bluuebunny/crossref_metadata_2025 huggingface dataset:
Congenital tibial aplasia with preaxial polydactyly: Soft tissue anatomy as a clue to teratogenesis
Authors: Hootnick David R. , Packard David S. , Levinsohn E. Mark
Published: June 2005

We performed preoperative arteriography and postamputation dissection on a human limb having complete tibial aplasia and preaxial polydactyly. The tibia was replaced by a tendinous band with an attached connective tissue mass. In the leg, the muscles were normal. Muscles usually arising from the tibia arose from the tendinous band. Intrinsic muscles of the foot were absent where skeletal elements were absent and there were supernumerary muscles where there were supernumerary skeletal elements. The tendinous insertions of the muscles that originated in the leg followed the skeletal pattern of the foot. The nerves were normally distributed with the exception that extra branches innervated the supernumerary toes. Both the anterior tibial and peroneal arteries were smaller than normal and progressively reduced in size as they coursed distally and could not be identified below the ankle. The dorsalis pedis artery was absent. The other arteries of the leg and foot were normal with the exception of extra branches supplying the supernumerary toes. The anatomy indicates that the foot is probably a double posterior duplication. Such a defect implies abnormal specification of the foot pattern due to a prespecification event. The tibial remnant with normal leg soft tissues indicates normal specification of the leg pattern and subsequent interruption of tibial morphogenesis due to a postspecification event. The presence of these different types of malformations in the same limb may seem to be contradictory. We suggest, however, that a single teratogenic event occurring at one moment in time could cause combined pre‐ and postspecification malformations. We further suggest that a diminished anterior tibial artery reduced the number of vessels available for collateral circulation and thus put the limb at risk for subsequent malformation.
Postnatal behavioral effects of ochratoxin a in offspring of treated mice
Authors: Poppe Susan M. , Stuckhardt Jeffery L. , Szczech George M.
Published: June 2005

Ochratoxin A is a toxic isocoumarin derivative produced by Aspergillus ochraceus and several Penicillium species, which are storage fungi. Many kinds of agricultural commodities can be contaminated with ochratoxin A, which has been reported in both animal and human foods. Pure crystalline ochratoxin A was dissolved in 0.1 N sodium bicarbonate solution and given intraperitoneally to pregnant ICR‐derived mice at dose levels of 1.25 and 2.25 mg/kg on gestation days 15, 16, and 17 (day 0, day of insemination). Dams were allowed to deliver, and their litters were culled to eight pups. During postnatal development, selected pups were tested for surface righting (days 3–12), swimming (even days 6–20) and pivoting (days 7, 9, and 11). Statistically significant differences for all three tests indicated that a developmental delay had occurred. Brains from the tested offspring were examined by light microscopy; no treatment or dose‐related pathoanatomic alterations were found.
Asplenia syndrome in conjoined twins: A case report
Authors: Ursell Philip C. , Wigger H. Joachim
Published: June 2005

Incomplete fission of the primordial cell mass is generally believed to be the cause of conjoined twinning. It may also explain the tendency towards increased symmetry in these twins. We report a case of the rostral duplication type of conjoined twins with an absence of symmetry; one twin had the asplenia syndrome, whereas the other twin was normal. Local environmental factors acting upon the organ anlage may explain the asymmetric development in these conjoined twins.
Embryotoxicity and teratogenicity of thalidomide in rats
Authors: Parkhie Mukund , Webb Michael
Published: June 2005

The teratogenicity of thalidomide in Wistar rats was investigated after a single maternal intravenous injection during the organogenetic period. Thalidomide was administered at 45 mg/kg in 0.5 ml dimethylformamide (DMF) on day 10, 11, or 12 of the pregnancy. Thalidomide induced skeletal deformities of thoracic ribs and of the spinal column in 33 and 56 percent of the fetuses upon maternal administration of the drug on day 11 or 12, respectively. As compared to the solvent (DMF) control, thalidomide caused two‐ to three‐fold higher skeletally malformed fetuses. Deformities of the eyeball in fetuses (ophthalmorrhexis and microphthalmia) were induced by the maternal administration of the drug on day 10 and 12. The solvent (DMF) failed to induce organ deformities. Thalidomide induced embryotoxicity (as measured by percent dead and resorbed fetuses), at a rate three to eight times higher than the DMF control and represented 11 to 24 percent of dead and resorbed fetuses in thalidomide treated groups as compared to three percent in the DMF control group. Mean fetal weight was significantly reduced after maternal administration of thalidomide on day 11 of pregnancy, as compared to the DMF control. These studies conclude that thalidomide is teratogenic and embryotoxic in rats, when administered intravenously at 45 mg/kg bw.
Morphogenesis of median facial clefts in mice treated with diazo‐oxo‐norleucine (DON)
Authors: Burk Dorothy , Sadler T. W.
Published: June 2005

