bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparative studies on the absorption of 3H‐thalidomide in rabbits and rats
Authors: Keller George R. , Blake David A.
Published: June 2005

An extensive review of the literature revealed that orally administered thalidomide produces a variable teratogenic response in rabbits at equal doses; while rats are uniformly resistant to the teratogenic effects of thalidomide. In an effort to explain these individual and species differences a study was made comparing the oral absorption of 3H‐thalidomide suspension in these species under identical conditions at teratogenic dosage levels (50, 100, and 200 mg/kg). New Zealand white female virgin rabbits and Sprague‐Dawley female virgin rats were employed. Unlike rats, rabbits were quite variable in absorbing thalidomide suspensions, and this was presumably related to the delayed gastric emptying time in some animals. However, the mean plasma concentrations were similar in both species during multiple daily administration of thalidomide suspensions. When thalidomide was administered to rabbits in hard gelatin capsules it was poorly absorbed because of slow dissolution of the powdered drug in gastrointestinal fluids. Regardless of the dosage form administered, only negligible absorption occurred from the rabbit stomach. The small intestine was shown to be the site of absorption in rabbits. These results suggest that the absorption of orally administered thalidomide suspension is so similar in rabbits and rats that it could not be responsible for the species difference in its teratogenic potency. However, the availability of thalidomide from encapsulated powder is so poor in rabbits that the positive teratogenic results recorded in the literature with this dosage form are questionable.
Teratogenicity of structural truncates of cyclophosphamide in mice
Authors: Gibson James E. , Becker Bernard A.
Published: June 2005

Truncates of cyclophosphamide including proposed in vivo metabolic products were administered to pregnant mice on day 11 of gestation. Minimal teratogenic dosages were determined: cytoxyl alcohol, 290 mg/kg; cytoxyl amine, 270 mg/kg; phosphoramide mustard, 154 mg/kg; nornitrogen mustard, 1.6 mg/kg; and 3‐amino‐l‐propanol, 5.7 mg/kg. Maternal toxicity was evident in each case. Malformations varied from agent to agent but no agent paralleled cyclophosphamide (20 mg/kg) teratogenicity. Cyclophosphamide produced more frequent and more severe soft tissue and skeletal malformations without maternal toxicity than did any of the cyclophosphamide truncates tested. Common teratogenic effects of cyclophosphamide, cytoxyl alcohol, and nitrogen mustard were polydactyly, oligodactyly, syndactyly, cleft palate, and some skeletal defects. Cytoxyl amine, phosphoramide mustard, nornitrogen mustard, and 3‐amino‐l‐propanol were less teratogenic. Alkylating activities of these agents were determined by nitrobenzyl pyridine reaction in plasma of mice 2, 4, 8, 16, 32, and 64 minutes after intraperitoneal dosages equimolar to cyclophosphamide (100 mg/ kg). No relation between teratogenicity and alkylating potencies of the various agents was demonstrated.
Teratogenic effects of lithium in rats
Authors: Wright T. L. , Hoffman L. H. , Davies J.
Published: June 2005

Developmental defects were observed in fetuses following intra‐peritoneal administration of lithium chloride to pregnant rats. The resulting malformations were almost exclusively cranial in location, primarily affecting the eye, external ear, and palate. In addition resorption rate was increased. Since this represents the first report of such effects in rats, the results are discussed with respect to previous experiments using lithium in other experimental animals and to the possibility of lithium‐induced teratogenesis in human beings.
Interorbital distance in cleft lip and palate
Authors: Aduss Howard , Pruzansky Samuel , Miller Marilyn
Published: June 2005

The bony interorbital distance (BIOD), as a measure of orbital hypertelorism, was determined for 285 children representing the major categories of cleft lip and/or cleft palate. The BIOD was measured on longitudinal postero‐anterior roentgencephalograms from 6 months to 16 years. There were no significant differences in BIOD between the males and females with complete unilateral and complete bilateral cleft lip and palate or between the combined cleft samples. The BIOD was increased more in those with cleft lip and cleft lip‐cleft palate than in those with only cleft palate. Although patients with clefts had an increased BIOD, in most cases the increase did not exceed 1 SD of that reported for a control group. In unoperated infants no association was found between increased BIOD and the width of the cleft or palate at the level of the maxillary tuberosities. This finding suggested that the BIOD may reflect abnormal development in the nasofrontal process, which also affects the lip but does not include the palatal shelves. Finally, it is suggested that the BIOD is a relevant developmental variable with a threshold character in the etiopathogenesis of cleft lip and cleft lip‐cleft palate.
Present status of drugs as teratogens in man
Authors: Wilson James G.
Published: June 2005

The literature pertaining to the effects of drugs on human in‐trauterine development has been reviewed. As far as quality and quantity of reported evidence permits, four categories of drugs were established, namely, those: (1) positively implicated as teratogenic, (2) suspected of having some teratogenic potential, (3) possibly teratogenic under some conditions, and (4) having little or no teratogenic potential under usual conditions of usage. Although a few compounds were judged to belong in each of the first three categories, it was concluded that drugs taken during pregnancy appear in total to make only a small contribution to the causation of human developmental defects.
Lupin alkaloids from teratogenic and nonteratogenic lupins. I. Correlation of crooked calf disease incidence with alkaloid distribution determined by gas chromatography
Authors: Keeler Richard F.
Published: June 2005

