions of the latter in both day‐15 and day‐18 cultured kidneys. The study of cultured mammalian fetal kidneys can provide information on the nature and genesis of renal cysts. It is possible that the same technique also may be helpful for examining the effects of teratogens directly on the kidney.
Ultrastructural changes in rat palatal epithelium after β‐aminopropionitrile
Authors: Mato M. , Uchiyama Y. , Aikawa E. , Smiley G. R.
Published: June 2005

β‐Aminopropionitrile (BAPN) retarded or suppressed epithelial changes in the medial edge of the palatal process in later stages of gestation in rats. Programmed cell death did not follow the usual pattern, and only a few lysosomes were observed on day 18 of gestation. The sensitivity of the medial epithelium to BAPN appeared to be different in various areas of the palatal epithelium; the epithelium on the anterior region of the palatal process was hypertrophied and keratinized, while posteriorly the medial or neighboring epithelium was very thin and, in neonatal rats, the covering was absent. A basal lamina was distinct in the anterior region and indistinct or fragmented posteriorly. Collagen fibers did not develop adjacent to the basal lamina, and an amorphous material was scattered throughout the mesenchymal tissue. These findings suggest that BAPN decreases the “connecting capacity” between mesenchyme and epithelium, and results in a modification of epithelial changes.
Teratologic evaluation of imipramine hydrochloride in bonnet (Macaca radiata) and rhesus monkeys (Macaca mulatta)
Authors: Hendrickx Andrew G.
Published: June 2005

Imipramine hydrochloride was administered orally twice daily to 18 bonnet and 3 rhesus monkeys between days 23 and 45 of pregnancy for 1–3 or 18–22 days at 1, 2, and 10 times the recommended human dose. No teratologic changes were observed, although signs of maternal toxicity occurred at the high dose level, and the abortion rate was higher than in controls.
Nonteratogenicity of captan in beagles
Authors: Kennedy Gerald L. , Fancher Otis E. , Calandra J. C.
Published: June 2005

Thirty and 60 mg/kg captan, administered in the diet during the entire gestation period or during gestation and an 8‐week lactation period, caused no adverse effects in either mothers or progeny, and captan is thus judged to be nonteratogenic in beagles.
Comparison of the teratogenic effects of mustine hydrochloride in rats and ferrets. The value of the ferret as an experimental animal in teratology
Authors: Beck F. , SchöN H. , Mould G. , Swidzinska P. , Curry S. , Grauwiler J.
Published: June 2005

The teratogenic effects on the offspring of ferrets given single sc injections of mustine hydrochloride on various days of gestation is described and compared with a smaller series of rats treated at similar stages of embryonic development. Distinct qualitative differences in the teratogenic responses of the 2 species were demonstrated. The predominant defects in ferrets were anophthalmia produced during early gastrulation, and tail abnormalities produced at the head‐process stage; whereas in rats the major deformities were limb defects and cleft palate and these resulted from treatment at the stage of the paddleshaped forelimb. The advantages of the ferret as an additional species for teratogenicity studies is discussed and methods of providing a continuously breeding colony required for such studies are described.
Accessory Spleens in domestic rabbits (Oryctolagus cuniculus). II. Increased frequency in hematological diseases and experimental induction with phenylhydrazine
Authors: Wkisbroth S. H. , Fox R. R. , Scher S. , Crary D. D.
Published: June 2005