The morphogenesis of median facial clefts induced in mice by treatment with diazo‐oxo‐norleucine (DON) was studied. Following maternal treatment with 0.4 mg/kg DON on the 11th gestational day, 23.1% of fetuses recovered at the 18th day exhibited median facial clefts, which were characterized by a separation in the midline of normal midfacial components, i.e., the premaxilla, nasal bones, and nasal capsule. Malformed embryos could first be identified grossly 24 hr after DON administration by the presence of an abnormally wide separation between the two narrowed medial nasal processes. Evidence of cellular degeneration was observed in the mesenchyme of the nasal processes of DON‐treated embryos 8 and 12 hr after treatment, but little or no pyknotic debris remained at 24 hr post‐injection. Loss of cells due to cell death was reflected in decreased cell density observed in all areas of facial mesenchyme examined 24 hr after DON administration. It is suggested that DON‐induced median facial clefts may be caused by a reduction in tissue volume, particularly in the midline, or by an interference with normal facial growth resulting in increased facial width and consequent failure of merging of the medial nasal processes.
Developmentally arrested oviduct: A structural and functional defect in mice following prenatal exposure to diethylstilbestrol
Authors: Newbold Retha R. , Tyrey Scott , Haney A. F. , McLachlan John A.
Published: June 2005

To determine the effects of exposure to diethylstilbestrol (DES) on the developing oviduct, timed pregnant CD‐1 mice were treated with DES (10–100 μg/kg subcutaneous) on days 9–16 of gestation. Prenatal DES‐exposed and age‐matched control mice were sacrificed from day 16 of gestation to 15 weeks of age and oviductal development was compared. Following prenatal exposure to DES (100 μg/kg), the oviduct at all ages examined was uncoiled and shorter, closely adherent to and wrapped around the ovary in an anatomical configuration similar to the fetal mouse. In addition, the demarcation between the oviduct and uterus was not readily apparent. Histological changes in the DES (100 μg/kg) oviduct as compared with control at 10–15 weeks of age included a proliferation of columnar epithelium lining the lumen with gland formation extending into the underlying stroma, absence of or a reduced amount of fimbrial tissue, increased thickness of the muscular wall, and inflammatory cell infiltration. Also, as a functional test of uterotubal junction integrity, Coomassie Blue dye was injected into the uterus. The control uterotubal junction confined the fluid to the uterus. In 80% and 100% of the animals exposed prenatally to DES (10 and 100 μg/kg, respectively), independent of the extent of the gross abnormality, the dye readily flowed into the oviduct and filled the ovarian bursa. We conclude that prenatal DES exposure can alter fetal development of the mouse oviduct, resulting in an apparent developmental arrest and functional disruption of the integrity of the uterotubal junction. The fetal like configuration of the ovary, oviduct, and uterus suggests the term developmentally arrested oviduct (DAO).
Comparative teratogenicity of phenytoin among several inbred strains of mice
Authors: Hansen D. K. , Hodes M. E.
Published: June 2005

Inbred strains of mice differ in their response to the embryopathic effects of phenytoin (PHT). A/J animals, the most susceptible strain, were mated to C57BL/6J mice, the most resistant strain. The susceptibility of the F1 hybrid offspring was determined by the susceptibility of the mother. B6AF1 animals were as resistant as C57BL/6J parental mice, and AB6F1 hybrids were as susceptible as A/J mice. This was especially evident when orofacial anomalies were tallied. (B6A)F2 hybrid offspring were as resistant as their C57BL/6J grandparents.
Evaluation of the teratogenic potential of Delalutin (17α‐hydroxyprogesterone caproate) in mice
Authors: Seegmiller Robert E. , Nelson Guy W. , Johnson Carl K.
Published: June 2005