A comparison was made by gas chromatography of lupin alkaloid distribution among members of the Lupinus genus that produced crooked calf disease experimentally and those that failed to do so. Further comparison of distribution was made of plants from areas where the disease is common and from areas where the disease is not known. There were alkaloid distribution similarities in all active plants that were not shared by the inactive ones. Four major alkaloid peaks were generally present in active samples, but peak 4 was the only one invariably present in active plants and invariably absent or of low concentration in inactive ones. The data do not positively incriminate an alkaloid as the active principal in the disease, but it is clear that if a major alkaloid is responsible it is the alkaloid of peak 4. That alkaloid is anagyrine. The data further indicate that one can recognize potentially teratogenic lupins by their alkaloid distribution patterns.
Effects of histone on morphogenesis of chick embryonic constituents. I. The teratogenic range
Authors: Hořejší J. , Jelínek R. , Láznička M. , Loštický C.
Published: June 2005

To investigate the claim that the teratogenic effects of histones in chick embryos are limited to a certain period of early development we used total calf thymus histone. After finding that 30 μg were effective at the somite stages, single doses of 0.3, 3, and 30 μg were applied subgerminally on day 2 and intraamniotically on days 3 and 4 to White Leghorn embryos. The teratogenic activity was much greater on days 3 and 4 than on day 2; treatment at the former times produced a characteristic syndrome consisting of cranioschisis, hyperlordosis, eventration, and transposition of the aorta. In view of these findings the opinion that histones lack teratogenic action at later developmental stages is no longer tenable. Furthermore the present results also support the view that the teratogenic effects of histone are caused by mechanisms other than suppression of genomic activity.
Spontaneous pleural effusion in a human fetus
Authors: Barr Mason , Burdi Alphonse R.
Published: June 2005

Left sided pleural effusion was found in a human fetus spontaneously aborted at 20 weeks postmenstrual. Pulmonary hypoplasia associated with the effusion suggested that the fluid had been present for some time before delivery. Absence of other anomalies supports the view that the effusion was due to maldevelopment of the thoracic lymph channels.
Comparative distribution and embryotoxicity of hydroxyurea in pregnant rats and rhesus monkeys
Authors: Wilson James G. , Scott William J. , Ritter Edmond J. , Fradkin Rochelle
Published: June 2005

Hydroxyurea was given to pregnant rhesus monkeys and pregnant rats in regimens adjusted to produce similar degrees of teratogenicity, for the purpose of comparing the distribution of the drug in the females and their embryos. Accordingly, in rats 137 mg/kg/day ip on days 9–12 resulted in a drug half‐life in maternal plasma of about 15 min and in embryos about 85 min, after the last injection; and in monkeys 100 mg/kg/days iv on days 23–32 resulted in drug half‐life in maternal plasma estimated to be 120 min and in embryos 265 min, after the last injection. Using as a baseline of biological effects the minimal concentration known to inhibit DNA synthesis in rat embryos and cancer cells, namely 10−4 M, it was calculated that the rat embryos in the present study were exposed to this level or more for approximately 12 h whereas the monkey embryos were exposed for approximately 100 h. Although the teratogenic effects were not identical in the two species, these data are interpreted to mean that rat embryos are teratogenically much more sensitive to hydroxyurea than monkey embryos. These observations have important implications in the selection of appropriate species for tests to estimate human teratogenic risks. The rat, which is currently the most widely used animal for such tests, displays sizeable differences from rhesus monkeys, which is one of the animals thought to be most like man in teratogenic susceptibility.
The teratogenic effects of 6‐mercaptopurine on chick embryos in ovo
Authors: Grubb Randall B. , Montiegel Ethel C.
Published: June 2005

Fertilized eggs of single‐combed White Leghorn hens were each injected through a shell window directly beneath the embryo at 70 or 96 h of incubation with 2 mg of the sodium salt of 6‐MP dissolved in 0.1 M phosphate buffer, and at 11 days of incubation the embryos were examined for gross morphological abnormalities. Various gross malformations and growth retardation were found, the most frequently and severely affected structures being limbs, beak, and eyes. Treatment at 70 h caused more severe abnormalities than at 96 h, but the spectrum of defects was not very different.
The in vivo and in vitro effects of lithium on human chromosomes and cell replication
Authors: De La Torre Rafael , Krompotic Eva , Kowlessard Leslie
Published: June 2005

Phytohemagglutinin (PHA)‐stimulated lymphocyte cultures of a healthy human donor, treated in vitro with 0.5, 1.0, and 1.5 mg LiCl/10 ml of culture (equivalent to 1.1, 1.5, and 2.1 mEq/l, respectively) had an increased incidence of chromosomal anomalies and a significant increase in satellite associations, compared with an unexposed culture. The in vivo effects of Li2CO3 on the chromosomes of psychiatric patients on lithium therapy showed increased chromosomal abnormalities, as compared with lithium‐free controls. A significant finding was a marked increase in satellite associations in all lithium‐treated patients. The mitotic index of PHA‐stimulated human lymphocytes exposed to doses of lithium salts (0.5–1.5 mg/10 ml of culture media) was decreased, as measured by [3H]thymidine incorporation into cells.
Accessory spleens in domestic rabbits (Oryctolagus cuniculus). I. Frequency, description, and genetic factors
Authors: Fox R. R. , Weisbroth S. H. , Crary D. D. , Scher S.
Published: June 2005

