bluuebunny/crossref_metadata_2025 huggingface dataset:
Interference of lead with implantation in the mouse: Effect of exogenous oestradiol and progesterone
Authors: Wide Mariann
Published: June 2005

The implantation inhibiting effect of an intravenous injection of 75 ppm of lead chloride, giving blood levels of about 32 μmol/l, could be counteracted by exogenous steroid hormones. Subcutaneous injections of 0.1 μg of oestradiol‐17β and 1 mg of progesterone were given together with the lead on day 4 of pregnancy, and the same hormone doses were given also on day 5. The frequency of animals having implantations on day 6 of pregnancy in this group was the same as in the control group (75%), whereas in animals given lead and no hormones, the frequency of pregnancies was only 20%. Morphological examination by light microscopy of implantation sites on day 6 of pregnancy in the lead + hormone‐treated group showed that the decidual swellings contained implanted embryos of a normal appearance. Serum levels of oestradiol‐17β and progesterone in nontreated and lead‐treated mice were not significantly different between the two groups on day 5 of pregnancy. It is suggested that the implantation failure may be due to an effect of lead on uterine responsiveness to ovarian steroids.
Retinoic acid‐induced heart malformations in the hamster
Authors: Taylor I. M. , Wiley M. J. , Agur A.
Published: June 2005

In order to determine the effect of retinoic acid on the developing mammalian heart, pregnant golden Syrian hamsters were given single doses of 80 mg/kg of the teratogen by gavage, at various times in gestation. Examination of the surface features of hearts from near‐term fetuses was followed by microdissection to reveal internal cardiac structures. This has proven to give more reliable results than other methods of determining congenital heart malformation. The results of the study demonstrate that retinoic acid is a potent cardiac teratogen capable of inducing high frequencies of heart abnormalities in a reproducible fashion. The highest rates of malformation resulted from maternal treatment on day 7 (69%), 8 (74%), and 9 (30%) of gestation. Ventriculo‐bulbar malformations including double outlet right ventricle, complete transposition, and an overriding aorta complex were the most commonly seen abnormalities. The findings support the hypothesis that these abnormalities are not entirely discrete entities but are instead part of a single spectrum of malformation.
The formation of caudal hematomas in trypan blue‐treated chick embryos as a function of morphological stage at treatment
Authors: Rajala G. M. , Kaplan S.
Published: June 2005

A number of investigations related to trypan blue‐induced hematomas in chick embryos employed variations in the amount of dye injected, route of administration, and length of incubation time before treatment. the present study was done to standardize and further define the teratogenic system to facilitate the design and interpretation of subsequent physiological experiments with trypan blue‐treated embryos.

Embryos at Hamburger‐Hamilton stages 11–15 were treated with 20 μl of 1% (w/v) trypan blue solution dissolved in 0.85% NaCl, and were observed at 12 and 24 hours after treatment for evidence of caudal hematomas and death. In this way the population of treated embryos was assessed in terms of malformation and death frequency according to the developmental stage at treatment.

The highest incidence of hematomas was found 24 hours after treating embryos at stage 13 (59%), and the highest incidence of death was found 24 hours after treating embryos at stage 11 (75%). These data indicate that stages 13 and 11 exhibit the maximum response to dye treatment in terms of hematoma formation and death. No significant differences (P >0.05) were found between stages 13 and 14 for hematoma or death frequency at 12 or 24 hours after treatment. We suggest that the optimum procedure for subsequent experiments with this teratogenic system would consist of choosing stage 13 and 14 embryos for trypan blue treatment.
Ectodermal and mesodermal cell death patterns in 6‐mercaptopurine riboside‐induced digital deformities
Authors: Scott W. J. , Ritter E. J. , Wilson J. G.
Published: June 2005

Intravenous injection of 5–20 mg/kg of 6‐mercaptopurine riboside on the 11th day of rat gestation resulted in a high percentage of preaxial polydactyly of the hindlimb. The pathogenesis of this deformity was similar to that of other polydactyly‐inducing drugs such as cytosine arabinoside and 5‐fluorodeoxyuridine. Following drug induced cell death in the limb bud mesoderm, the normal pattern of physiological necrosis in the apical ectodermal ridge was disrupted. Subsequently, a zone of physiological necrosis within the preaxial mesoderm thought to be instrumental in controlling preaxial digitation was abolished. A speculative causal connection between these events is discussed.
Protection against cadmium‐induced limb malformations by pretreatment with cadmium or mercury
Authors: Layton W. M. , Ferm Vergil H.
Published: June 2005

Administration of 12 μmol/kg of cadmium sulfate ip to C57BL/6J mice within 3 weeks prior to pregnancy significantly reduced the incidence of limb malformations induced by 6 μrnol/kg of cadmium sulfate given ip on day 9 of pregnancy. In another experiment it was shown that administration of 6 μmol/kg or 12 μmol/kg of mercuric acetate on day 6 of gestation significantly reduced the incidence of limb malformations induced by 6 μmol/kg of cadmium given on day 9. It is postulated that this protective effect is due to the induction of increased maternal synthesis of a metal binding protein, probably metallothionein. This effect may be important in the design and interpretation of teratogenicity tests and in the evaluation of teratogenic risks to human populations chronically exposed to metals.
Fetal toxicity of cadmium in the rat: Maternal vs fetal injections
Authors: Levin Arthur A. , Miller Richard K.
Published: June 2005