Swiss Webster female mice weighing 25–30 gm were injected subcutaneously on days 6–15 of gestation with the synthetic sex steroid Delalutin (17α‐hydroxyprogesterone caproate). Treatment was given daily in doses ranging from 42 to 833 mg/kg body weight, or 10, 100, and 200 times the human therapeutic dose. On day 18 fetuses were removed from the uterus and examined for malformations and other fetotoxic effects. Prenatal treatment with the two higher doses resulted in 8 and 13% maternal deaths, and all doses resulted in a slight increase (4–12% above control) in resorption frequency. Treatment with Delalutin did not significantly affect intrauterine growth, sex ratio, or malformation rate of the offspring. The results of the present study confirm other reports that Delalutin is not androgenic, and that it, like progesterone and certain other sex steroids, does not alter the development of nonreproductive organs.
Potentiating effects of methylxanthines on teratogenicity of mitomycin C in mice
Authors: Nakatsuka Toshio , Hanada Satoshi , Fujii Takaaki
Published: June 2005

A previous study demonstrated that caffeine strongly potentiated the teratogenic action of mitomycin C in mice. In the present study the effect of methylxanthines including caffeine, theophylline, theobromine (theobromine sodium salicylate), paraxanthine, and 1‐methylxanthine was compared in order to analyze the structure‐activity relationship. Jcl:ICR mice were injected IP with 3 mg/kg of mitomycin C, immediately followed by SC injection of each methylxanthine on day 11 of gestation. The doses of methylxanthines were calculated so that the mice received 50 mg/kg of caffeine or the equimolecular amount of the other methylxanthines. Fetuses were examined for external malformations on day 18 of gestation.

Mitomycin C at 3 mg/kg and the methylxanthines at the doses used were not teratogenic. Combined administration of caffeine or theophylline with mitomycin C produced more than 80% of malformed fetuses. Although less effective than caffeine or theophylline, paraxanthine also significantly increased the incidence of malformed fetuses. Theobromine and 1‐methylxanthine were virtually ineffective. From these findings, it is suggested that the methyl group at N‐1 position of the xanthines is important for the enhancement but the N‐1 methylation alone is ineffective unless accompanied with the substitution of the methyl moiety at the other position(s).
Maternal phenytoin administration affects DNA and protein synthesis in embryonic primary palates
Authors: Hicks Heraline E. , Johnston Malcolm C. , Banes Albert J.
Published: June 2005

Recent studies have shown that phenytoin (Dilantin®) administration to pregnant A/J mice on day 10 causes reduced growth in embryonic primary palates. The current investigation concentrates on biochemical and autoradiographic changes toward the end of primary palate formation (gestational day 11), which coincides with the developmental period used for the previously conducted morphological studies. On gestational day 10, one group of pregnant A/J mice was injected intraperitoneally (IP) with 60 mg/kg phenytoin and the other group with vehicle. Twenty‐three hours after phenytoin administration, all animals were injected (IP) with either [3H]‐thymidine or [3H]‐leucine. After one hour of incorporation, animals were sacrificed, embryos removed and placed in ice‐cold Eagle's minimum essential medium containing 0.02% NaN3 for biochemical assay or fixed immediately in Bouin's solution for autoradiography. For biochemical analyses, palates and limb buds were removed, homogenized, TCA precipitated, lyophilized, and acid hydrolyzed. Examination of the data revealed that DNA synthesis in control palates was 3.8‐fold greater than in primary palates from embryos of phenytoin‐treated mothers. Results were similar for limb buds from control embryos and from embryos of phenytoin‐treated mothers. Experiments utilizing [3H]‐leucine indicated that protein synthesis was 2.6‐fold greater in primary palates from phenytointreated mothers than in control primary palates. Similar results were obtained for protein synthesis in limb‐bud tissue from controls and embryos of phenytoin‐treated mothers. Autoradiographic data supported the biochemical findings. DNA synthesis in primary palates from embryos of phenytoin‐treated mothers decreased 3‐fold; protein synthesis increased 2.2‐fold compared with control primary palates. Similar autoradiographic results were obtained from limb‐bud tissue from embryos of phenytoin‐treated mothers. The results indicate that DNA synthesis is decreased and protein synthesis is increased in embryonic primary palates from phenytoin‐treated mothers. Similar changes in DNA and protein synthesis in embryonic limb buds indicate that phenytoin alterations are not limited to primary palates.
Effect of 2,450 MHz microwave radiation on the development of the rat brain
Authors: Inouye Minoru , Galvin Michael J. , McRee Donald I.
Published: June 2005

