bluuebunny/crossref_metadata_2025 huggingface dataset:
The asplenia syndrome: An explanation for absence of the spleen
Authors: Monie Ian W.
Published: June 2005

Study of a case of the so‐called asplenia syndrome with a miniscule spleen suggested that the latter was caused by the pressure of neighboring viscera and interference with blood supply. Consequently, it is considered that splenic disturbance arises independently of the other malformations in this syndrome. It is also possible that similar factors may be operative in the formation of multiple spleens in the polysplenia syndrome.
Fetal manifestation of a chromosomal disorder: Partial duplication of the long arm of chromosome 5 (5q33→qter)
Authors: Passarge Eberhard , Bartsch‐Sandhoff Margret , Rehder Helga
Published: June 2005

Two live‐born children and one fetus were found to be affected by autosomal imbalance consisting of a partial duplication of the long arm of chromosome 5 (5q33→qter) and partial deficiency of the short arm of chromosome 8 (8p23‐pter), resulting from segregation of a paternal translocation heterozygote t(5;8) (q33;p23). The phenotype of the children was rather similar to that of the fetus. The main features included Craniofacial dysmorphia consisting of downward slant of eyelids and corners of the mouth, flat and widened nasal bridge, prominent philtrum, and small mandible. Ventricle and atrium septum defects were associated with overriding aorta and right heart hypertrophy in all three. Statomotoric retardation was evident postnatally in the two children. This observation indicates that structural autosomal imbalance may produce a fetal phenotype that is specific for the karyotype and comparable to that seen in the newborn.
Infections in pregnancy: Highlights from the collaborative perinatal project
Authors: Sever John L.
Published: June 2005

The longitudinal study of approximately 60,000 pregnant women was conducted at 14 major medical centers throughout the United States. Clinical data was obtained under prescribed protocols for each of the study women throughout their pregnancy, at delivery, and through the postpartum period. The children were followed with uniform examinations from birth through seven years of age. In addition blood samples were taken from the pregnant women at registration, every two months through pregnancy, at delivery, and six weeks postpartum. Cord blood samples were also taken from the children during the last half of the study. We have used this material from the Collaborative Perinatal Project for the investigation of the role of infections in the production of damage to the fetus and newborn.

The frequency of clinically recognizing infections during pregnancy was determined and geographic variation was demonstrated. Serological tests were used to document certain diseases. The frequency of confirmed clinical cases per 10,000 were: rubella, 8; rubeola, 0.6; mumps, 10; varicella‐zoster, 5. The epidemiology and clinical findings associated with infections were studied using serological methods. This has provided data on the frequencies of infections such as cytomegalovirus, herpes simplex, mumps, rubeola, respiratory syncytial virus, and others. The study of abnormal pregnancies and matched controls is in progress using serological techniques. A number of specific studies have been reported on infections including rubella, neonatal meningitis, cytomegalovirus, maternal urinary tract infections, and toxoplasmosis. Further testing is now in progress employing more sophisticated laboratory methods and more complete data analysis.
Susceptibility to cleft palate and the major histocompatibility complex (H‐2) in the mouse
Authors: Vekemans M. , Fraser F. C.
Published: June 2005

The congenic mouse strains B10 and B10.A differ genetically only at the H‐2 locus, B10 having the H‐2b and B10.A the H‐2a haplotype. The two strains also differ in susceptibility to cortisone‐induced cleft palate, B10 being more resistant than B10.A Since stage of palate closure is also associated with susceptibility to cortisone‐induced cleft palate it was postulated that the H‐2 haplotype may affect the cortisone‐induced cleft palate susceptibility by altering the stage of palate closure. The present study shows that palate closure occurs at the same stage in the two strains, so this hypothesis must be rejected.
Computer program for searching the biomedical literature in teratology, developmental biology, and reproductive biology
Authors: Brent Robert L.
Published: June 2005

A word profile program has been developed in conjunction with the services of the Institute for Scientific Information for surveying the literature in teratology, developmental biology, and reproductive biology. It has been revised many times to improve the discriminating qualities of the program. It should provide scientists with a current review of the published articles in the field for a relatively low cost. This same program, if purchased as an individual subscriber, would cost ten times the ISI regular subscription price for the ASCA service. Colleagues and subscribers are encouraged to make recommendations that will improve the program.
An epidemiologic study of neural tube defects in Los Angeles County I. Prevalence at birth based on multiple sources of case ascertainment
Authors: Sever Lowell E. , Sanders Mark , Monsen Rita
Published: June 2005

Epidemiologic studies of the neural tube defects (NTDs), anencephalus and spina bifida, have for the most part been based on single sources of case ascertainment in past studies. The present investigation attempts total ascertainment of NTD cases in the newborn population of Los Angeles County residents for the period 1966–1972. Design of the study, sources of data, and estimates of prevalence rates based on single and multiple sources of case ascertainment are here discussed. Anencephalus cases totaled 448, spina bifida 442, and encephalocele 72, giving prevalence rates of 0.52, 0.51, and 0.08 per 1000 total births, respectively, for these neural tube defects–rates considered to be low. The Los Angeles County prevalence rates are compared with those of other recent North American studies and support is provided for earlier suggestions of low rates on the West Coast.
Interactions between cycloheximide and T‐locus alleles during mouse embryogenesis
Authors: Lary Joseph M. , Hood Ronald D. , Lindahl Ronald
Published: June 2005