Fetal death in rats was produced by subcutaneous injections of CdC12 (40 μmoles/kg) on day 18 of pregnancy. The incidence of fetal death following these maternal injections was 74.9%, with mean (±SD) fetal cadmium burdens of 8.6 ± 4.4 nmoles. To separate maternal from fetal effects of cadmium, doses of CdCl2 up to 60 μmoles/kg fetal weight were injected directly into fetuses on day 18 of gestation. Fetal viability was then determined on gestational day 21. Following direct fetal injection, mean fetal body burdens of cadmium were 74.6 ± 34.8 nmoles, but the incidence of fetal death was only 11.5%. The high incidence of fetal death following maternal exposure to CdC12 is not solely explained by the direct effects of CdC12 on the fetus. Thus, the fetal toxicity of cadmium may be the result of some extra‐fetal mechanism such as maternal toxicity or the observed placental necrosis.
Craniosynostosis with associated cranial base anomalies: A morphologic and histologic study of affected like‐sexed twins
Authors: Woon Kok‐Chin , Kokich Vincent G. , Clarren Sterling K. , Cohen M. Michael
Published: June 2005

A set of like‐sexed male twins with the same malformation syndrome and exhibiting identical anomalous alterations of the craniofacial complex were studied in detail. The right and left coronal and left lamboidal sutures were prematurely synostosed in both specimens. The cranial base exhibited a mediolateral asymmetry, with the right half larger than the left. The occipital bone demonstrated the greatest abnormality, including bilateral clefting of the basioccipital component and alterations in the size and shape of the exoccipital bone. In lateral view, the cranial base was flattened and the ventral flexure occurred between the two components of the basioccipital. The odontoid process of the second cervical vertebra was rotated anteroinferiorly and formed part of the cranial floor. Histologically, the bilateral clefts of the basioccipital bone were united by fibrous connective tissue, and the central area of union contained chondroid‐like bone. The cartilaginous spheno‐occipital synchondrosis and the epiphyseal cartilage of the finger demonstated similar dystrophic alterations. The brain was normal but exhibited external cerebral deformation secondary to aberrant skull shape.
Asymmetry and discordance for congenital anomalies in conjoined twins: A report of six cases
Authors: Ornoy A. , Navot D. , Menashi M. , Laufer N. , Chemke J.
Published: June 2005

Six pairs of conjoined twins have been studied. The first case was a pair of 13‐week‐old omphalopagus fetuses. One was a holoacradius amorphus and the other had rachischisis and anencephaly. The second case was a pair of omphalopagus twins. One of the twins was macerated and corresponded to a developmental age of 13–14 weeks, while the other was developed to 28–30 weeks of gestation and exhibited urogenital and gastrointestinal defects not found in the smaller twin. In the third case, that of a thoracoomphalopagus, one had cleft lip and palate, pulmonic stenosis, and atresia of the ileocecal valve, while the other did not show these anomalies. In the fourth case, also omphalopagus twins, one had a lumbosacral meningomyelocele and severe gastrointestinal and urogenital anomalies not found in the second twin. The fifth case was a pair of thoracoomphalopagus twins, sharing a common heart with asymmetrical anomalies. The sixth case was a diprosopus anencephalic conjoined twin. The first four pairs of conjoined twins were discordant for several abnormalities in nonshared organs, in addition to having abnormalities of the conjoined organs. It seems that discordance in conjoined twins is not a rare finding. The factors that play a role in discordance of anomalies in conjoined twins are probably similar to the factors in monozygotic twins — i.e., environmental, genetic, and abnormal placental and/or fetal circulation.
Hypothesis: Overdistention of the neural tube may cause anomalies of non‐neural organs
Authors: Gardner W. James
Published: June 2005

This hypothesis is offered by a neurological surgeon interested in anomalies of the central nervous system. It is based on accumulating evidence indicating that some neural tube defects result not from failure of the tube to close but from its rupture after closure. The central nervous system, serving all organs, is the first to develop and its maldevelopment may cause damage to other emerging structures. The neural tube closes during the fourth week and is immediately distended by a proteinaceous neural tube fluid (NTF) secreted by its lining cells at a pressure four to five times that of the surrounding amniotic fluid. This NTF has been miscalled “cerebrospinal fluid.” The choroid plexus does not begin to secrete true cerebrospinal fluid (CSF) until 2 weeks later. If oversecretion of NTF should occur during this 2‐week interval, the resulting overexpansion of the neural tube may spread apart the developing somites, eventuating in a combination of anterior and posterior spina bifida that constitutes bilateral hemivertebrae. If the distending neural tube ruptures beneath intact cutaneous ectoderm, the escaping NTF will infiltrate mesoderm. The resulting dislocation of cells and their possible injury by the extraneous protein may damage the as yet unidentifiable anlagen of mesodermal organs. If neural tube overdistention splits the underlying notochord and damages primitive gut, anomalies of entodermal organs may result. The neuroenteric cyst is one such anomaly that the neurosurgeon is called upon to treat. He finds it accompanied by hemivertebrae and hydromyelia. A preliminary report on this hypothesis has been published (Gardner and Breuer, '80).
The cranial base in anencephaly and microcephaly studied histologically
Authors: Melsen Birte , Melsen Flemming
Published: June 2005