Analysis of several inbred strains of rabbits with high (30–50%) frequencies of accessory spleens revealed that hereditary hematological diseases, autoimmune hemolytic anemia and lymphosarcoma, occurred in some of them. Twenty‐one per cent of individuals in these strains, though phenotypically normal, had globulin‐coated (Coombs'‐positive) erythrocytes. These findings supported observations of increased frequency of accessory spleens in human beings with similar diseases (e.g., autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, “secondary hypersplenism,” Gaucher's disease, hereditary spherocytosis, etc.) and suggested that accessory spleens represent physiological responses to demand for phagocytic capacity provided by the reticuloendothelial system in the spleen, rather than as passive developmental anomalies. This hypothesis predicted that simulation of the basic defect might yield a laboratory model for the induction and study of accessory spleens in rabbits. Phenylhydrazine was used for this purpose and it was shown that the frequency of accessory spleens in 80 rabbits so treated was 45%. Most of these accessories appeared to arise de novo because pretreatment examination in situ by laparotomy revealed a naturally occurring frequency of about 7.5%. These results supported, and provide a basis for, observations by surgeons that subsequent to an initial splenectomy, during which spleniculi were noted to be absent, recurrent indications for splenectomy would later reveal functional accessory spleens. No evidence was found to relate anemia, per se, or cardiovascular anomalies to the increased frequency of accessory spleens in rabbits. It was suggested that heritable factors limit the upward expression of accessory spleens in “normal” populations, as well as during the course of certain diseases and of phenylhydrazine treatment.
Quantitative assessment of effects on fetal rat eyes of fixative and of time postmortem at fixation
Authors: Barash Beverly A. , Shepard Thomas H.
Published: June 2005

Numbers of mitotic figures present in parasagittal sections of lens capsules of day‐20 fetal rat eyes and comparison of relative lens volume provided a quantitative basis for comparing tissues fixed in neutral buffered formalin and Bouin's and Lillie's fluids. The number of mitotic figures at 1 or 6 h postmortem was significantly higher in Bouin's and Lillie's‐fixed material than in that fixed in formalin. The estimated volume of the tissue fixed in Bouin's was significantly greater than that of lenses in the other 2 fixatives. In addition the overall appearance of the sectioned lens was examined in an effort to evaluate possible artifacts, especially those that might be interpreted as cataracts. Excessive shrinkage and fragmentation of formalin‐fixed lenses was observed.
Cervical dislocation of the cerebellum in children with meningomyelocele
Authors: Variend S. , Emery John L.
Published: June 2005

In a study of 100 cerebellums from children dying with meningomyelocele, the lobular pattern of the dislocated segment was identified and classified. There was a graded variation in the degree of cerebellar deformity ranging from complete absence of cerebellar tissue in the upper cervical canal to one in which the upper cerebellar lobules were displaced through the foramen magnum. Within this range there were 2 instances in which the cerebellar defect conformed to that found in the Chiari type 1 deformity, consisting of prolapse of tonsillar tissue only. During fetal life the lobular relation in the caudal aspect of the cerebellum undergoes considerable change and it is likely that the type of deformity present in the cervical canal is closely related to the stage of cerebellar development at which the alteration in growth has its inception. The evidence presented argues against the defect being of a primary developmental nature. The terms “Chiari type 1 deformity” and “Arnold‐Chiari malformation” have outlived their usefulness and future descriptions of the cerebellum in children with hindbrain deformities should indicate the shape of the lobules and precise ones involved in the herniation.
Influence of coxsackievirus B infections on fetal growth in mice
Authors: Lansdown A. B. G.
Published: June 2005

Coxsackieviruses B1, B3, B4, and B5 injected into TO outbred mice on the 8th day of pregnancy resulted in increased fetal wastage and growth retardation. Coxsackievirus B2 caused increased fetal wastage, whereas Coxsackievirus B6 exhibited no fetal effects. Pregnant animals injected with viruses causing fetal growth impairment ate more food than controls yet did not increase their body weight as much as control animals. Autopsy and pathological findings of advanced destruction of pancreatic exocrine‐tissue and hepatic‐cell vacuolation suggest that the animals were subject to a dietary defect resulting from pancreatic exocrine insufficiency. Fetal growth impairment in mice due to infection with certain Coxsackieviruses of the B group appears to be largely due to a virus‐induced reduction in the state of maternal health. However, since some of these viruses have been shown to pass transplacentally, further studies are necessary to show whether the viruses may also exert a direct effect on fetal tissues.
Concerning so‐called sexual dimorphism in acetazolamide‐induced dysmelia of rats
Authors: Vickers T. H.
Published: June 2005