Female CD‐1 mice were mated with CD‐1 × T/ + F1 males that were heterozygous for the brachyury (T) semidominant lethal gene or were +/+. Fetuses from CD‐1 × +/ + matings were normal when observed on gestation Day 17 (plug day = Day 0). Those from the CD‐1 × T/+ cross exhibited the expected 1:1 ratio of short:normal tail lengths, but 10% of these fetuses were tailless, apparently due to factors in the CD‐1 genotype that increased the expressivity of the T‐gene with regard to reduction of tail length. Additional CD‐1 females were mated with CD‐1 × tw18/+ F1 males. Fetuses from the CD‐1 × tw18/+ matings were normal. CD‐1 females carrying CD‐1 X +/+, CD‐1 × T/+, or CD‐1 × tw18/ + litters were injected ip on gestation Day 9 with 30 mg/kg cycloheximide or were untreated. Cycloheximide was teratogenic for litters from all three crosses. Polydactyly, oligodactyly, and a variety of skeletal abnormalities were observed. Gross malformations and total skeletal malformations were increased in treated CD‐1 × T/ + or tw18/ + litters in comparison with CD‐1 × +‐/ + litters, as were nonvertebral skeletal defects in CD‐1 × tw18/+ litters. Prenatal mortality was also greater in treated mutant‐containing litters than in + / + litters, and fetal weights were similarly decreased in treated CD‐1 × tw18/ + litters. The incidence of taillessness was also higher in treated (26%) than in control (10%) CD‐1 × T / + litters. Thus both the T and tw18 alleles appear to have enhanced the teratogenicity of cycloheximide, and the inhibitor may have increased the expressivity of T.
Characteristics of the androgenization produced in mice by neonatal exposure to alpha‐fetoprotein antibodies
Authors: Mizejewski G. J. , Vonnegut M.
Published: June 2005

Neonatal male and female mice, ages 1–5 days, were injected intracranially with either anti‐alpha‐fetoprotein (AFP) IgG, steroids, or various control solutions. The mice were autopsied 60–70 days later and the spleen, thymus, liver and gonads were examined by light microscopy. The antibody to AFP produced a gonadal response which was sexual specific. Histological examination of the tissue sections from female mice treated with either anti‐AFP IgG or steroids revealed the presence of polyfollicular ovaries lacking in corpora lutea formation. A comparable antibody‐induced specific effect on the testes could not be demonstrated; however, steroidal administration induced aspermatogenesis and delayed maturation in parallel studies. In the anti‐AFP IgG‐treated groups, there appeared a gross neurological lesion which was termed external hydrocephaly. The physiologic responses in the female gonad were found independent of the presence of this anatomical brain lesion, whereas those in the male gonad were found causally related. The immunological specificity of the gonadal response was demonstrated by the use of IgG devoid of anti‐AFP IgG and by various IgG control solutions. Thus, exposure to anti‐AFP IgG during the critical period of sexual development in the brain appears to mimic steroidal androgenization of the female mouse.
Trisomy 16 in the mouse fetus associated with generalized edema and cardiovascular and urinary tract anomalies
Authors: Miyabara Shinichi , Gropp Alfred , Winking Heinz
Published: June 2005

Murine trisomy (Ts) 16 occurs in the fetal and neonatal progeny of males doubly heterozygous for the Robertsonian metacentric chromosomes Rb(16.17)7Bnr/Rb(9.16)9Rma and “all acrocentric” females. The developmental aspects of this trisomy were studied between day 12 of gestation and birth. So far, postnatal survival longer than a few hours after birth has not been observed. The frequency of Ts 16 among all implants decreased from more than 20% on day 14 to values between 4% and 7% shortly before term.

Main features of Ts 16 are moderate general hypoplasia, slight developmental retardation, and cardiovascular anomalies. These latter were found in 96% of the trisomies, the great majority belonging to the transposition type, i.e., riding aorta, double outlet right ventricle (DORV) and transposition of the great arteries (TGA). Association with common atrio ventricular (AV)‐canal was frequent. Other anomalies as “open eyelid”, hydronephrosis, and hydroureter seem to be attributable to the effects of retardation. Generalized transient edema was frequent in the later gestational stages of Ts 16.

Severe cardiovascular malformation is possibly one of the factors responsible for late fetal or neonatal death in some cases. Another factor probably contributing to Ts 16 fetal mortality is insufficiency of placental function due to hypoplasia of the fetal vasculature of this organ. The teratological study of Ts 16 demands interest since evidence has been forwarded to consider this trisomy as an animal model of human trisomy 21.
Effects of mercury compounds on ovulation and meiotic and mitotic chromosomes in female golden hamsters
Authors: Watanabe Toshiaki , Shimada Takamichi , Endo Akira
Published: June 2005

When female golden hamsters were subcutaneously injected with either CH3HgCl or HgCl2 in doses of 6.4 mg or 12.8 mg Hg/kg body weight, the incidence of chromosome aberrations was slightly increased in bone marrow cells, but not in metaphase II oocytes. In the HgCl2‐treated animals the ovulation was inhibited, although mercury concentrations in ovaries were relatively low. However, in the CH3HgCl‐treated groups, despite high concentrations of mercury in ovaries, the ovulation was not affected.
Altered glycosaminoglycan composition of rat forelimb‐buds during hydroxyurea teratogenesis: An indication of repair
Authors: Sugrue Stephen P. , Desesso John M.
Published: June 2005