A histological microradiographical analysis was carried out on the cranial base removed at autopsy from three infants—two with microcephalia, one with anencephalia. The histological findings were compared with those from normal individuals of the same age. It was shown that a reduced size of the brain was accompanied by a change in the remodeling pattern of the internal as well as the external surface of the cranial base, leading to a flattening of the cranial base. The findings further suggest that the development of the brain influences the ossification of the chondrocranium.
Assessment of adult skeletons to detect prenatal exposure to 2,4,5‐T or Trifluralin in mice
Authors: Beck Sidney L.
Published: June 2005

A group of 88 spontaneously occurring variations of the skeleton were studied in adult CD‐1 mice which had been exposed in utero to the herbicides 2,4,5‐T or Trifluralin, administered to their dams by gavage, in an attempt to detect subtle biological effects of these compounds even in the absence of gross malformations. Sixty‐seven characters showed variation in this population. Of these, 19 were significantly different in frequency from untreated controls in mice having received a teratogenic dose of 2,4,5‐T, with an average difference of 23.7%. Seventeen of them were increased in frequency. By contrast, only three traits differed from untreated among mice receiving a no‐effect dose of 2,4,5‐T. Twelve traits differed significantly from untreated in the Trifluralin‐treated group; the average difference was 18.8%, with 10 of the traits being increased in frequency.

Two clusters of affected variants specific to the 2,4,5‐T high dose group included frontal bone variants in the skull (presence of an interfrontal bone and fusion of the frontals) and variants in the cervical vertebrae (imperfect foramina in the first and second cervicals, dyssymphysis of the second cervical, and a shift of the arch foramen from the fourth to the fifth cervical). Two other effects peculiar to the 2,4,5‐T‐treated specimens were a loss of the prominent dorsal spine of the second thoracic vertebra and a reduction in the number of caudal vertebrae. The most obvious effects specific to the Trifluralin treatment were an increase in occurence of 14 ribs, an undoubled foramen ovale, and the occurence of accessory foramina in the cervical vertebrae. A striking increase in frequency of parted frontals was seen in both 2,4,5‐T high dose and Trifluralin‐treated groups.

The skeletal variant assay system may be useful as a postnatal screen for detecting prenatal exposure to potentially noxious substances.
Anatomy and embryology in cephalothoracopagus twins
Authors: Herring Susan W. , Rowlatt Ursula F.
Published: June 2005

Anatomical features are described in a case of cephalothoracopagus female twins with laterally fused heads. There was a single foregut, shared equally by the two individuals. The tracheae, lungs, hearts, livers, and gallbladders were also shared by the two individuals. They were located in the anterior and posterior regions of the joined bodies. These peculiarities occur in other cases of Cephalothoracopagus twinning reported in the literature, and may have been caused by spatial problems in the developing twin embryos. In particular, each heart is considered to be a composite organ, formed by tissue from both individuals. The occipital region of the skull was double, but the remainder of the cranium was single. The oral cavity was divided in two by a midline mandibular body thought to represent the fused medial portions of two mandibles. Each compartment so formed contained a tongue. This midline body is considered responsible for a cleft lip and palate. Finally, we propose that anencephaly in this and other cases of laterally fused heads is associated with mechanical difficulty in closing the rostral neuropore.
The facial features of holoprosencephaly in anencephalic human specimens. I. Historical review and associated malformations
Authors: Lemire Ronald J. , Cohen M. Michael , Beckwith J. Bruce , Kokich Vincent G. , Siebert Joseph R.
Published: June 2005

At least 19 human anencephalic specimens have been published which have the facial features of holoprosencephaly. All categories of holoprosencephaly are represented except ethmocephaly, the rarest form. Because of current scientific and clinical interest in both neural tube defects and holoprosencephaly it seems important to establish whether or not this association occurs by chance alone. The study of human embryos with holoprosencephaly by Matsunaga and Shiota ('78) and the anencephalic collection of Lemire et al ('78) suggests the association may be real.
Fetal ear malformations induced by maternal ingestion of thalidomide in the bonnet Monkey (Macaca radiata)
Authors: Newman L. M. , Hendrickx A. G.
Published: June 2005

Gross malformations of the external, middle, and internal ear were seen in fetal monkeys following maternal ingestion of thalidomide. Twenty‐five pregnant bonnet monkeys (Macaca radiata) were each given a single oral dose of 10 mg/kg of thalidomide on day 24, 25, 26, 27, 28, or 29, or 30 mg/kg on day 25 or 28 of gestation. (Day of mating is assumed to be day zero of pregnancy.) The skeletons, processed and stained with Alizarin Red S, were examined for changes in configuration and/or ossification of the ossicles and temporal bones. Bilateral temporal bones of one case, treated on day 24, were sectioned at 10 μm and examined histologically. Twelve fetuses collected at 70 ± 3 days of gestation showed no gross ear defects, while 10 out of 13 fetuses collected at 100 ± 3 days of gestation had structural anomalies similar to those observed in humans. All malformations were severe in fetuses treated on day 24 of gestation and lessened in degree of severity with treatments on days 25–28. Fetuses treated on day 29 were normal. External ear anomalies included microtia with meatal atresia or stenosis, and varying degrees of auricular hypoplasia. Defects of the middle ear were predominantly hypoplasia of malleus, incus, and tympanic ring. Fused ossicles and cochlear and vestibular window abnormalities were only seen in animals treated on day 24. The internal ear exhibited petrosal hypoplasia and delayed ossification of the lateral aspect of the lateral and posterior semicircular canals. Cochlear, vestibular, semicircular, and transcapsular canal defects were confirmed histologically in one case.
Polydactyly and polysyndactyly induced by prenatal exposure to ethanol
Authors: West James R. , Black Asa C. , Reimann Paul C. , Alkana Ronald L.
Published: June 2005