Examination, including gonadal sexing, of Sprague‐Dawley‐derived rats with acetazolamide‐induced dysmelia did not reveal deformity in significantly more females than males. The attributes considered were frequency of defects, prevalence of bilateral lesions, number of litters in which both sexes were present but only 1 was malformed, and severity of anomalies as assessed by the number of residual digits in malformed paws. Unlike the morphological pattern of the dysmelia, which seems stereotyped among the sexes in mice and rats, sex‐determined variation in its severity is not a constant feature of the limb lesions induced by acetazolamide in rats.
The effects of medroxyprogesterone acetate on the maintenance of pregnancy in ovariectomized rats and rabbits
Authors: Bruce N. W. , Bartholomeusz R. K.
Published: June 2005

Fetal survival, malformation rate, and fetal and placental weights were examined near term in control rabbits, rabbits treated on day 6 with 5 mg of medroxyprogesterone acetate (MPA), a long acting progestin, and rabbits treated with 5 mg of MPA on day 6 and ovariectomized on day 7. MPA alone had no apparent effect on fetal or placental development but MPA plus ovariectomy increased fetal weight by 19% and placental weight by 60%. Fetal and placental development were examined near term in rats given similar treatments. One milligram of MPA administered alone on day 7 had no apparent effect. However, in rats given 1 mg of MPA on day 6 and ovariectomized on day 7 no fetuses survived. In rats given 1 mg of MPA on day 11 and ovariectomized on day 12 only 4.7% of the fetuses survived and all were pressure malformed. In rats given 1 mg of MPA on day 11, ovariectomized on day 12, and supplemented daily with 0.5 μg of estradiol benzoate thereafter, 40% of the fetuses survived and none was malformed, but fetal weights were 22% and placental weights 15% below those of the controls. The underlying problem in the ovariectomized rats supplemented with progestins alone appeared to be failure of myometrial growth. These results highlight the species differences in steroid hormone requirements for fetal, placental, and myometrial development during pregnancy.
Down syndrome in british columbia, 1952‒73: Incidence and mean maternal age
Authors: Lowry R. B. , Jones D. C. , Renwick D. H. G. , Trimble B. K.
Published: June 2005

Records of children with Down syndrome (DS) at the BC Health Surveillance Registry were linked to their Birth Registrations to derive maternal ages. Incidence and maternal‐age specific rates were calculated for 1952‒73. Mean maternal age has declined both for normal and DS children, the latter to a marked degree, so that in 1972‒73 80% were horn to women under 35 years. Using maternal age of 40 and over as an indication for amniocentesis would only detect 10% of DS children. The crude incidence rate (mean 1.28/1000 livebirths) has not changed appreciably over the study period except for 1969 in which a statistically significant peak occurred. The standardized rate showed an increasing trend but it is not clear whether this was a true biological increase or resulted from better ascertainment.
Transplacental passage of label after administration of [3H]retinoic acid (vitamin A acid) to pregnant mice
Authors: Kochhar D. M.
Published: June 2005