We report here the effect of hydroxyurea (HU), which is an inhibitor of DNA synsthesis and a known cytotoxic and teratogenic agent, on the composition of glycosaminoglycans (GAGs) in the extracellular matrix of the developing forelimb of the rat. HU injected on day 12 has been shown to produce one missing digit and multiple missing digits on day 13 (Ritter et al., '73). Pregnant Wistar rats were treated (IP) with 1,000 mg/kg HU on either day 12 or day 13 (9:00 a.m.) of gestation and sacrificed 0–96 hours later. Forelimbs were dissected and pooled by litter. GAGs were extracted and then separated by microzone electrophoresis on cellulose acetate membranes. Identification of GAG was confirmed by digestion with specific polysaccharidases. Such analysis of control forelimb‐buds revealed hyaluronic acid decreasing from 62% of total GAG at day 12 to 36% total GAG at day 16, whereas chondroitin sulfate increased from 34% to 58%. HA content of forelimb‐buds treated on day 12 was 22% greater than controls at 12 hours posttreatment, 45.5% at 24 hours posttreatment, returning to control levels at 60 hours after treatment. Chondroitin sulfate (CS) level decreased by 20% at 48 hours after treatment, returning to control level by 72 hours. Hyaluronate levels of HU 13 treated forelimb‐buds were 46% greater than controls at 24 hours after HU treatment, returning to control levels at 36 hours. CS levels were significantly lower than controls at 36 hours posttreatment. Histochemical analysis was performed to localize these alterations in GAG composition within the forelimbs. Beginning 12 hours posttreatment and continuing until 48 hours, an increase in HA content was observed in the mesenchymal compartment of the forelimb (1) beneath the apical ectodermal ridge and (2) between the ectoderm and prechondrogenic blastema (peripheral zone). This HA increase may be interpreted as a recovery (repair) phase of the pathogenesis of the HU malformation. To confirm that this shift in GAG is indicative of a compensatory phenomenon mitotic indices of the forelimbs were examined. At 36 hours posttreatment substantial increase in mitotic activity was observed in the subridge and peripheral regions of forelimbs treated on day 12, whereas those treated on day 13 demonstrated a significant increase only in the subridge zone. The increase in HA composition in the zones of the forelimb correlated well with the increase of mitotic activity. It is suggested that elevated HA/CS ratio allowed for increased proliferation and reorganization of the mesenchymal cell population, whereas the return to control levels marked the cessation of repair and resumption of differentiation.
Growth characteristics of the murine trisomy 19 thymus
Authors: Bersu Edward T. , Crandall Clare , White Beverly J.
Published: June 2005

Development of the trisomy 19 mouse thymus was studied by (1) evaluation of cell and nuclear counts and volume distributions and (2) examination of the in vivo cell cycle characteristics using flow cytometry. Direct preparations of thymuses from affected animals and their normal littermates at 17, 18, 19 gestational days, and at term were used. Cell numbers in aliquots from the trisomic thymus suspensions were always significantly less than those in the normal animals. There were no differences in cellular or nuclear volumes between the two groups. However, the populations of cells in the trisomic suspensions showed a lag in the normally occurring transition from a larger to a smaller size. DNA distribution histograms from these suspensions were generated using a TPS‐1 Cell Sorter, and percentages of cells in different phases of the cell cycle were estimated using computer analysis. The resulting graphs and numerical data from the trisomic mice, when compared with the normals, showed consistent increases in the relative numbers of cells in the S and G2 + M phases of the cell cycle. Because growth retardation is a major feature of trisomy 19, as well as in other murine trisomies, these results suggest that cell cycle alterations may, in part, contribute to the reduced cell number, delayed development, and smaller size of the trisomic animals.
An analysis of fetotoxicity using biochemical endpoints of organ differentiation
Authors: Kavlock Robert J. , Chernoff Neil , Rogers Ellen , Whitehouse Douglas , Carver Brenda , Gray Jacqueline , Robinson Kathy
Published: June 2005

The biochemical differentiation of the brain, lungs, liver, and kidneys of the late gestation rat fetus was examined to characterize the immediate implications of retarded growth on fetal development. Initially, the normative profile of development of the brain (weight, DNA content, and protein content), lungs (weight and surfactant accumulation), liver (weight and glycogen deposition), and kidneys (weight, alkaline phosphatase activity, and protein content) was determined on gestation days 19, 20, 21, and 22 (day 1 = finding of sperm in the vaginal smear). Subsequently, five compounds known to induce fetotoxicity (chlorambucil, methyl salicylate, mirex, nitrofen, and toxaphene) were administered during organogenesis, and the effects on organ differentiation were determined in day 21 fetuses. The effects of fetal growth retardation resulting from exposure to exogenous agents were not equally distributed among the organs studied. The liver and kidney appeared more sensitive to insult by these agents than did the brain and lungs.
Muscle abnormalities associated with radial aplasia
Authors: Stephens Trent D.
Published: June 2005

The purpose of this paper was to report the muscle variations in eleven cases of radial aplasia and to extract information relative to normal and abnormal limb muscle development. The cases all involved other defects ranging from acardia to “thrombocytopenia‐absent radius” (TAR) and included several multiple malformations. The muscle patterns did not seem to depend upon the etiology of the radial aplasia but appeared to be more dependent upon late embryonic or early fetal muscular repositioning.
The causes of perinatal death induced by prenatal exposure of rats to the pesticide, mirex. Part I: Pre‐parturition observations of the cardiovascular system
Authors: Grabowski Casimer T. , Payne Doris B.
Published: June 2005