Polydactyly and polysyndactyly of the great toes of the hindpaws and polysyndactyly of the forepaws were observed in rats born to mothers who received ethanol (5 gm/kg body weight) daily during gestation. This is the first observation of polydactyly in rats as a consequence to exposure to ethanol in utero. These observations may be related to the occurrence of polydactyly and polysyndactyly in the fetal alcohol syndrome, which occurs in children born to human mothers who abuse alcohol during pregnancy.
Immunological effects of antitestis antisera on the development of mouse fetuses
Authors: Yamamoto Masaharu , Takayama Yoh‐Ichi , Watanabe Masatomo , Ito Seiki , Watanabe Gen‐Ichi
Published: June 2005

Antimouse testis antisera (AMTAS) were prepared in rabbits by the injection of testis extracts of the adult mice. Administration of 35.6 mg of AMTAS into pregnant mice on day 12.5 of gestation resulted in 27.3% fetal malformations, while administration of 17.8 mg of the same antisera induced 6.0% malformations. Malformations such as limb anomalies, cleft palate, omphalocele, and spina bifida were often accompanied by hemorrhagic lesions. No malformations associated with hemorrhage were found in the control group in spite of the occurrence of hematomas. The immunofluorescent analysis revealed the localization of antitestis antibody (ATAb) in the basement membrane of the testis, in the spermatozoa, the mesometrial vessels, trophectroderm, and the Reichert's membrane. In contrast, there was no localization of IgG when normal rabbit sera were used. The results suggest that the antibody against the basement membrane or against the spermatozoa may be responsible for the occurrence of congenital malformations in the pregnant mice injected with rabbit AMTAS.
An exploration of the role of hydroxyurea injection time in fetal growth and teratogenesis in rats
Authors: Barr Mason , Beaudoin Allan R.
Published: June 2005

Pregnant Wistar rats were injected with hydroxyurea (HU) intraperitoneally (IP) at one of several 6‐hour intervals on days 9–10.75 to study the role of circadian growth variations in the teratologic response of the fetuses. Two stocks of rats were studied and the results in each compared. The fetal response to HU, as observed at day 21, was not detectably modified by circadian fetal growth variation. No correlations between hour of HU administration and fetal weight, placental weight, resorption, or total malformation rates were found. Cyclic variations in the incidence of hydronephrosis and left umbilical artery was observed, but it was not clear that these were related to maternal light:dark cycles. Differences of response between two stocks of rats included marked variation in the incidence and type of malformations and variations in the tuning of peak incidence for some but not all malformations.
Embryotoxic effects of magnesium deficiency and stress on rats and mice
Authors: Günther T. , Ising H. , Mohr‐Nawroth F. , Chahoud I. , Merker H‐J.
Published: June 2005

Pregnant rats and mice received a magnesium (Mg)‐deficient diet with different Mg contents from 40 to 360 ppm. The controls received 2,000 ppm. At the end of gestation, the Mg concentration in the maternal serum was found to have decreased by up to 0.3 mmole/liter, depending on the Mg content of the food. Mg‐dose‐dependent embryotoxic effects (resorptions, retardation, disturbed bone development, and skeletal malformations) were observed only below a threshold value of 0.7 mmole/liter of the maternal serum Mg concentration. Noise stress in rats, in addition to a mild Mg deficiency (360 ppm Mg), which by itself had no effects, increased the rate of resorptions only.
Differences in the toxicity and teratogenicity of cytochalasins D and E in various mouse strains
Authors: Austin W. Lena , Wind Marilyn , Brown Kenneth S.
Published: June 2005

Adult toxicity, embryo lethality, and teratogenicity of cytochalasins D and E (CD and CE) were determined for A/J, C57BL/6J, aeae, and OELN mouse strains. The adult LD50 for CD (1.9–2.6 mg/kg) and CE (3.1–3.3) were similar for the strains. Although adult LD50s were similar, the embryo lethality and teratogenicity of CD and CE vary from strain to strain when all were treated with intraperitoneal injections on days 7–9 of gestation. CD was more teratogenic than CE and frequently produced exencephaly while CE did not. CD was more teratogenic in OELN and aeae (ED50 ± 0.7 mg/kg) than in A/J or C57BL/6J (ED50 > 1.2 mg/kg). OELN fetuses were more resistant to lethal effects of CD than the other strains which had fetal LD50s ± 1.2 mg/kg maternal weight. The F1 fetuses of a cross of sensitive aeae and resistant C57BL/6J showed intermediate sensitivity to exencephaly. The results suggest a genetic contribution to the response and differences in action of CD and CE as teratogens.
Teratogenic effects of cyproterone acetate and medroyprogesterone treatment during the pre‐ and postimplantation period of mouse embryos. I
Authors: Eibs H. G. , Spielmann H. , Hägele M.
Published: June 2005

Pregnant mice were treated with a single subcutaneous injection of either cyproterone acetate (CA) or medroxyprogesterone acetate (MPA). In the first experiment the animals received 5–900 mg/kg of the hormone before implantation (day 2 of pregnancy). CA treatment on day 2 caused a dose‐dependent decrease in fetal weight and a significant dose‐dependent increase in the rates of cleft palate and urinary tract abnormalities. Exencephaly and heart abnormalities were also significantly more frequent, but this increase was not dose‐dependent. MPA treatment on day 2 was followed by sporadic increases in dead and resorbed fetuses, a decrease in fetal weight and an increase in the rates of cleft palate and malformed or abnormally developed fetuses. None of these effects, however, was dose‐dependent.