To determine whether there is transplacental passage of retinoic acid (vitamin A acid) or its metabolites levels of radioactivity were measured in embryos after administration to 12th‐day pregnant ICR/DUB mice of nonteratogenic or teratogenic quantities of [3H]retinoic acid. After the former treatment radioactivity was demonstrable in embryos, placentas, and visceral yolk sacs (VYS) at 1 h after treatment. Expressed in terms of radioactivity per unit protein content, embryos at 1 h had about one‐third as much radioactivity as maternal livers. The placentas had maximum radioactivity at 2 h, whereas embryos and VYS accumulated maximum levels by 6 h after treatment. At 6 h the level in embryos was twice that in placentas. After teratogenic treatment placentas and embryos attained peak levels of radioactivity at 6 and 12 h later, respectively. Again, embryos at peak level contained 2‐3 times as much radioactivity as placentas or VYS. The amount of retinoic acid, metabolites, or both, in embryos after the teratogenic treatment, calculated on the basis of specific activity of the injected label, was 26 times greater than after nonteratogenic treatment; the amount in maternal liver was 75 times greater. The results support previous evidence that the teratogenic effects of retinoic acid are associated with raised levels of retinoic acid, its metabolites, or both, in embryos.
Cholinomimetic teratogens. IV. Effects of the genotype for muscular dystrophy in chickens
Authors: Landauer Walter , Clark Ellen M. , Larner Melva M.
Published: June 2005

Embryos of a family of chickens homozygous for muscular dystrophy (md/md) reacted with a higher incidence of malformations to treatment with carbachol than did White Leghorn embryos. The same difference in response of embryos from the two stocks occurred after treatment with sulfanilamide. Embryos of reciprocal crosses between these two stocks differed greatly, however, in their response to carbachol, F1 embryos from dystrophic hens producing a much higher incidence of malformations than did those from Leghorn hens. In contrast, both F1 sibs reacted similarly to sulfanilamide, the teratogenic effects being intermediate between those of embryos from the parent stocks.
Graphic reconstructions of craniofacial structures during secondary palate development in rats
Authors: Diewert Virginia M.
Published: June 2005

Lateral and ventral graphic reconstructions of coronally sectioned rat fetuses at four stages of secondary palate development were made to illustrate the size, form, and spatial relations of craniofacial structures at each stage, and to indicate changes between stages. The results illustrated extensive changes in the nasomaxillary and tongue‐mandibular complexes and spatial relations in the oronasal cavity during this 2‐day period. During closure of the palate the palatine processes and molar dental laminae moved medially, the vertical dimension between the cranial base and Meckel's cartilage increased, and the Meckel's cartilage changed in shape from a “U” to a “V.” During the 2‐day period extensive increases in anteroposterior and vertical dimensions and limited changes in lateral dimensions resulted in a change in shape of the complete orofacial region. More extensive investigations, preferably quantitative, of the changes shown are indicated to identify the relative contribution of various craniofacial components and to establish the role of differential growth in secondary palate closure.
Embryonic development in ectoptic human pregnancy
Authors: Poland B. J. , Dill F. J. , Styblo C.
Published: June 2005

Ectopic pregnancy in the fallopian tube occurs in about 1 in 50 human pregnancies. Maternal factors in the etiology of this condition have been well documented. There is less information available on the development of the embryo or fetus. To document this information morphological and cytogenetic data were obtained from 76 embryos and fetuses obtained from pregnancies occurring in the fallopian tube. Analysis of the data showed that tubal implantation was associated with a high proportion of severely disorganized embryos. There was also a high incidence of maternal tubal disease. The importance of these factors and the etiology of ectopic pregnancy is discussed.
The “Straight‐jacket” syndrome in chicks. II. Mechanism of development
Authors: Jelínek Richard , Doskočil Milan , Loštický Cyril
Published: June 2005