Accessory spleens in 2 separate necropsy series of (a) 1848 randombred rabbits and (b) 21,802 inbred and partially inbred and 880 hybrid rabbits were described and illustrated. The overall frequency in the randombred population (8.9%) was comparable to that in unselected human necropsy series (10%). The predominant locations of accessory spleens in the rabbits (adjacent to the splenic hilus, the gastrosplenic ligament, and the tail of the pancreas) arranged in descending order, were comparable to their locations in human beings. The inbred rabbits had an overall frequency of at least one accessory spleen of 22.5%, similarly located, and ranged from 1–50%, depending on the strain. It was shown by crosses of high‐ and low‐frequency strains that the presence of accessory spleens is due in part to genetic factors and that a high frequency of accessory spleens is probably a recessive characteristic. The latter interpretation is also supported by the fact that the low or “normal” strains had an overall frequency of at least 1 accessory spleen of 8.8% which is in accord with both the randombred rabbit population and human necropsy findings.
Distribution of 203Hg in pregnant and fetal rats
Authors: King Richard B. , Robkin Maurice A. , Shepard Thomas H.
Published: June 2005

The distribution of mercury was studied in pregnant and fetal rats after administration at days 11, 13, and 19 of pregnancy. Methyl‐203Hg‐chloride was used as a tracer to determine amounts of mercury in brain, kidneys, liver, heart, placenta, and whole fetus. The fetal brain was shown to accumulate 19 times more of the amount in the fetus than did the maternal brain the amount in the pregnant female. In addition, the fetal brain concentration was 3.4 times higher than the maternal brain concentration. Clearance studies showed that the organ concentrations were variable with little change occurring in maternal brain and fetus. These results are consistent with sensitivity to mercury damage being greater in the fetal than the maternal brain.
Analysis of fetal development in rats following maternal exposure to subanesthetic concentrations of halothane
Authors: Lansdown A. B. G. , Pope W. D. B. , Halsey M. J. , Bateman P. E.
Published: June 2005

Pregnant Sprague‐Dawley rats were exposed to 50, 100, 200, 800, 1600, or 3200 ppm halothane on days 8, 9, 10, 11, and 12 of pregnancy. This did not result in increased fetal death and resorption rates, growth retardation, or an increased frequency of skeletal anomalies. When rats were exposed to 1600 ppm halothane on days 1–21 of pregnancy fetal growth was retarded but the differences in the number of centers of ossification in the skeletons were not significant. Skeletal anomalies including supplementary ribs, defective or delayed ossification of sternebrae, and missing centers of ossification in the lower parts of the limbs were seen in some fetuses in all groups but the frequency was not treatment related. Our results indicate that in Sprague‐Dawley rats halothane is not teratogenic or otherwise fetotoxic at subanesthetic concentrations.
Cardiovascular malformations found in 1286 externally normal human embryos alive in utero
Authors: Semba Reiji
Published: June 2005

The heart and great vessels of 1286 human embryos were microdissected and examined for malformations. Most of the embryos were obtained by induced abortion conducted for socioeconomic reasons and the remainder by hysterectomy performed because of some minor disturbance. Only embryos that were alive in utero, at Carnegie stages 18–23, and showed no external anomalies were included. A microdissection procedure that enables precise examination of the heart was used. Criteria for diagnosis of such defects as ventricular septal defect, stenosis, and coarctation were established. Twenty‐seven (2.1%) embryos with congenital cardiovascular malformation (CCM) were found. The frequency was higher than that (0.46–1.17%) reported for newborns. The defects included most of the comparatively common types of CCM, and it was confirmed that the major types of CCM are manifested early in life. It was also noted that certain severe types of anomaly, reported to be scarce in infants, are relatively common in embryos.
Test of the hypothesis that embryonic face shape is a causal factor in genetic predisposition to cleft lip in mice
Authors: Juriloff D. M. , Trasler D. G.
Published: June 2005

It was proposed that embryonic face shape is one of the quantitative variables underlying the threshold trait, cleft lip. To test the hypothesis several facial dimensions were measured in photographs of embryos at an early stage of formation of the face in 3 lines of mice. The lines had been selected from one original population using frequency of cleft lip induced by 6‒aminonicotinamide as the selection criterion. Line L was susceptible to spontaneous cleft lip; lines M and C were not. Line L had a significantly smaller distance between the nasal pits than the other 2 lines, but did not differ in overall head size. A trend towards reduced angle between the medial nasal processes in the L line was noted, though this was not statistically significant. These results were predicted by the face‐shape hypothesis.
The teratogenic effects of β‐aminopropionitrile in hamsters
Authors: Wiley M. J. , Joneja M. G.
Published: June 2005

The teratogenicity of β‐aminopropionitrile (βAPN) was evaluated in golden Syrian hamsters; single doses of 1250, 2500, and 3750 mg/kg given on days 7‒13 produced fetal mortality, growth retardation and malformations. All time‐dose combinations produced gross external abnormalities with the highest rate (92.5%) occurring following day‐12 treatment. High frequencies of skeletal abnormalities including deformities of the ribs, fibula, and scapula occurred after days‐10‒12 treatment. Deformed ribs occurred in 100% of fetuses exposed on day ll to any of the dosages. The types of abnormality generally resembled those produced by lathyrogens in other species except for exencephaly and encephalocele, which occurred after treatment on day 7. These results indicate that βAPN is a typical teratogen, capable of producing abnormalities of the central nervous system early in gestation, and may reflect a broader mechanism for its activity than previously suggested.
Neural‐tube defects caused by 5‐bromodeoxyuridine in chicks
Authors: Lee Hsin‐Yi , Hikida Robert S. , Levin Martin A.
Published: June 2005