Prenatal exposure to mirex, a chlorinated hydrocarbon insecticide, induces a high rate of perinatal death, but only a low incidence of visible abnormalities which could help to account for these deaths. This study is an attempt to determine the cause of these deaths. Pregnant rats were intubated with a moderate dose of mirex, in oil, 6 mg/kg/day, on days 8½‐15½ of gestation. Observations, on 78 control and 136 treated fetuses, were made on the morning before parturition was expected. Fetuses were sequentially exposed and electrocardiograms obtained with the fetus attached to the placenta and uterus. ECGs were evaluated for rate of beat, regularity of beat, PR intervals, and other features. Fetuses were examined for edema level and vitality. None of the controls were dead and none had abnormal ECGs. Of the treated group, 14% were dead, 16% had a first‐degree heart block, and 2% had a second‐degree heart block. Some (6%) had slow, feeble atrial beats only, possibly a third‐degree block, and appeared to be dying. The severity of the symptoms was proportional to the degree of visible edema. Most of the fetuses with little or no visible edema had normal ECGs, but the majority of the moderate to severely edematous fetuses (i.e., with a layer of subcutaneous edema across the back of 0.5 mm or more) had abnormal ECGs and/or were either dead or dying. These data show that the effects of mirex on the fetal cardiovascular system are a major factor in inducing prenatal death.
Teratogenicity of triamcinolone acetonide in rats
Authors: Rowland J. M. , Hendrickx A. G.
Published: June 2005

The objective of this investigation was to study the teratogenic effects of triamcinolone acetonide (TAC) in the rat. Pregnant females were injected intramuscularly once each day for three consecutive days (days 9–11, 12–14, or 15–17 of gestation) either with vehicle alone or with 0.125, 0.25, or 0.5 mg/kg TAC. All animals were euthanized on day 20 of gestation, and the fetuses were fixed for razor blade sectioning and skeletal examination. No maternal lethality was elicited in any of the treatment groups. There were decreases in fetal viability in the two higher dose groups treated on days 12–14 and the group treated with 0.5 mg/kg on days 15–17. These same three treatment groups showed significant increases in the percentage of malformed fetuses. The most prevalent malformation was cleft palate, with both complete and partial clefts being detected. Umbilical hernias and undescended testes were also found to be significantlymore frequent in the high‐dose group treated on days 12–14. A reduced degree of ossification was found in all TAC‐treated groups, but no specific skeletal malformations were detected. Fetal weight was significantly reduced in all TAC‐treated groups. The results demonstrate that (1) TAC affects a variety of developmental processes resulting in resorption, cleft palate, umbilical hernias, undescended testes, reduced ossification, and fetal growth retardation, (2) these teratogenic effects are elicited at doses causing no maternal lethality, and (3) fetal growth retardation can be produced at doses below those required to produce malformations and during periods of gestation where no malformations are produced, supporting the use of this parameter as a sensitive indicator of embryotoxicity.
Complications of pregnancy in mice exposed prenatally to DES
Authors: Walker Bruce E.
Published: June 2005

Women exposed prenatally to diethylstibestrol (DES) develop a variety of reproductive tract anomalies. Most of these anomalies have been replicated in strain CD‐1 mice after similar DES exposure. Recently, impaired reproductive performance in DES‐exposed women has been reported. To see whether the mouse model also replicates this defect, at study of reproduction was performed. Pregnant CD‐1 mice were injected with DES and their female offspring were raised to breeding age. The latter were then exposed continuously to untreated males for a maximum of 4 months. Among 74 mated mice, 34 became pregnant and 11 of these pregnancies ended in abortion or stillbirth. Other anomalies encountered were: two fetuses with compressed heads, one of which seemed blocked from delivery by a vaginal adenocarcinoma; two uterine tumors, one of which was a teratocarcinoma; two teratomas located in uterine lumina; and two uteri containing placentas without embryos. Since the frequency of successful pregnancies in the DES‐exposed mice was reduced below control levels to a degree similar to that reported for DES‐exposed women, the validity of the mouse model has been confirmed for this characteristic.
Regeneration by dissociated adult hydra cells: A histologic study
Authors: Chun Yong H. , Johnson E. Marshall , Gabel Bradley E. G. , Cadogan Albert S. A.
Published: June 2005

Adult Hydra attenuata with vitally stained gastrodermal cells were dissociated into their component cells which were then randomly reaggregated into pellets by low‐speed centrifugation. Representative examples of these preparations, which develop into normal adult hydra if left undisturbed, were examined fresh at low magnification and at higher magnification in fixed, stained, and sectioned specimens. The actual pellet stage lasts less than 1 hour because the adult ectodermal and gastrodermal cells rapidly sort themselves into an inner and outer layer and seem to secrete a new mesoglea immediately thereafter. The “embryo” becomes trilaminar and attains a central cavity by extruding a large amount of cellular debris at the end of the first day. At about this same time, new tentacles begin to differentiate from rapidly dividing and undifferentiated interstitial cells. Regulation of tentacle number and position occurs at the end of two days, and the body form is essentially reestablished within 60 hours by further differentiation of the hypostomes and body wall. Complete separation of the preparation into individual polyps does not occur until about 190 hours of development.
Effect of vinblastine sulfate on the growth and histologic development of reaggregated hydra
Authors: Chun Yong H. , Johnson E. Marshall , Gabel Bradley E. G. , Cadogan Albert S. A.
Published: June 2005