In a longitudinal study including measurement of the pressure in the amniotic cavity, amniotomy, and planimetric evaluation of the size of the amniotic sac, we investigated the development of the “strait jacket” syndrome in White Leghorn chicken embryos injected intraamniotically (ia) or paraamniotically on the fourth day of incubation with histone or embryotoxic serum, with the following results. Hyperlordosis and eventration developed as an outcome of tonic contraction of the amnion, which was observed only three hours after ia administration. Contraction of the amnion caused elevation of the intraamniotic pressure, which, 12 hours after ia injection, attained a mean value of 22,4 Pa (2.3 mm H2O). This value was not only significantly higher than the mean for control embryos (3.9 Pa), but it was critically close to the mean fluid pressure in thehrain vesicles. Loss of the latter overpressure caused the vesicles to collapse, and the walls shriveled and exencephaly developed, Paraamniotic injection was not followed by either contraction of the amnion, or significant increase in intraamniotic pressure. This did not prevent, heart malformations and cranioschisis of various extent. The majority of cardiovascular malformations were probably the hemodynamic consequence of overfilling of the intraembryonic vascular bed, which was one of the early signs of the effect in question. Cranial‐vault defects can be causally associated with the formation of amnionic adhesion and fusion with the epidermal ectoderm. This observation stresses the significance of the embryonic membranes and the fluid pressures within them for the development of certain congenital deformities and concentrates attention on teratological study of substances that induce protracted contraction of smooth muscle.
Embryotoxicity of the folate antagonist methotrexate in rats and rabbits
Authors: Jordan Robert L. , Wilson James G. , Schumacher Herbert J.
Published: June 2005

The prenatal effects of methotrexate (MTX) in rats and rabbits were assessed. It was found highly embryotoxic in postimplantation rat embryos; 0.3 mg/kg ip or less caused nearly total embryolethality with slight teratogenicity. Rabbit embryos were far more resistant to small doses of MTX than rats, but 19.2 mg/kg iv, when given during days 10 to 15 of gestation, produced little death and a constant spectrum of malformation in a high percentage of offspring. Cleft palate, skull defects, and severe fore‐and hindlimb dysplasias, occurred with a high degree of regularity and were strongly dose and developmental‐stage specific.
Epithelial breakdown in the palatal processes of mouse fetuses with spontaneous cleft lip and palate
Authors: Tsai H. M. , Carl Verrusio A.
Published: June 2005

Contact and fusion of the palatal processes are prevented by mechanical obstruction in A/J mice with spontaneous cleft lip and palate. Histological examination of cleft‐lip fetuses revealed a very thin epithelial covering on the tip of the palatal process at day 15 1/2 of gestation, when the palate normnlly undergoes fusion, but at day 16 the palatal epithelium was completely disrupted, exposing the underlying mesenchyme. This epithelial discontinuity lasted only one day — by day 17 epithelial continuity was reestablished. These findings support the hypothesis that contact between the palatal shelves is not a prerequisite for epithelial degeneration.
Simultaneous prevention of blood abnormalities and hereditary congenital amputations in a brachydactylous rabbit stock
Authors: Petter Claude , Bourbon Jacques , Maltier Jean‐Paul , Jost Alfred
Published: June 2005

Hematological and histological studies of the rabbit brachydactyly mutant were made to clarify the question of the blood abnormality that had previously been implicated in the teratogenic process leading to congenital amputation. The hemoglobin of fetal and adult br/br rabbits, studied by electrophoresis and cyanmethemoglobin assay, exhibited no differences from that of controls. The br/br fetuses were polycythemic and severely macrocytic. Fetal limb vessels showed thrombosis leading to hemorrhages in the extremities. The hepatic tissue was abnormal, being particularly poor in hematopoietic cells; blood cell macrocytosis was attributed to impaired erthropoiesis. Treatment of pregnant rabbits with folic acid plus vitamin B12 or with folinic acid was able simultaneously to prevent the fetal blood cell macrocytosis and the congenital abnormalities.
Descriptive system for congenital limb anomalies
Authors: Frias Maria Luisa Martinez , Castilla Eduardo Enrique , Paz Joaquin Eugenio
Published: June 2005

A descriptive system for the nomenclature, notation and classification of congenital limb malformations, suitable for clinical, epidemiological and experimental use is presented. Every developmental limb anomaly is described by stating the type of anomaly and the affected anatomic structure. All anomalies are classified into three basic types: excess, deficiency and fusion. The anatomic structure of the affected limb is defined within a two dimensional order.