Chick embryos were explanted at HH stage 4 and cultured for 24 h on thin albumen with 10 μg/ml 5‐bromodeoxyuridine (BrdU). BrdU inhibited closure of the neural tube in over 90% of the embryos. Mitotic figures were found throughout adversely effected neuroepithelium, suggesting that interkinetic nuclear migration had been inhibited. Electron microscopic studies of BrdU‐treated neural‐tube cells showed fewer and more amorphous cytoplasmic extensions, microfilaments, and desmosomal (functional) tonofibrils than in controls, but micro‐tubules were unaffected.
Ca‐DTPA‐induced fetal death and malformation in mice
Authors: Fisher Darrell R. , Calder Scott E. , Mays Charles W. , Taylor Glenn N.
Published: June 2005

Increased fetal mortality and congenital malformation were induced in mice by Ca‐DTPA, a chelate widely used for the removal of internally deposited plutonium in human beings. Mated C57BL/Do female mice were given five daily injections of 720–2,880 μmol/kg Ca‐DTPA during early, mid, or late gestation. Damage probably occurred as a result of the depletion by Ca‐DTPA of zinc and manganese, trace elements essential to growth and development. By extension, it seems likely that Ca‐DTPA could damage human fetuses. A much safer chelate, Zn‐DTPA, is recommended for the treatment of accidental plutonium contamination.
Reduced interlitter variability in rats resulting from a restricted mating period, and reassessment of the “Litter effect”
Authors: Holson J. F. , Scott W. J. , Gaylor D. W. , Wilson J. G.
Published: June 2005

Rats were mated for two or 15 hours and variability of day‐12 embryos in weight, protein content, and [3H]thymidine incorporation was compared in the long mating period (LMP) and short mating period (SMP) groups by a 2‐level nested analysis of variance. Variability in day‐20 fetal weight was similarly compared. In both groups day‐12 embryonic weight was relatively more variable than day‐20 fetal weight, and variability was less in SMP than LMP animals for each comparison made, although statistical significance was attained only for thymidine incorporation. “Litter effects” were noted but not of the magnitude reported by other investigators. It was concluded that inappropriate statistical methods have encouraged the belief that among‐litter variability usually exceeds within‐litter fetal weight variability. The teratological implications of reduced developmental variability and the “litter effect” are discussed.
Studies of teratogenic effects of the dithiocarbamates maneb, mancozeb, and propineb
Authors: Larsson K. Sune , Arnander Claes , Cekanova Eva , Kjellberg Marianne
Published: June 2005

Oral administration of high dosages of the dithiocarbamate pesticides maneb and mancozeb was teratogenic in rats but not in mice. The malformations, severe limb and craniofacial defects, were pronounced after maneb treatment but less so after mancozeb and propineb, zinc‐containing compounds. The teratogenic effect of maneb was progressively reduced by simultaneously adminstering increasing amounts of zinc acetate. The mechanism of the teratogenic effect may involve the compounds being chelating agents, trapping zinc required for many important enzyme systems.
Craniosynostosis. I. Sagittal synostosis; Its genetics and associated clinical findings in 214 patients who lacked involvement of the coronal suture(s)
Authors: Hunter Alasdair G. W. , Rudd Noreen L.
Published: June 2005

The clinical and genetic findings in 214 patients with sagittal synostosis are described. Seventy‐three per cent of the patients were male. Children with sagittal synostosis were treated earlier than those with coronal synostosis. Major malformations occurred in 22%, and 8.9% were mentally retarded. The retardation was clearly unrelated to the synostosis in almost half the patients. The remaining retarded patients had a significantly lower mean birth weight, higher frequency of malformations, and later age at operation than the control group. We believe the late age at operation was due to bias in the ascertainment of this group of retarded children, and that sagittal synostosis was simply one of a number of malformations that can occur in children with intrinsic retardation. Familial data and the skull measurements of a sample of parents of affected children were compatible with multifactorial inheritance; however there is need for prospective family studies and parental measurements on ethnically uniform groups.
Inhibition of pinocytosis in rat yolk sac by trypan blue
Authors: Williams Kenneth E. , Roberts Graham , Kidston M. Elizabeth , Beck Felix , Lloyd John B.
Published: June 2005

Day 17.5 yolk sacs from rats injected with partially denatured 125I‐labeled bovine serum albumin (I‐BSA) were cultured in vitro by a raft technique. The rates of release of [125I] iodotyrosine were similar in control yolk sacs and in yolk sacs from rats preinjected with trypan blue. Day 17.5 rat yolk sacs were also cultured in medium containing I‐BSA. Following pinocytic uptake the substrate was degraded intracellularly and [125I]iodotyrosine released into the medium. Trypan blue, when present in the medium in concentrations above 100 üg/ml, inhibited pinocytosis of I‐BSA and so decreased the rate of [125I]iodotyrosine production. Trypan blue similarly decreased the rate of pinocytic uptake of 125I‐labeled polyvitiylpyrrolidone. Pinocytic uptake of macromolecules was not decreased in yolk sacs from rats pretreated with trypan blue. The relevance of these results to the mechanism of teratogenic action of trypan blue is discussed. It is proposed that if trypan blue in teratogenic doses similarly inhibits pinocytosis by the yolk sac during the organogenetic period teratogenests might result from a transient interruption in the flow of metabolites through the yolk sac to the embryo.
Digital anomalies of mouse limbs induced by treatment with urethan in vitro
Authors: Yasuda Yoshiko
Published: June 2005