In the second experiment the mice were given one single injection (30 mg/kg) of CA or MPA on any one of days 1–12 of gestation. Treatment with CA on one day between days 1 and 12 revealed that the specific sensitivity for abnormalities of the urinary tract was on days 5 and 6, for the respiratory tract on days 8 and 9, and for cleft palate on days 10 and 11. Treatment with MPA on one day between days 1 and 12 only revealed a high rate of respiratory and urinary tract abnormalities on day 9. After treatment with MPA cleft palate was again significantly more frequent in all treated groups, however, days of peak sensitivity were not detected.

The long half‐life of CA (60 hours) explains the teratogenic effect of high doses of this progestin after treatment on day 2 and also the pattern of abnormal development found after treatment with a single dose of CA on one of the days between day 1 and day 12.
Biography of Josef Warkany
Authors: Brent Robert L.
Published: June 2005

Josef Warkany was born in Vienna, Austria, March 25, 1902. He received his formal education in Vienna, graduating from the medical school of the University of Vienna in January 1926, with the MD degree. He interned at the University Pediatric Clinic from 1926 to 1927. At that time, Professor Pirquet was the director of the program. From 1927 to 1931, he was Assistant Reichsanstalt for Mothers and Children in Vienna. He came to this country in 1931 to the city of Cincinnati as an appointee at the new Children's Hospital Research Foundation. He has remained at that institution to this day. In 1937 he married his present wife Suzanne, who has been an important part of his professional and personal life. They have two children, Joseph Henry and Stephen Ford.
Syndromes with cephaloceles
Authors: Cohen M. Michael , Lemire Ronald J.
Published: June 2005

Encephaloceles may occur as isolated malformations or together with other anomalies making up various syndromes or associations. With the possible exception of the aberrant tissue band syndrome and the Meckel syndrome, little attention has been paid to syndromes with encephaloceles as a group. This paper discusses syndromes of known genesis, including the aberrant tissue band syndrome, Chemke syndrome, cryptophthalmos syndrome, dyssegmental dwarfism, frontonasal dysplasia, Knobloch syndrome, Meckel syndrome, pseudo‐Meckel syndrome, von Voss syndrome, and warfarin syndrome. Associations include a wide range of anomalies that may occur with encephalocele. Some abnormalities are secondary to encephalocele formation; others represent primary noncontiguous embryonic malformations. Associated anomalies include absent corpus callosum, orofacial clefting, craniostenosis, Dandy‐Walker defect, Arnold‐Chiari defect, ectrodactyly, hemifacial microsomia, hypothalamic‐pituitary dysfunction, Klippel‐Feil anomaly, iniencephaly, and myelomeningocele. Finally, several other conditions with encephalocele are discussed. Some may represent true low‐frequency associations; others are spurious.
Concepts of multiple congenital contractures (arthrogryposis) in man and animals
Authors: Swinyard Chester A.
Published: June 2005

This is a concept of multiple congenital contractures, based upon clinical experience with the malformation and available literature, leading to a conception of the multiple categories of etiology, which cause neuropathic or myopathic muscle weakness or limb immobilization. The muscle weakness and imbalance of muscle power around the joints elicits a physiological compensatory collagenic response, which replaces atrophied muscle fibers with connective tissue and thickens the joint capsule sufficienty to result in prenatal fixation of limb segments at the joint.
A study of alcohol effects on the brain during gestation and lactation
Authors: Borges Salvador , Lewis Paul D.
Published: June 2005

Pregnant Wistar rats were maintained on a diet of food pellets and a 10% (v/v) solution of ethanol in water during pregnancy and up to 21 days postpartum. Control groups were given food pellets and water ad libitum. The consumption of food and liquid was monitored throughout this period, so that daily food‐ and ethanol‐derived caloric intake, daily liquid intake, and dose of alcohol ingested could be determined. The body weights and whole brain weights of ethanol‐exposed offspring did not differ significantly from controls at any time from birth up to 21 days postpartum. However, cerebellar weights were significantly reduced in 21‐day‐old ethanol‐exposed offspring. Areal analysis of the cerebellar vermis showed a 9% reduction in 21‐day‐old ethanol‐exposed offspring compared with controls. Although there were no differences in total vermal area between control and treated rats at 12 days, ethanol‐exposed offspring had a significantly more extensive external granular layer. In midgestation, pregnant females registered peak alcohol levels of 118 mg/100 ml blood 1 hr prior to the end of the dark cycle, while during lactation peak levels of 135 mg/100 ml blood were obtained. Neonate alcohol levels peaked slightly later and reached much lower values (44 mg/100 ml blood) during the lactation period. Ingested alcohol intake and blood alcohol levels fall within the range associated in man with the fetal alcohol syndrome, and it is suggested that the experimental regime described is a useful method for invest gating the effects of alcohol on the developing nervous system.
Malformations in infants of diabetic mothers
Authors: Mills James L.
Published: June 2005