This system was used to describe 652 cases with isolated developmental limb anomalies obtained from two series of observations. The observed data are presented in a progressively expanded classification ranging from 4 to 497 diagnostic categories. Observed incidence rates for the four main types of anomaly from a sample of 297,299 consecutive livebirths, are: excess: 1.22; deficiency: 0.17; fusion: 0.20; combined: 0.24 per thousand.
Trypan blue accumulation in the embryonic gut of rats and mice during the teratogenic phase
Authors: Dencker Lennart
Published: June 2005

Four to 48 hours after iv and sc administration of teratogenic doses of trypan blue to rats and mice the uterus was removed and rapidly frozen, after having been placed in a horizontal plane, and frozen sections were attached to tape and dried at a low temperature. By this procedure embryos and placental structures were present in the same sections and loss or redistribution of the dye was minimized. The dye was found in the yolk‐sac cavity and to be accumulated in the visceral (proximal) endoderm. It was also accumulated in the embryonic endoderm—forming the embryonic gut. This accumulation occurred after the administration of the trypan blue up to the time of closure of the vitelline duct, which occurs at 11 days postconception in rats and 9.5 days in mice. None was found when injection was made after this closure. No dye was detected in the ecto‐ and mesodermal layers. The period of embryonic uptake of trypan blue largely corresponds with the period of teratogenic sensitivity in these species as reported by others.
Spina bifida and so‐called asplenia syndrome occurring separately in sibs
Authors: van Went Johan J. , van Went Greta F. , Willem Delleman J. , Becker Anton G.
Published: June 2005

Attention is drawn to the possibility that neural‐tube defects may sometimes be associated with the so‐called asplenia syndrome (Ivemark syndrome). This hypothesis is based upon a family in which one child had spina bifida and hydrocephaly and another had cardiovascular and other fissural anomalies, similar to Ivemark syndrome. The family history, moreover, revealed several cases of anencephaly and/or spina bifida, both on the paternal and maternal sides.
Cleft palate following prenatal food restriction in mice: Association with elevated maternal corticosteroids
Authors: Hemm Roger D. , Arslanoglou Leontios , Pollock John J.
Published: June 2005

Following food restriction of pregnant CD‐1 mice, the maternal serum corticosteroid levels and incidence of skeletal and visceral abnormalities of the progeny were determined. Dams from the groups receiving restricted food on gestation days 6 to 15 had increased resorptions, and the progeny had delayed ossification of the skeleton with cleft palate accompanied by delayed ossification of the presphenoid bone. The incidence and intensity of these changes was correlated with the level of food restriction. The incidence of cleft palate for progeny from dams receiving 4.0 to 2.5 g of feed per day ranged from 6.3% to 100.0%, respectively. Serum corticosteroid levels of pregnant control and food restricted dams were similar on gestation day 10, but the levels of food restricted dams were 6 to 10 times greater than controls on gestation day 15. Thus cleft palate, delayed skeletal ossification, and increased resorptions are predictably produced by food restriction of CD‐1 mice and were highly correlated with the elevated endogenous serum corticosteroid levels.
Influence of cyclophosphamide and 4‐ketocyclophosphamide on mouse limb development
Authors: Manson Jeanne M. , Smith Carl C.
Published: June 2005

Many studies have been performed on the in vivo teratogenicity of cyclophosphamide, and there is uncertainty whether the parent compound or P‐450 generated alkylating metabolite(s) is the proximal teratogen(s). We have examined the influence of cyclophosphamide and a metabolite, 4‐ketocyclophosphamide, on mouse limb development. Pregnant mice were injected with 10, 15 or 20 mg/kg of cyclophosphamide on days 9 to 11 of gestation. Hindlimb buds were maximally sensitive to 20 mg/kg of cyclophosphamide at 9 A. M. on day 11, and the predominant malformations formed were preaxial ectrodactyly and hemimelia. Hindlimb buds of the same gestational age exposed to cyclophosphamide in vitro responded identically to controls in morphology and uptake of 3H‐thymidine and 35SO4. Exposure to 4‐ketocyclophosphamide in culture, however, resulted in the formation of limbs with a “hemimelic” appearance and distal limb reduction, and with reduced uptake of 3H‐thymidine and 35SO4. These findings support the position that the P‐450 generated metabolite (s), and not the parent compound, is the proximal teratogen(s).
Evaluation of the teratogenic potential of tertiary butylhydroquinone (TBHQ) in the rat
Authors: Krasavage Walter J.
Published: June 2005