The effects of urethan on ICR/JCL mouse limbs were examined in forelimbs of day‐11 embryos cultured in concentrations of 0, 50, and 100 μg/ml for one to four days, and in forelimbs of day‐12 embryos and in fore‐ and hind limbs of day‐13 embryos in 0, 10, 50, and 100 μg/ml for one to four days. Urethan did not cause digital malformations in day‐11 limbs but induced syndactyly in day‐12 forelimbs and polydactyly in day‐12 forelimbs and day‐13 fore‐ and hind limbs. The polydactyly may have been due to effects on mesenchymal cells producing localized cell proliferation, whereas syndactyly may have been due to effects on precartilage cells, resulting in excess migration of mesenchymal cells toward the digits, leaving the connective tissue at the interdigital space to develop inadequately.
An analysis of the age and size of 483 human embryos
Authors: Skidmore F. D.
Published: June 2005

The crown‐rump length of 483 fixed human embryos of Carnegie stages 6–23 was analyzed and median and predicted mean lengths were calculated. The results were compared with those of other series and confirmed that early human growth rates are different from those of macaques with which human embryo growth has previously been compared. The study indicated that it is possible to predict: 1. the median size of an embryo of given Streeter horizon or Carnegie stage; 2. the age of a fresh embryo, or one of undisputed Streeter staging, by comparison with mean figures of other authorities; and 3. the corrected age of an embryo of known length or known Streeter staging or both in terms of postovulation age. Since teratogens may reduce the embryonic growth rate this information is relevant in the analysis of teratogenic factors in human development.
Craniomyeloschisis: A spontaneous mutation of the rat
Authors: Layton W. M. , Smith J. M.
Published: June 2005

Craniomyeloschisis (proposed gene symbol cms) was a spontaneous mutation of the rat inherited as an autosomal recessive trait with complete penetrance. Homozygous offspring died at birth with failure of closure of the neural tube caudal to the midbrain. Neural crest derivatives were relatively normal. There were associated severe malformations of the axial skeleton including skull, vertebral column, and ribs. The pattern of malformations was quite uniform. Heterozygotes were anatomically normal. The mutation is extinct.
Biochemical basis of skeletal defects induced by hydralazine: Inhibition of collagen synthesis and secretion in embryonic chicken cartilage in vitro
Authors: Rapaka Rao S. , Parr Robert W. , Liu Tsan‐Zon , Bhatnagar Rajendra S.
Published: June 2005

Hydralazine (1‐hydrazinophthalazine) produces skeletal defects resembling those observed in experimentally induced manganese deficiencies. Since glycosylation of collagen, a step preceding its secretion, requires Mn2+, the effect of hydralazine on collagen secretion and the formation of hydroxylysine glycosides was examined in explants of embryonic chicken long‐bone rudiments. Auto‐radiographic studies showed that hydralazine blocked collagen secretion. Secretion was restored by Fe2+ alone or Fe2+ + Mn2+ but not by Mn2+ alone, suggesting that a Fe2+ ‐requiring step was involved. Biochemical analyses showed that hydralazine inhibited the formation of hydroxylysine, a step requiring Fe2+, but it did not inhibit the formation of hydroxylysine‐glycosides by Mn2+ ‐requiring steps, although the reaction was inhibited in vitro. Hydralazine also failed to inhibit intracellular mucopolysaccharide synthesis which involves several Mn2+ ‐requiring enzymes. These observations suggest that the deleterious effects of hydralazine on bones are caused by its inhibition of hydroxylation steps in collagen synthesis.
Potentiation by the injection vehicle of the teratological action of acetazolamide in rats
Authors: Muther Thomas F. , Jones Jeff C. , Smoak Nancy S.
Published: June 2005

The high alkalinity of the injection vehicle of certain parenteral solutions of acetazolamide produces necrosis of the skin upon sc injection. The possible modification of this effect on the teratogenicity of acetazolamide was examined. Acetazolamide in a vehicle of pH 10.5 produced 36.6% fetal malforma tions, in a vehicle of pH 8.7, 6.1%, and in neutral suspension, 11.8%. Adrenal medullectomy or phentolamine plus the high pH acetazolamide reduced the fre quency to 23.2 and 24.4%, respectively. The teratogenicity of the low pH acet azolamide was increased by epinephrine to 64.2%. The frequency of hemimelia and micromelia, and of bilateral involvement, was greater in litters exposed to the high pH acetazolamide or the epinephrine‐acetazolamide combination, and was reduced by phentolamine or adrenal medullectomy. Neither the high pH vehicle nor epinephrine produced fetal defects in the absence of acetazolamide. The biological disposition of acetazolamide was not altered by any of the treat ments. Reduction of uterine blood flow may be responsible for the potentiation of teratogenicity by the high pH vehicle.
Asbestos and embryonic development
Authors: Schneider U. , Maurer R. R.
Published: June 2005