Maternal insulin‐dependent diabetes has long been associated with congenital malformations. As other causes of mortality and morbidity have been eliminated or reduced, malformations have become increasingly prominent. Although there is not universal agreement, the great majority of investigators find a two‐ to threefold increase in malformations in infants of insulin‐dependent diabetic mothers. This increase is not seen in infants of gestational diabetics. It probably is not present in women whose diabetes can be controlled by diet or oral hypoglycemic agents. The risk does not appear to be primarily genetic since diabetic fathers do not have an increased number of malformed offspring. Most studies show a generalized increase in malformations involving multiple organ systems. Multiple malformations seem to be more common in diabetic than non‐diabetic infants. Caudal regression has the strongest association with diabetes, occurring roughly 200 times more frequently in infants of diabetic mothers than in other infants. The teratogenic mechanism in diabetes is not known. Hyperglycemia may be important but human studies focusing on the period of organogenesis are lacking. Hypoglycemia has also been suggested based mainly on animal experiments. Insulin appears unlikely. Numerous other factors including vascular disease, hypoxia, ketone and amino acid abnormalities, glycosylation of proteins, or hormone imbalances could be teratogenic. None has been studied in sufficient detail to make a judgment. A large‐scale prospective study is required to determine early fetal loss rates, correlate metabolic status during organogenesis with outcome, and assess the effect of diabetic control on malformation rates.
Neonatal deaths and pulmonary dysplasia due to D‐penicillamine in the rat
Authors: Kilburn Kaye H. , Hess Rex A.
Published: June 2005

D‐penicillamine, added to a low copper diet fed through pregnancy or given by gavage to pregnant rats which were on a copper‐deficient or a normal diet produced fetal resorptions and malformations. Doses of 300 to 400 mg per day for 6 days (days 9–14 of gestation) with a diet normal for copper prevented maternal weight gain and at 350 or 400 mg/day caused fetal death on day 16 or 17. Forty percent of offspring had tracheobronchomegaly and 42% had cystic lungs. Associated abnormalities included pleural hemorrhages, dilated esophagi, and unaerated lungs. The lungs had large, poorly formed, thick‐walled acini without partitioning and a thick rim of connective tissue around vessels and bronchi. At the higher doses, all members of one of 12 litters had angulation of the spine and half the members of another litter had cleft palates. A postulated mechanism for these alterations in pulmonary connective tissue productive of malformations which model human tracheobronchomegaly and cystic lungs, is interference with lysyl oxidase, a copper‐requiring enzyme, which cross‐links elastin.
The effects of chlorpromazine and phenobarbital on cerebellar Purkinje cells
Authors: Hannah R. S. , Roth S. H. , Spira A. W.
Published: June 2005

The morphological effects of two chemically different neuroactive drugs (chlorpromazine and phenobarbital) on developing Purkinje cells in the rat cerebellum were examined to determine the presence of cytological alterations. Therapeutic dosages of both durgs were chronically administered to separate groups of maternal rats beginning on day 18 postcoitus. Entire litters were sacrificed on postnatal days 13, 15, 18, and 21. Light microscopic quantitation of Purkinje cells demonstrated a statistically significant reduction in total numbers below control levels at all ages examined for both drugs. Pyknotic Purkinje cells, which appeared more numerous in the drug tested groups, had a paucity of synaptic contacts on both the soma and dendritic branches. Both drugs tested produced similar results within the parameters examined. These alterations have been discussed in relation to possible mechanisms and sites of action.
Birth weight and birth defects in relation to maternal spermicide use
Authors: Polednak Anthony P. , Janerich Dwight T. , Glebatis Donna M.
Published: June 2005

The possible effects of maternal spermicide use on birth characteristics of offspring were examined in two studies. First, birth weight of offspring was examined in a cohort study of 302 women who reported using spermicides and 716 women who used no contraceptive methods in the year prior to pregnancy resulting in a 1974 live birth (without a malformation) in Upstate New York. There was no evidence that spermicide use prior to the last menstrual period (LMP) had an effect on mean birth weight or on the proportion of lower weights. Mean birth weight of female births was significantly lower in post‐LMP spermicide users than in pre‐LMP‐only spermicide users and no‐contraceptive users. In multiple linear regression analyses of birth weight among births to spermicide users, including maternal smoking during pregnancy and other variables, time of discontinuation of spermicide use was an important predictor of female (but not male) birth weight. In the second (case‐control) study of 715 Upstate New York births with selected birth defects and 715 control births (matched on maternal age and race), no significantly increased relative risks were associated with maternal spermicide use prior to LMP or after LMP. Based on small numbers, relative risks for post‐LMP spermicide use were greater than 1.00 for hypospadias (8/2 or 4.00, not significant) and for limb reduction defects (6/3 or 2.00, not significant).
X‐ray induced dysplasia in the developing telencephalic choroid plexus of mice exposed in utero
Authors: Heinzmann Ulrich
Published: June 2005

Pregnant NMRI‐mice were X‐irradiated with single doses of 0.95 Gy (100 R) and 1.9 Gy (200 R) on day of gestation (dg) 12. For sampling, anesthetized animals were perfused with buffered glutaraldehyde solution or fixed by immersion in Karnovsky solution. LM, SEM, and TEM studies were carried out on brains prenatally and up to the age of 20 months to follow the radiation effects on the developing lateral choroid plexus. Radiation‐induced changes were found using all three methods and at all stages studied. The normally sickle‐shaped and stretched choroid plexus is shortened and irregular, and the dome‐shaped plexus cells are flattened. Their superficial fine structures, i.e., the microvilli and cilia, are altered. Three stages of severity can be distinguished and the internal hydromicro‐cephalus increases from stage I to III. Intercellular spaces of the treated plexus epithelium are often dilated, but the tight junctions at the ventricular surface seem to be intact. The interstitium shows large dilations in comparison with the controls. Thus, gross changes and alterations in the fine structure can be induced in the choroid plexus by doses of 0.95 Gy and 1.9 Gy, which persist throughout postnatal life.
Teratogenicity of chlorambucil in rat embryos in vitro
Authors: Mirkes Philip E. , Greenaway Jean C.
Published: June 2005