In the presence of vinblastine, the sorting of individual cells proceeded normally but mesogleal formation was delayed. The “embryo” became highly distended and failed to expel a central mass of unused or residual cells as occurs during regeneration of “embryos” that have not been treated with a test chemical. The epithelial cells became vacuolated and failed to maintain their sheetlike arrangement and attachments, although they did begin secretion of basement membrane. Interstitial cells failed to increase in number.
Regional variations in guinea pig uterine blood flow during pregnancy: Relationship to intrauterine growth of the fetal‐placental unit
Authors: Garris David R.
Published: June 2005

The relationship between regional variations in uterine blood flow and fetal‐placental weight/size was examined in guinea pigs possessing three pregnancy sites per horn. Pregnancy sites were localized in either the tubal, middle, or cervical third of the uterus. Throughout pregnancy, the middle uterine pregnancy sites consistently received a lower blood flow rate than did either of the other two uterine zones. The middle zone also possessed the lowest fetal‐placental weights and smallest fetuses, based on crown‐rump length measurements, of all three zones. Significant correlation coefficients were found to exist between uterine blood flow and placental weight, placental and fetal weights, and fetal weight and crown‐rump length. Experimental reduction of uterine blood flow to the tubal pregnancy site effectively induced a retardation of intrauterine fetal‐placental growth, which was comparable to that found in the middle uterine zones. These data indicate that variations in regional blood flow rates to the guinea pig uterus affect intrauterine growth of the fetal‐placental unit.
The embryotoxic effects of ultrasound exposure in pregnant ICR mice
Authors: Kimmel C. A. , Stratmeyer M. E. , Galloway W. D. , Laborde J. B. , Brown N. , Pinkavitch F.
Published: June 2005

The embryotoxicity of ultrasound exposure during pregnancy was investigated in DUB:(ICR) mice. On day 0 of gestation (day of plug), pregnant mice were assigned to one of five groups: cage control, sham exposed (0 W/cm2), 0.05 W/cm2, 0.50 W/cm2, or 1.00 W/cm2. Females were anesthetized on day 8 of gestation and their abdomens were shaved to assure good acoustic coupling. The animals were strapped on a lucite board and placed vertically into a distilled degassed water bath (30°C) so that the abdomen was fully submerged and centered in the axis of the ultrasonic beam. Insonation was carried out using a PZT transducer with a radius of 1.27 cm and a frequency of 1 MHz under continuous wave conditions. Each animal was placed at a distance of 25 cm from the transducer and exposed to the appropriate intensity for 120 seconds. On day 17 of gestation, the maternal animals were killed, the uterine contents were examined, and live fetuses were weighed and then shipped in cold lactated Ringer's solution from Maryland to Arkansas. Fetuses were examined on the day following maternal sacrifice for external and visceral defects and skeletons were prepared and examined subsequently. Slight but significant differences were detected between the cage control and shamexposed groups. No statistically significant changes were seen that could be attributed to ultrasound exposure, although there was a slight increase in the incidence of malformed fetuses and the occurrence of multiple malformations in individual fetuses as intensity of the ultrasonic exposure increased.
Combined embryotoxic action of toluene, a widely used industrial chemical, and acetylsalicylic acid (aspirin)
Authors: Ungváry Gy. , Tátrai E. , Lõtrincz M. , Barcza Gy.
Published: June 2005

CFY rats were exposed to inhalation of fresh air at days 10–13 of gestation; at day 12 the dams were given 0, 125, 250, 500, or 1,000 mg/kg acetylsalicylic acid (ASA) by gavage. During the same period of gestation (days 10–13) further groups of rats were exposed to toluene at 1,000, 2,000, and 3,600 mg/m3 atmospheric concentration and were given 250 mg/kg ASA by gavage; two subgroups of animals treated with 250 mg/kg ASA in combination with 3,600 mg/m3 toluene inhalation were given 0, 2.5, or 5 gm/kg glycine 2 hours before the ASA dose. At day 21 the animals were killed and examined for teratogenic effects and histological changes. After 48 hours toluene exposure other groups of rats were treated with ASA or with ASA plus glycine (administered 2 hours earlier) on day 20 of gestation. These animals were killed 2 hours later and the salicylic acid concentration in maternal and embryonic plasma and in amniotic fluid was measured by gas chromatography. With the rising ASA doses both maternal toxicity (increased mortality, decreased food consumption, and weight gain) and embryonic toxicity (postimplantation loss, increased incidence of weight‐retarded fetuses, increased minor anomalies and malformations, decreased average weight of fetuses) increased. Toluene was found to potentiate the toxic effect of ASA and to increase both maternal and embryonic toxicity. The type of ASA‐induced minor anomalies and malformations was also found to be altered under the effect of toluene pretreatment. By raising the toluene concentration the salicylic acid level in the maternal and embryonic plasma and in the amniotic fluid was increased above the expected concentration. The mechanism of the potentiating interaction should be looked for in the depletion of the glycine pool by toluene (and its metabolites) and in the resultant increase of salicylic acid level. Increasing ASA embryotoxicity caused by toluene can be warded off by glycine administration.
Developmental toxicology of acetonitrile in the syrian golden hamster
Authors: Willhite Calvin C.
Published: June 2005