Chrysotile asbestos was administered to pregnant CD‐I mice in their drinking water and to Day 4 blastocysts during culture. Administration to pregnant mice did not affect embryo survival. In vitro administration of asbestos did not interfere with embryo implantation upon transfer of blastocysts to recipient females but did result in a decrease in postimplantation survival. These studies did not demonstrate asbestos to be teratogenic whether administered to the dam or to the blastocyst in vitro.
The effect of practolol and butoxamine on aortic arch malformation in beta adrenoreceptor stimulated chick embryos
Authors: Gilbert Enid F. , Bruyere Harold J. , Ishikawa Shizen , Cheung Matthias O. , Hodach Richard J.
Published: June 2005

An equimolar dose of the beta‐1 ndrenorocoptor antagonist practolol administered to embryonic chicks prevents the induction of aortic arch malformations by isoproterenol. Whereas 3.75 × 109 mole isoproterenol in 5 μ1 saline solution induced aortic arch anomalies in 39% of embryos injected at Hamburger‐Hamilton developmental stage 26, pretreatment with practolol one to two minutes before catecholamine administration reduced the anomaly rate to 4%. Practolol when injected alone did not influence survival rate nor did it cause cardiovascular malformations. Probably the most significant result of this study involves the prevention by practolol of aortic hypoplasia and interrupted aortic arch complexes, anomalies frequently induced by isoproterenol when administered at this stage of embryonic chick development. Butoxamine, a beta‐2 adrenoreceptor antagonist, did not block the overall effect of isoproterenol nearly as effectively as did practolol. Results from the present study suggest that aortic arch anomalies may be induced in embryonic chicks via beta‐1 adrenoreceptor stimulation. Beta‐2 receptor stimulation does not appear to be as significantly involved.
Effect of intraamniotic administration of vitamin A on rat fetuses
Authors: Nanda Ravindra , Romeo David
Published: June 2005

The present study examines the effect of intraamniotic (i/a) administration of vitamin A to rat fetuses. Vitamin A aquasol in concentrations of 50 I.U., 100 I.U., and 300 I.U., was mixed in 5 μl of saline. On day 13 of gestation, each of the three experimental subgroups were injected i/a with varying doses of vitamin A. The four control subgroups consisted of: (1) i/a injection of 5 μl of saline only, (2) amniotic puncture only, (3) laparotomy or (4) i/a injection of sorethytan oleate. The fetuses were recovered on day 18 of gestation, and were weighed and examined for gross malformations. The viable fetuses from the experimental groups showed various malformations such as cleft palate, micrognathia and limb defects. The percentage of resorbed fetuses was significantly high. The control fetuses showed a moderate number of resorptions; however the percentage of malformations was small. The results show that the i/a method can be used effectively to study the direct teratogenic effect of vitamin A on the fetuses.
The effects of methylxanthines on catecholamine‐stimulated and normal chick embryos
Authors: Gilbert Enid F. , Bruyere Harold J. , Ishikawa Shizen , Cheung Matthias O. , Hodach Richard J.
Published: June 2005

Doses of theophylline and caffeine which do not produce aortic arch anomalies in embryonic chicks have been shown to potentiate catecholamine‐induced aortic arch malformations in that experimental animal. Theophylline (2.1 × 10−5 mole per milliliter isotonic saline solution) potentiated the effective dose of norepinephrine more than 100 times. The greatest potentiation observed with epinephrine (2.5 ×) was induced by 2.6 × 10−5 mole caffeine. This study also demonstrated that both methylxanthines specifically induce aneurysms of the ascending aorta and complete absence (or nearly complete constriction) of the right ductus arteriosus. The incidences of these types of cardiovascular malformations proved to be dose dependent with theophylline a more potent teratogen than caffeine. The mobilization of calcium and/or cyclic nucleotide phosphodiesterase inhibition by the methylxanthines are suggested as significant actions in the potentiation of catecholamine‐induced aortic arch anomalies.
Toxicity studies with dieldrin: Teratological studies in mice dosed orally with HEOD
Authors: Dix K. M. , Van Der Pauw C. L. , McCarthy W. V.
Published: June 2005

Doses of 1.5 and 4.0 mg/kg/day of HEOD in corn oil and 0.25, 0.5 and 1.0 mg/kg/day of HEOD in dimethyl sulphoxide (DMSO) were administered to pregnant CF1 mice on days 6 to 14 (inclusive) of gestation. Some maternal and foetal toxicity was seen in the HEOD in DMSO and DMSO control groups compared with the untreated controls, such as reduced body weight gains, some maternal deaths, lower foetal body weights and increased incidence of delayed ossification of the foetal bones. No maternal or foetal toxicity was seen in the HEOD in corn oil or the corn oil control groups. No compound‐related teratogenic effects were observed.
Cytosine arabinoside‐induced transplacental dysgenetic hydrocephalus in mice
Authors: Kasubuchi Yasuo , Wakaizumi Satoru , Shimada Morimi , Kusunoki Tomoichi
Published: June 2005

Pregnant mice were injected with 30 mg of cytosine arabinoside/kg body weight on 13‐1/3 and 14 days of gestation. Within six hours after the first injection, pyknotic nuclei and nuclear debris were found at the matrix layer surrounding the lateral ventricles of the embryonic brain. Autoradiographic studies using tritiated thymidine revealed that most of the matrix cells exposed to cytosine arabinoside during DNA synthesis were killed by this dose of the drug. Twenty‐four hours after the second injection, most of the matrix cells had disappeared. When experimental animals were examined after birth, they showed marked dilatation of the lateral ventricles. The dilatation of the lateral ventricles was more pronounced in the parieto‐occipital region. The young showed rapid enlargement of the cranial vault and subsequently died by 35 days of age.
Holoprosencephaly in human embryos: Epidemiologic studies of 150 cases
Authors: Matsunaga Ei , Shiota Kohei
Published: June 2005