Chlorambucil, a bifunctional alkylating agent and antitumor drug, is a potent teratogen in rodents and possibly teratogenic in humans. Unlike cyclophosphamide, a related bifunctional alkylating agent, chlorambucil is a direct‐acting cytotoxic agent. However, several studies indicate that the cytotoxic potential of chlorambucil is enhanced by metabolism of the parent compound. Using day‐10 rat embryos cultured in vitro, we have demonstrated that chlorambucil is a direct acting teratogen but that its teratogenicity can be enhanced by the addition of rat liver S‐9 preparations to culture medium containing the durg. Our data also suggest that this enhancement is not related to cytochrome P‐450 monooxygenases. This conclusion is based upon three lines of evidence. First, enhancement occurs under culture conditions which lack cofactors necessary for cytochrome P‐450 monooxygenases. Second, metyrapone, a known inhibitor of cytochrome P‐450, did not abolish the enhancement. Third, induction of cytochrome P‐450 by two specific inducers of monoxygenase activity had no effect on the observed enhancement. We postulate that the observed enhancement of chlorambucil teratogenicity is related to the β‐oxidation of the butyric acid side chain of chlorambucil generating the more cytotoxic (teratogenic) metabolite, phenylacetic acid mustard. Finally, our data indicate that the teratogenic effects elicited by chlorambucil are indistinguishable from those elicited by cyclophosphamide.
Induction of prenatal toxicity in the rat by diethylstilbestrol, zeranol, 3,4,3′,4′,‐tetrachlorobiphenyl, cadmium, and lead
Authors: Wardell R. E. , Seegmiller R. E. , Bradshaw W. S.
Published: June 2005

A teratological study was conducted in pregnant Sprague–Dawley rats dosed orally with diethylstilbestrol (DES), zeranol (ZN), 3,3′,4,4′‐tetrachlorobiphenyl (4CB), cadmium, or lead on days 6–18 of gestation. Fetuses were examined on day 19 for growth retardation, resorption, gross malformations, and organ‐level anomalies. Synthesis of protein, DNA, and proteoglycan in fetal limb cartilage was also studied by measuring the incorporation of labeled precursors in vitro. DES, ZN, and 4CB produced a dose‐dependent increase in embryolethality. Treatment with DES caused an increase in cryptorchidism and edema, and reduced average fetal weight. Zeranol also decreased fetal weight, but was not teratogenic nor did it alter rates of synthesis of macromolecules in cartilage. 4CB caused severe intestinal lesions that were associated with accumulation of blood in the digestive tract and amniotic fluid. 4CB also decreased overall fetal size and total and ossified tibia lengths. Cadmium produced no malformations although incorporation of [3H]amino acids by limb cartilage was slightly increased. Lead was not teratogenic.
Ethanol teratogenicity in mice: A light microscopic study
Authors: Bannigan John , Burke Paul
Published: June 2005

The objective of this study was to see what, if any, cellular changes occurred in the mouse embryo following a single injection of ethanol, a known teratogen in humans and animals, on day 9 of gestation. No changes were seen until 6 hours after injection, when many degenerating cells and necrotic fragments were seen in the neuroepithelium of the neural groove and of the neural tube. In addition, large clear vacuoles were seen in the cytoplasm of many cells and the pseudopodia at the luminal side of the neural groove appeared swollen. The cytoplasm of the latter also contained vacuoles. When tritiated thymidine was injected 5 hours after ethanol and 1 hour before sacrifice, many degenerating cells were labelled. In addition, many cells with labelled nuclei had abnormal vacuoles in the cytoplasm. Hence, it is likely that the toxicity of ethanol is exerted primarily on some component of the cytoplasm and not on DNA synthesis. Twelve hours after ethanol, the cytoplasmic vacuoles and swollen pseudopodia had disappeared, but dying cells were still evident. By 24 hours, the necrotic debris had been completely phagocytosed by healthy neuroepithelial cells. By 50 hours, the neuroepithelium had been cleared of cell debris, although many ethanol‐treated embryos had open defects of the cranial neural tube. Treatment of pregnant mice with single doses of acetaldehyde, also an established teratogen in animals, did not produce any cellular changes. However, a single dose of acetaldehyde is rapidly metabolized by the mother, and would not be comparable to the small but continuous blood levels that a dose of ethanol would produce. Hence, we could not conclude with certainty that the cytotoxic effects of ethanol were exerted directly.
Blood flow during pregnancy in the rat: II. Dynamics of and litter variability in uterine flow
Authors: Buelke‐Sam J. , Holson J. F. , Nelson C. J.
Published: June 2005