Tertiary butylhydroquinone (TBHQ), an approved antioxidant used alone or in combination with other antioxidants produced no teratogenic effects after administration via the diet to pregnant rats at concentrations of 0.125, 0.25 and 0.50% during the sensitive period of gestation. The mean body weight and feed consumption of the dams were unaffected. The average number of corpora lutea, implantation sites, viable fetuses, resorptions and fetal body weights and mortality did not differ between the control and treated groups. A significant number of rudimentary ribs were seen in all groups. However, the incidence of this variation was two times greater in the control group than in any treatment group. It is concluded that TBHQ is not teratogenic in rats at 62.5, 125 and 250 times the approved use level for humans.
Incidence rates for cleft lip and palate in British Columbia 1952‐71 for North American Indian, Japanese, Chinese and total populations: Secular trends over twenty years
Authors: Lowry R. B. , Trimble B. K.
Published: June 2005

The incidence of cleft lip and/or cleft palate was examined for the 1952‐71 period for the Province of British Columbia. Although there were some fluctuations, some of which were significant, there was no general trend which indicated that the rates were either increasing or decreasing. These rates are important for a background calculation when investigating new environmental teratogens. The total rate of 1.97 per 1,000 live births is comparable with other Caucasian populations where there is good ascertainment and adequate follow‐up period. This study also confirmed the previously reported high rate for North American Indians in British Columbia (3.74 per 1,000 live births) and established rates for the Japanese (3.36 per 1,000 live births) and Chinese (1.76 per 1,000 live births) of British Columbia. Since these three sub‐populations are relatively small in relation to the total population, they do not influence the overall total rate to any great extent.
The effect on fetal development and utero‐placental blood flow of ligating a uterine artery in the rat near term
Authors: Bruce Neville W.
Published: June 2005

The uterine artery of one horn of 13 rats was ligated on day 18 of gestation; the remaining horn was used as a control. The effect, four days later, on blood flow to the reproductive tract, was measured with radioactive microspheres and compared to the effect on fetal and placental weights. Fetal survival in the ligated horns, 41%, was significantly lower (P < 0.05) than that in the control horns, 98%. Fetal and placental weights of the survivors in the ligated horns, 3.159 ± 0.133 g (SE) and 450 ± 18 mg respectively, were similarly lower than those in the control horns, 3.814 ± 0.111 g and 529 ± 27 mg respectively. Maternal placental blood flow closely reflected the weight of tissue being supplied and was similar in the ligated and control horns, 129 ± 21 and 130 ± 18 ml.min−1. 100g−1, respectively. Myometrial blood flow was again similar in the ligated and control horns, 34 ± 5 and 37 ± 4 ml.min−1. 100 g−1, respectively, and in the ovarian, middle and cervical sections of each horn. These results are compatible with the view that ligation causes only a temporary reduction in uterine blood flow which permanently checks placental and fetal, or placental thus fetal, growth. Blood flow then returns to normal levels compatible with the reduced weights of tissues being supplied.
Non‐confirmation of thalidomide induced teratogenesis in rats and mice
Authors: Scott W. J. , Fradkin R. , Wilson J. G.
Published: June 2005