One hundred fifty embryos with holoprosencephaly were found among the total of 36,380 conceptuses obtained through induced abortion in the period from 1962 to 1974, giving an overall incidence of 0.4%. The occurrence was largely at random through time, and no “epidemic” was noted in particular years or months, but there appeared more cases derived from conceptions in winter than in summer months. The mean maternal age did not differ significantly from that of the general embryonic population, indicating that, although none of our cases were karyotyped, chromosome aberrations such as trisomies 13 and 18 that are closely associated with maternal age may not constitute a major part as causes of holoprosencephaly in human embryos. Maternal age did not differ by the presence or absence of associated external anomalies. No association was found with paternal age, parental consanguinity nor with maternal medical history, including irregularity of menstrual cycles, and smoking and drinking habits. There was an indication that the mothers were prone to have repeated miscarriages, supporting the view that some kind of maternal predisposition is responsible for the causation of holoprosencephaly. Argument was made that, apart from various chromosome aberrations well documented as causes of this malformation, polygenic mechanism probably accounts for the majority of the cases with normal karyotype.
Congenital cerebral and ocular malformations induced in rhesus monkeys by Venezuelan Equine Encephalitis virus
Authors: London W. T. , Levitt Neil H. , Kent Stephen G. , Wong Vernon G. , Sever John L.
Published: June 2005

Rhesus monkey fetuses were inoculated with Venezuelan Equine Encephalitis (VEE) vaccine virus by the direct intracerebral route at approximately 100 days gestation to determine possible teratogenicity of the virus. Congenital micrencephaly, hydrocephalus and cataracts were found in all animals and porencephaly in 67% of the cases. The virus replicated in the brain and other organs of the fetus. VEE vaccine virus is teratogenic for non‐human primates and must be considered a potential teratogen of man.
Effect of 6‐aminonicotinamide in teratogenic doses on the DNA‐ and RNA‐concentration in rabbit embryos
Authors: Scheil H.‐G. , Claussen U. , Grote W.
Published: June 2005

Pregnant rabbits were injected ip with 5 mg/kg 6‐ANA at day 10, 11, 12 or 12.5 respectively of gestation. Embryos removed at day 13 of gestation had reduced DNA and RNA concentrations. The differences (DNA: 14%; RNA: 22.4%) were significant in the group treated on the twelfth day. Some possible mechanisms are discussed.
A lethal neonatal dwarfing condition with short ribs, polysyndactyly, cranial synostosis, cleft palate cardiovascular and urogenital anomalies and severe ossification defect
Authors: Piepkorn Michael , Karp Lawrence E. , Hickok Durlin , Wiegenstein Louise , Hall Judith G.
Published: June 2005

A case of severe lethal neonatal dwarfism is reported. It appears to be a new variety of short rib‐polydactyly dwarfism. It is characterized by severe lack of ossification of all bones except the clavicle and the presence of cleft palate, as well as genitourinary, central nervous system and cardiovascular anomalies. Electronmicroscopy revealed accumulations of granular material in the chondrocytes.
Congenital kyphoscoliosis and spinal cord lesion produced in the rat by β‐aminopropionitrile
Authors: Nogami H. , Terashima Y. , Tamaki K. , Oohira A.
Published: June 2005

Pregnant rats received the lathyrogen β‐aminopropionitrile (1,500 mg/kg) intraperitoneally on day 16 (plug day = 0 day). Kyphoscoliosis was produced in a high incidence in the fetuses at the level of the upper thoracic spine as early as 24 hours after treatment. Although most of the affected newborns died within two weeks, survivors were studied until 20 weeks after birth. Survivors developed paraplegia in consequence of kyphoscoliosis. Both spinal deformity and motor disturbance were progressive. Biochemical and electron microscopic observations suggested that β‐aminopropionitrile treatment resulted in an inhibition of collagen formation in the spinal column and surrounding longitudinal ligaments of the fetuses six hours after the treatment. In addition, electron micrographs of vertebral bodies showed a decrease of proteoglycan granules in the extracellular matrix. Therefore, rupture and collapse of weakened ligaments and vertebral bodies might result in severe spinal deformity and spinal cord lesion.
The association of sex ratio anomalies with pyloric stenosis
Authors: Bear J. C.
Published: June 2005

Published family data were examined for evidence of aberrant sex ratios in relatives of pyloric stenosis index cases. An excess of males over females was found among unaffected members of sibships in which there occurred more than one case of pyloric stenosis. The male excess among affected members of these sibships did not differ from that among index cases without affected sibs. An unusual frequency of spontaneous abortions in these sibships, which might account for the observed excess of males, was not observed. No evidence was found of sex ratio anomalies in other classes of relative of pyloric stenosis index cases, whether or not the index cases had affected sibs.
Effects in mice of simultaneous prenatal exposure to ochratoxin A and T‐2 toxin,
Authors: Hood Ronald D. , Kuczuk Maureen H. , Szczech George M.
Published: June 2005