Normal blood flow patterns were characterized in individual CD rats, nonpregnant (NP) or on day 6, 7, 8, 10, 11, 12, 13, 16, 18, or 20 of gestation using the radioactive microsphere technique. Five animals were evaluated at each stage of pregnancy. Weights and flow values were determined for several maternal organs and uterine tissue samples. Embryo/fetal (E/F) sex was determined from day 11 on by measuring the prevalence of nuclei with sex chromatin in amnion smears. There was a marked increase in absolute flow to the uterus and all uterine contents during gestation (0.28 ± 0.13 ml/min to the NP, diestrous uterus; 9.07 ± 0.97 ml/min on day 20 of pregnancy). However, relative blood flow (ml/min/g tissue) decreased by day 20 to one‐third NP values. Thus, though blood flow greatly increased, it did so at a rate lower than total tissue growth (including the uterus, placental tissues, and the E/F itself). There was a rapid redistribution of blood flow from the decidua parietalis (DEC) to the chorioallantoic placenta (CAP) on days 11–13, with nearly equal flow being delivered to the CAP and DEC of the “average” embryo on day 12 of gestation. By day 16 the DEC functionally had atrophied, and nearly 100% of the flow was delivered to the CAP. Male E/Fs tended to weigh more than female; however, these differences were statistically significant only on days 13, 18, and 20. E/F sex was not found to be strongly related to any of the variable evaluated in this study except E/F weight. Significant interlitter variability in E/F weight and blood flow consistently was observed at all gestational stages. Differences in litter size and E/F distribution within the two uterine horns did not account for the majority of this variability.
Trypan blue teratogenesis in the rat: Further observations in vitro
Authors: Gulamhusein Amir P. , Moore Weiland J. , Gupta Madhu , Beck Felix
Published: June 2005

Explanted 9½‐ and 10½‐day rat conceptuses were cultured for 24 or 48 hours and 24 hours respectively in immediately centrifuged, heat‐inactivated rat serum to which trypan blue was added at concentration of 150 μg/ml or 300 μg/ml or 450 μg/ml. The embryos were assessed for normal growth and differentiation using the following criteria: heart beat, vitelline circulation, fusion of the allantois with the chorion, normal turning, normally closed neural tube, presence of optic vesicles, presence of forelimb buds, tail, somites, somite number, yolk sac diameter, crown‐rump length, and protein content. The results indicated that trypan blue is more teratogenic when 9½‐day conceptuses are cultured for the first 24 hours, and that its teratogenicity decreases after 10½ days. Morphological abnormalities produced included neural tube defects, turning defects, and tail defects, the tail abnormalities being manifest as fluid‐filled blebs. Ten and one‐half–day conceptuses cultured for 24 hours in treated serum produced predominantly tail defects. The conceptuses were cultured at 11 days, when the embryo lies completely within the yolk sac. Culture of such conceptuses in serum containing 450 μg/ml trypan blue produced mainly tail defects. Injection of 0.5 μl of 0.5% dye solution into the yolk sac cavity also produced tail abnormalities; sham treatment, or the injection of sterile water or a nonteratogenic dye, azo blue, did not affect embryonic development.
Craniofacial, caudal, and visceral anomalies associated with mutant sirenomelic mice
Authors: Orr Beatrice Y. , Long Sally Y. , Steffek Anthony J.
Published: June 2005

Craniofacial anomalies were correlated with mutant murine sirenomelia. Ninety‐eight newborn sirens from heterozygous matings were examined and analyzed. In the 96 sirens that had intact craniofacial structures, micrognathia was seen in 39% of the sirens, microstomia in 34%, macroglossia in 26%, and cleft palate in 21%. Even when not cleft, the siren palates were narrower and more highly arched than those of nonsiren littermates. The frequency of abnormal craniofacial development was greater in those sirens that were more severely affected caudally. Even though some earlier studies had indicated a preponderance of males, 46 of the 95 sirens with intact pelvic viscera were females. Fifth‐three percent of the sirens were monopodal, 35% were apodal, and 11% were dipodal. A penile‐like projection on the genital tubercle occurred on 15 apodal sirens and four monopodal sirens; all but three of these sirens were males. Bladder agenesis was seen in 100% of the sirens, anal atresia in 80%, and bilateral renal agenesis in 43%. No siren was found with bilaterally normal kidneys. The srn gene responsible for sirenomelia might either directly affect the embryo at both the caudal and cranial regions or indirectly affect the embryo by producing lateral mechanical compression at both these sites. The srn gene was earlier characterized as autosomal‐recessive; our data confirm this. Sirenomelia was found in only 11% of the newborns from crosses of carrier mice in the colony. Analyses of uterine contents at days 12–14 suggest that the srn gene is fully penetrant, but often lethal, during the fetal period.
Prospective study of suspected associations between certain drugs administered during early pregnancy and congenital malformations
Authors: Michaelis J. , Michaelis H. , Glück E. , Koller S.
Published: June 2005

From 1964 to 1976, a cohort study was performed in West Germany to study the possible influence of various factors on pregnancy and child development. Results of the evaluation of 13,643 pregnancies are given with respect to possible teratogenetic effects of antiemetic drugs and sex hormones administered in early pregnancy. There was no evidence of an increased risk of major malformations following the intake of certain antiemetic drugs and progesterone. Also, the use of a hormonal pregnancy test was not significantly associated with an increase of major malformations.
Supradiaphragmatic accessory lobe of the liver in BB Wistar rats
Authors: Wright James R. , Sharma Hari M. , Yates Allan J. , Thompson Bruce M. , Thibert Pierre
Published: June 2005

Supradiaphragmatic accessory livers were observed in two closely related rats in a series of 172 necropsies on BB Wistar rats. The gross and histological appearance of both accessory lobes are described. This abnormality has been reported in only one other inbred strain of rats where it also arose with a very low incidence. As in the previous report, the pattern of occurrence of these accessory lobes suggests a mode of inheritance that is either polygenic or autosomal recessive with low penetrance.