It has been reported that thalidomide, dissolved in a 1:3 mixture of Tween 20 and physiological saline and administered intraperitoneally to pregnant mice and rats induces a variety of malformations, including limb deformities, characteristic of the primate syndrome. The studies reported herein attempted to confirm these findings without success although the rodent strains used were not the same. A low level of non‐specific malformations was observed in the fetuses of both species at dose levels reported to cause a 47% and 92% rate of malformation in mice and rats respectively. One possible source of difference was Tween 20 which was toxic to the point of lethality in these studies at dose levels reported to be non‐toxic in the earlier studies.
Chronotropism and blood flow patterns following teratogenic doses of catecholamines in 5‐day‐old chick embryos
Authors: Cheung Matthias O. , Gilbert Enid F. , Bruyere Harold J. , Ishikawa Shizen , Hodach Richard J.
Published: June 2005

In vivo heart rates of 5‐day‐old chick embryos were recorded from electrodes placed in close proximity to the heart. L‐epinephrine (4 × 10−10 mole), 1‐norepinephrine (1 × 10−9 mole) and 1‐isoproterenol (1.6 × 10−10 mole) in 5 μl of isotonic saline transiently accelerated the mean heart rate by almost 9%. L‐phenylephrine (2 × 10−9 mole/5μl) and the experimental procedure produced no appreciable effect. The positive chronotropic effect of the catecholamines was found to be highly significant (P < 0.0005) as computed by Student's t test. However, no direct relationship could be established between the chronotropic response and the aortic arch anomalies produced. A prolonged reduction of blood flow in the primitive heart tube and the sixth aortic arch after administration of epinephrine and isoproterenol is apparently related to the induction of hypoplastic right pulmonary artery with absent or hypoplastic right ductus arteriosus.
Teratogenic effects of ribavirin on hamster and rat embryos
Authors: Ferm Vergil H. , Willhite Calvin , Kilham Lawrence
Published: June 2005

Ribavirin, a synthetic nucleoside with marked antiviral activity, induced developmental malformations when administered to pregnant hamsters by oral, intraperitoneal or intravenous routes. Abnormalities of the limbs, eyes and brain were the most common defects found in the hamster. Higher doses (about 10 ×) were required to induce anomalies in rat embryos and the malformations were generally restricted to the head region. In both rats and hamsters oral administration of the drug seemed to be more teratogenic than administration by other routes suggesting that metabolism of ribavirin in the maternal gastro‐intestinal tract and/or liver may change it into its active form.
Cranio‐dirachischisis totalis in cephalothoracopagus twins
Authors: Ferm Vergil H.
Published: June 2005

A set of conjoined 13‐day‐old male hamster twins is described. The twins were joined at the head and thorax. The brain was exencephalic and the neural plate was completely open throughout its length. The notochord was duplicated throughout its entire length. Partial twinning of the neural plate as indicated by histologic reconstruction is suggested with fusion or non‐separation of the neural plates in the medial alar wing area. There was complete separation of the neural plates together with duplication of the lower extremities and tails in the caudal region of this specimen.
Cholinomimetic teratogens. VI. The interaction of cholinomimetic teratogens with the antimalarial drugs chloroquine and chlorguanide
Authors: Landauer Walter
Published: June 2005

A typical syndrome of short and crooked neck together with muscular hypoplasia of the legs occurs with low incidence in chicken embryos following injection into the egg at 24 hours of incubation of the antimalarial drug chloroquine; but treatment at later stages does not have similar effects. When, however, chloroquine was used in addition to carbachol or neostigmine at 96 hours of incubation the malformations caused by the two cholinomimetic compounds, i.e., carbachol and neostigmine, occurred with greatly increased frequency and tended also to be exaggerated in expression. Chlorguanide, another antimalarial drug, when used as additive, reduced the teratogenic effects of such compounds as decamethonium and neostigmine. It appears that the neuromuscular pathways to teratogenicity are for carbachol and neostigmine and for chloroquine clearly related, if at different levels of expressivity.
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

The 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

The 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

The 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

Pregnant 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

Chlorcyclizine 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

Rats 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

The 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

The 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.