Aspergillus ochraceus and Fusarium tricinctum are food contaminating molds whose toxic metabolites, ochratoxin A and T‐2 toxin, are known mammalian teratogens. In order to determine the possible effects of simultaneous exposure to such environmental agents, ochratoxin A (2 or 4 mg/kg) and T‐2 toxin (0.5 mg/kg) were injected ip, either together or individually, in CD‐1 mice on gestation days 8 or 10. Ochratoxin induced craniofacial malformations when given alone on day 8, but not on day 10. T‐2 toxin induced tail and limb anomalies particularly when given on day 10. When the two toxins were given together on day 10, ochratoxin exacerbated the incidence of T‐2 induced gross malformations. An increase in fetocidal effects was also noted in groups treated at the high dose combination on either day, and effects on fetal growth of the high dose combination given on day 10 were greater than those of the other treatments. Few skeletal or visceral malformations were noted. These results indicated that two teratogens with presumably differing mechanisms of teratogenesis may have additive effects when administered concurrently to the same animal. Such results could be due to generalized toxic effects on the fetus or to more specific mechanisms, but further information is needed to differentiate between the two possibilities.
Teratogenicity testing in humans: A method demonstrating safety of Bendectin
Authors: Smithells Richard W. , Sheppard Sheila
Published: June 2005

We investigated the incidence of birth defects in the offspring of women who took Bendectin during pregnancy. Copies of all prescriptions issued for Bendectin in two Cities, Leeds and Liverpool, over periods of 12 and 14 months, respectively, were scanned and a record initiated for each patient. Birth notifications were later searched for matching with indexed patients. Births were traced for 2,298 patients and the incidence of major defects compared with those in the relevant populations. We found no evidence to suggest that Bendectin is teratogenic in humans.
Palate development after fetal tongue removal in cortisone‐treated mice
Authors: Walker Bruce E. , Patterson Anita
Published: June 2005

Morphological studies of cortisone‐induced cleft palate have shown retardation in the rotation of palatine shelves from a sagittal to a transverse plane. Cortisone also reduces fetal muscular movements, which may explain why displacement of the tongue from between the palatine shelves is delayed. Previous work with extrauterine development of control fetuses demonstrated that fetal membranes and tongue were major obstacles to shelf rotation. Thus, removal of these obstacles might permit rotation and fusion of palatine shelves in cortisone‐treated fetuses. In the present experiment, fetuses from cortisone‐treated strain CD‐1 mice were released from uterus and membranes and allowed to develop for eight hours in a fluid medium with the umbilical cord left intact. Compared to 4% fusion in utero, there was palatal fusion in 20% of fetuses released from membranes. When the fetal tongue was removed during extrauterine development, the frequency of fusions increased to 61%. Fusion appeared normal by the criteria applicable through light microscopy. Thus, cortisone induces cleft palate primarily through interference with shelf rotation. The palatine shelves of treated fetuses retain their ability to fuse when they can come in contact during the normal time for palate closure.
The craniofacial skeleton in anencephalic human fetuses. II. Calvarium
Authors: Garol James D. , Fields Henry W. , Metzner Louis , Kokich Vincent G.
Published: June 2005

A detailed study of the calvarium of twelve anencephalic and four normal human fetuses 26 to 40 weeks gestational age using gross dissection, alizarin red S staining, silver nitrate radiography and histology revealed dramatic alterations in the presence, form, location and relationship of the individual bones. In the larger dorsal cranial defects the interparietal portions of the occipital bone were relocated anteriorly to approximate the frontal bone. The occipital components were rotated anterolaterally and inferiorly with lack of fusion of the chondrocranium posterior to the foramen magnum. The squamae of the frontal bone were collapsed horizontally and reduced in size to lie peripheral to the anterior cranial fossa forming most of the orbital roofs. In anencephaly the bones derived from the chondrocranium were not as severely affected morphologically as those derived from the neurocranium. The sutures were narrow and smooth instead of wide and serrated as in the normally developing calvarium. In general the degree of maldevelopment was proportional to the extent of the dorsal cranial defect in anencephaly.
The craniofacial skeleton in anencephalic human fetuses. III. Facial skeleton
Authors: Metzner Louis , Garol James D. , Fields Henry W. , Kokich Vincent G.
Published: June 2005

A sample of 12 anencephalic fetuses with gestational ages ranging from 26 to 40 weeks and exhibiting varying degrees of severity of the dorsal cranial defect was compared to three normal fetuses of comparable gestational ages with regard to the morphology and positional relationships of the maxillofacial skeletal complex. Gross dissection, alizarin red S staining, radiographs, cephalometric tracings, and histologic techniques were utilized. It was found that some facial bones were severely affected in morphology, size, spatial and angular relationships. The manner in which these were altered suggests that their morphogenesis is an adaptation to the primary defect of the neurocranium.
Congenital central nervous system malformations and vinyl chloride monomer exposure: A community study
Authors: Edmonds Larry D. , Anderson Carol E. , Flynt J. William , James Levy M.
Published: June 2005

Incidence rates for central nervous system (CNS) malformations in infants born to residents of Kanawha County, West Virginia, 1970‐1974, were significantly higher than comparable United States rates during those years. Since Kanawha County contains a polyvinyl chloride (PVC) polymerization plant, a case‐control study was conducted on the possible relationship between the occurrence of CNS defects and parental occupational or residential exposure to vinyl chloride monomer emissions from this plant. No relationship with parental occupation was found. While a tendency was noted for residences of case families to be located in an area northeast of the plant, this observation did not entirely correlate with existing data on local patterns of wind direction and air pollution.