Pregnant hamsters were exposed to acetonitrile by inhalation, ingestion, or ip injection during the early primitive streak stage of embryogenesis. Inhalation of 1,800 or 3,800 ppm acetonitrile for 60 min failed to induce malformations in the near‐term offspring whereas inhalation of 5,000 or 8,000 ppm acetonitrile was associated with production of severe axial skeletal (dysraphic) disorders. One fetus afflicted with extrathoracic ectopia cordis was recovered from a dam exposed to 8,000 ppm acetonitrile. An oral or ip dose of 100–400 mg/kg acetonitrile in hamsters of equivalent gestational age also caused malformations identical to those noted following inhalation exposure. Some dams exposed to the highest concentrations or doses of acetonitrile displayed overt signs of poisoning. Multiple injections of sodium thiosulfate antagonized the mortality and signs of intoxication associated with acetonitrile treatment. Offspring of thiosulfate‐treated hamsters exposed to acetonitrile failed to exhibit the marked teratogenic response that was associated with exposure to equivalent concentrations or doses of acetonitrile alone. Elevated concentrations of cyanide and thiocyanate were detected in all tissues studied at 2.5 hr after an oral or ip dose of acetonitrile. Cyanide was liberated when acetonitrile was incubated in vitro with hamster liver slices or NADPH‐fortified hepatic microsomal preparations. The results suggested that in vivo liberation of cyanide from acetonitrile was responsible for the production of terata.
Maternal factors in cleft lip with or without palate: Evidence from interracial crosses in the United States
Authors: Khoury Muin J. , Erickson J. David , James Levy M.
Published: June 2005

Maternal determinants of oral clefts have been documented in studies of experimental animals but not of humans. We studied maternal and paternal influences on the well‐known differences in the incidence of oral clefts between Whites and Blacks in the United States. Using United States birth certificate data for 1973–1978, we compared the incidence of oral clefts in offspring of White‐White, Black‐Black, and White‐Black couples. Because oral clefts are underreported on birth certificates, we also compared oral clefts as a proportion of all defects reported for offspring of various combinations of parental races. After adjusting for fathers race, offspring of White mothers had a higher rate of cleft lip with or without palate (CLP) than those of Black mothers (odds ratio [OR] = 2.33, P < 10−4) and a higher proportion of CLP in their reported defects (OR = 2.41, P < 10−4). This maternal race effect did not apply to cleft palate (CP), and it persisted after adjusting for mother's age, parity, and education. However, after adjusting for mother's race, offspring of White fathers did not have a higher rate or proportion of CLP or CP than those of Black fathers. The study shows that the difference in the reported rates of CLP between Whites and Blacks is due to the effect of mother's race, whereas the difference in the reported rates of CP cannot be attributed to the independent effect of mother's or father's race. The study documents the existence of maternal determinants of CLP in humans.
Suppression of morphogenesis in embryonic mouse limbs exposed in vitro to excess gravity
Authors: Duke Jackie C.
Published: June 2005

This paper is a report of the first investigation of the effect of excess gravity on in vitro mammalian limb chondrogenesis. Limb buds from mice of various gestational stages were exposed to excess gravity (2.6G) using a culture centrifuge. Both forelimbs and hind limbs were cultured and the development of various limb elements was scored after four to six days. The 2.6G force significantly depressed the development of limb elements when applied during the teratogen‐sensitive period of chondrogenesis. There was a proximodistal gradient of sensitivity to excess gravity in the limb with proximal structures being less susceptible than distal ones. In some cases, proximal limb elements present prior to explantation disappeared upon exposure to excess gravity. Hypergravity's teratogenic effect is assumed to operate viachanges in tension and/or pressure on the cells, accompanied by alterations in cell morphometry and membrane properties.
Dose‐response relations of palatal slit, cleft palate, and fetal mortality in mice treated with a glucocorticoid
Authors: Kusanagi Takao
Published: June 2005

C57BL/6 (C57BL) and SWV mice were treated subcutaneously with triamcinolone acetonide in a single dose of 1.0–7.0 mg/kg on day 12 of pregnancy, and the palate of their fetuses was examined at term. In C57BL mice palatal slit occurred spontaneously and its frequency increased with increasing doses of triamcinolone. However, this defect was not seen in SWV fetuses, even when dams were treated with the doses that induced cleft palate. The frequency of cleft palate increased in both C57BL and SWV as the dose of triamcinolone increased. Fetal mortality increased in SWV, but not in C57BL, with increasing doses of triamcinolone. Dose‐response relations were analyzed by the log‐probit transformation method. In C57BL mice, the slope of the doseresponse curve of palatal slit was significantly different from that of cleft palate. In contrast, the dose‐response curves of cleft palate were similar in both C57BL and SWV; the median effective dose was significantly greater in C57BL than in SWV. The mechanism of induced palatal slit appears to be different from that of induced cleft palate; the mechanism of cleft palate induction may be the same in both C57BL and SWV. The slope of the dose‐response curve of fetal mortality in SWV mice was different from that of cleft palate; the mechanisms underlying the resorption and cleft palate responses must be different.
Congenital and hereditary anomalies in the rhesus monkeys (Macaca mulatta) of Cayo Santiago
Authors: Rawlins Richard G. , Kessler Matt J.
Published: June 2005

During seven annual birth seasons, from January 1976 to July 1982, 963 infants were born in the Cayo Santiago, Puerto Rico, colony of free‐ranging rhesus monkeys (Macaca mulatta). The reproductive rate for mature females, 4 years of age and older, ranged between 74.1% and 84.7%, with a cumulative mean of 80.8% over 7 years. Live births comprised 95.3% of the total and the secondary sex ratio was 109 male to 100 female births. No twinning was observed. Aborted and stillborn monkeys represented 4.7% of all births. The percentage of stillborn females was greater than that of males (4.0% vs. 3.1%). Neonatal death, defined as mortality within 48 hours postpartum, occurred in 0.8% of the live births.

Two cases of congenital abnormalities were observed. The first was an anencephalic, acranial female and the second a congenitally blind male. Both infants were born to matrilineally unrelated 7‐and 8‐year‐old multiparous females with no prior history of delivering malformed offspring. The incidence of each defect, based on 963 births, was 0.10%, with a cumulative incidence of 0.20% for all teratisms seen during the study.

Multiple occurrences of a rare, nonpathological and nonlethal hereditary anomaly were also seen. Five “golden” macaques were born into two genetically distinct social groups within the last 2 years of observation. The incidence of this phenotype, based on five cases, was 0.52%, 52 times the expected rate (.01).
Prenatal diazepam: Distribution and metabolism in perinatal rats
Authors: Simmons Roy D. , Miller Richard K. , Kellogg Carol K.
Published: June 2005

Previous investigations have revealed that prenatal exposure to diazepam (DZ) alters brain development and behavior in the offspring of rats and mice. In order to understand how DZ may affect the developing nervous system it is necessary to examine its metabolic fate in the neonate. It is therefore the aim of this study to investigate the disposition, metabolism, and persistence of DZ in the neonate. Dams were injected s.c. with 2.5 mg/kg of 14C DZ (10 μCi/day) on days 13–20 of gestation and their litters were fostered at birth. Dams killed within 24 hours postpartum and neonates killed at postnatal days 0, 10, and 20 were analyzed for 14C activity. Brain levels (pmoles DZ and metabolites/100 mg tissue SE) were 3.4 ± 0.3 in the dam and in the neonates were 3.2 ± 0.3 (day 0), 3.4 ± 0.3 (day 10), and undetectable at day 20. Neonatal peripheral tissue 14C activity was undetectable by day 10. Brain regional analysis indicates 14C is highest in the colliculi at day 0, but not at day 10. Brain levels of DZ, oxazepam (OXA), N‐desmethyldiazepam (NDZ), and the glucuronide (GLU) determined by high‐performance liquid chromatography (HPLC), were GLU (49%), DZ (28%), and NDZ (24%) in the dam; GLU (52%), DZ (24%), and NDZ (25%) in the day 0 neonate; and GLU (32%), DZ (12%), NDZ (39%), and OXA (19%) at day 10.

The distribution and metabolism of 14C DZ that persists in the neonate following prenatal exposure differs from that which occurs in the dam. The neonatal brain contains OXA and a higher concentration of 14C exists in the colliculi region of day 0 neonates when compared with maternal brain. Prenatal 14C DZ activity persists longer in the neonatal brain than in peripheral tissue but all tissue levels are undetectable at day 20. Therefore, DZ and its pharmacologically active metabolites persist longest in the neonatal brain and could therefore alter both prenatal and postnatal developmental processes. However, no drug is present in the neonate at 20 days of age and therefore could not directly affect behavior measured then or at later ages.
An in vivo/in vitro evaluation of the teratogenic action of excess vitamin A
Authors: Steele C. E. , Trasler D. G. , New D. A. T.
Published: June 2005

Pregnant rats of CFHB strain were injected 8 1/2 days postcoitum with a 1% suspension of retinoic acid (RA) in arachis oil to give 20 mg RA per kg body weight. Control rats were injected with arachis oil only. After 26 hours, one uterine horn was removed from each rat and the embryos cultured in serum from untreated rats. The embryos in the other horn were allowed to continue development in vivo. After a further 48 hours the cultures were terminated and the second uterine horn removed from each rat. This provided four groups of embryos for comparison: (1) embryos from RA‐treated rats, (2) cultured embryos from RA‐treated rats, (3) embryos from control rats, and (4) cultured embryos from control rats. The results showed that the effects of the teratogen on the cultured embryos were similar to those on the embryos allowed to continue development for the same period in the mother. In both groups RA reduced protein synthesis, inhibited somite and limb bud formation, and caused various neural tube defects, particularly microcephaly and abnormalities in the closure of the anterior and posterior neuropores.
Experimental induction of two inner cell masses in mouse embryos by vinblastine treatment in vitro
Authors: Naruse Ichiro , Kano Satoshi , Shoji Ryujiro
Published: June 2005

Induction of artificial fission of the inner cell mass in an in vitro embryonal culture system was attempted. Mouse blastocysts were collected from uteri on day 3 of gestation and exposed to vinblastine sulfate after removal of zona pellucida. Embryos in the control group had a single inner cell mass on the trophectoderm and developed to the postblastocyst stage. On the other hand, the inner cell masses of the embryos in experimental groups subdivided into two or more. The present results, therefore, revealed that the vinblastine treatment at the blastocyst stage induced fission of the inner cell mass in mouse embryos. Further studies are planned in improved culture conditions to determine whether each inner cell mass subdivision develops into independent embryos.
A kinetic analysis of rat embryo response to cyclophosphamide exposure in vitro
Authors: Mirkes Philip E. , Greenaway J. C. , Shepard Thomas H.
Published: June 2005

Day 10 rat embryos were exposed in vitro to a teratogenic dose of cyclophosphamide (25 μg/ml) in the presence of a metabolic system (activated CP) for varying lengths of time and then were recultured in drug‐free medium. Development was assessed after a total of 24–26 hours of culture. Exposure periods of 2.5 hours or less had no significant effects on growth, incidence of malformed embryos, mitotic index, or necrotic index when compared to control cultures from which cofactors for metabolic activation were omitted. Embryos exposed to activated CP for 5 hours and then recultured in drug‐free medium for 19–21 hours were indistinguishable from embryos exposed to activated CP continuously over a 24–26‐hour period. These embryos are characterized by retarded growth as well as abnormalities of the prosencephalon, mandibular arches, limbs, and tail. Histological examination of embryos exposed to activated CP for 5 hours and immediately fixed revealed a decrease in the mitotic index and an increase in the necrotic index of the neuroepithelium and the surrounding mesenchyme of the prosencephalon. Our findings indicate that a 5‐hour exposure to activated CP during day 10 of rat gestation is sufficient to produce the molecular lesions necessary to elicit the teratogenic effects of cyclophosphamide.
External malformations in chick embryos following concomitant administration of methylxanthines and β‐adrenomimetic agents: 1. Gross pathologic features
Authors: Bruyere Harold J. , Fallon John F. , Gilbert Enid F.
Published: June 2005

The objectives of this report are to document external malformations observed in chick embryos following concomitant administration of methylxanthines (caffeine, theophylline) and β‐adrenomimetic agents (isoproterenol, epinephrine) and to suggest reasonable explanations for the anomalies. Administration of caffeine or theophylline alone (2.5–5.0 mg/egg) retarded growth in a dose‐dependent fashion. Doses of 5.0 mg caffeine and theophylline produced beak malformations in 4.9% and 57.1% of embryos, respectively. Limb malformations, seen in low frequency (3.6% in 56 embryos) after administration of 1 μg isoproterenol, were not seen in 224 methylxanthine‐treated embryos. Structural defects following coadministration of methylxanthines and β‐adrenomimetics were frequently observed in limbs (primarily lower limbs with predilection for left‐sided oligodactyly) and beak. Other findings included limb hematomas, hygromas in the nuchal region, and prominent generalized edema. The most dramatic effects observed in this study were those induced by concomitant administration of 2.5 mg caffeine and 1 μg isoproterenol. This combination produced at least one of the embryopathies listed above in 87.9% of treated embryos and frequently induced beak (24.2%) and lower limb defects (75.8%) in addition to nuchal hygromas (9.1%). Similar severe malformations were observed following administration of 3.8 mg theophylline with 1 μg epinephrine. Embryos that died within 12–48 hours following drug insult demonstrated marked cardiac dilation, apparently due to congestive heart failure. The results of this study suggest that methylxanthines and β‐adrenomimetic agents are synertistic in their action in the developing chick. Doses of β‐adrenomimetic agents that were used in this study were not synergistic with methylxanthines. Increased intracellular cyclic adenosine monophosphate (AMP) is offered as an explanation for digital anomalies due to inhibition of proximodistal development of limbs. Increased intracellular cyclic AMP may also explain limb hypoplasia and loss of intermediate limb structures as a result of inhibited mitosis and/or necrosis of embryonic tissue.
A critical review of the McCredie‐McBride hypothesis of neural crest influence on limb morphogenesis
Authors: Stephens Trent D. , Strecker Teresa R.
Published: June 2005

A number of hypotheses have been presented to explain the mechanism of action of thalidomide. The most widely published and apparently widely accepted hypothesis is that of embryonic neuropathy advanced by McCredie and McBride. This paper reviews the points of the hypothesis and analyzes it in light of known limb embryology supported with recent experimental evidence which directly tests the hypothesis. The hypothesis may be considered as being composed of two separate parts. The first part proposes that thalidomide‐induced limb defects exhibit a segmental pattern. The second proposes that the segmental pattern of limb defects is a result of segmental peripheral neuropathy. We are in complete agreement with the first portion of the hypothesis, but find the second portion quite unlikely.
Craniofacial malformation in Xenopus laevis tadpoles caused by the exposure of early embryos to ethanol
Authors: Nakatsuji Norio
Published: June 2005

The principal features of fetal alcohol syndrome (FAS) include microcephaly, reduced body size, and characteristic facial malformation, most of which are associated with hypoplasticity of structures around the mouth. A recent study using pregnant mice suggested that the malformations in FAS are caused by the effects of ethanol on early embryos during gastrulation and neurulation. Exposure of Xenopus laevis early embryos to 1–2% ethanol until they developed to the late neurula stage produced craniofacial malformations in tadpoles which have many similarities with the described features of FAS. They include reduced length of brain, reduced body size, and hypoplasticity of the anterior end of the body around the mouth. Size reduction from the control group was about 20% in the mouth region, and 10% in other head regions. Ethanol inhibited migration of mesodermal cells toward the animal pole during gastrulation, thus inducing a smaller neural plate with reduced anterior—posterior length. These very early effects of ethanol in development seem to produce various craniofacial malformations in tadpoles, and possibly also in human infants with FAS. In contrast to mammalian embryos, one can conveniently study in detail the effects of ethanol on morphogenetic movements in various in vitro experiments by using a large number of amphibian embryos. Thus, amphibian embryos represent a valuable animal model for the study of mechanisms of the teratogenic effects of ethanol.