Male Sprague‐Dawley rats were exposed to 2,450 MHz microwave radiation at an incident power density of 10 mW/cm2 daily for 3 hours from day 4 of pregnancy (in utero exposure) through day 40 postpartum, except for 2 days at the perinatal period. The animals were killed, and the brains removed, weighed, measured, and histologically examined at 15, 20, 30, and 40 days of age. The histologic parameters examined included the cortical architecture of the cerebral cortex, the decline of the germinal layer along the lateral ventricles, the myelination of the corpus callosum, and the decline of the external germinal layer of the cerebellar cortex. In 40‐day‐old rats, quantitative measurements of neurons were also made. The spine density of the pyramidal cells in layer III of the somatosensory cortex, and the density of basal dendritic trees of the pyramidal cells in layer V were measured in Golgi‐Cox impregnated specimens. In addition, the density of Purkinje cells and the extent of the Purkinje cell layer in each lobule were measured in midsagittal sections of the cerebellum stained with thionin. There were no remarkable differences between microwave‐exposed and control (sham‐irradiated) groups for any of the histologic or quantitative parameters examined; however, the findings provide important information on quantitative measurments of the brain. The data from this study failed to demonstrate that there is a significant effect on rat brain development due to microwave exposure (10 mW/cm2) during the embryonic, fetal, and postnatal periods.
Caffeine‐induced limb malformations: Description of malformations and quantitation of placental transfer
Authors: Scott William J.
Published: June 2005

Caffeine was administered intraperitoneally to CD‐1 mice on days 11 and 12 of pregnancy at doses of 80–250 mg/kg. A dose‐related pattern of malformations was seen that included mainly cleft palate, limb malformations, and hematomas. Many of the limb malformations were examined in preparations stained for cartilage and bone and a number of unique structural arrangements were found. As in previous studies, an asymmetric response was seen, the left limbs being affected more often than the right.

Transplacental passage of caffeine was also studied. Caffeine and many metabolites pass into the embryo and attain concentrations slightly below those in maternal plasma. A peak caffeine concentration of 1 mM is attained after a teratogenic dose, which is at least an order of magnitude greater than that of any of the metabolites.
Amniotic adhesion malformation syndrome: Fetal and placental pathology
Authors: Herva Riitta , Karkinen‐Jääskeläinen Marketta
Published: June 2005

We describe 11 severely damaged fetuses, their placentas, and defective membranes involved in the amniotic adhesion malformation syndrome. The constantly abnormal relation between the fetus and placenta, the absence of the free umbilical cord, the extremely short umbilical cord, common absence of an umbilical artery, and severe malformations in internal organs suggest that instead of a single rupture of the amnion, the early germinal disk might have been defective. We have no clue of possible cause. Heredity seems to be improbable; the most likely explanation is a teratogenic condition during early pregnancy.
A teratological evaluation and analysis of fetal tissue levels following administration of tetrachlorobenzene isomers to the rat
Authors: Kacew S. , Ruddick J. A. , Parulekar M. , Valli V. E. , Chu I. , Villeneuve D. C.
Published: June 2005

Three tetrachlorobenzene (TCB) congeners (1,2,3,4‐, 1,2,3,5‐, and 1,2,4,5‐) were administered daily by gavage to pregnant Sprague‐Dawley rats at levels of 50, 100, or 200 mg/kg from day 6 through day 15 of gestation. Mothers were sacrificed on day 21 of gestation and the pups removed by cesarian section for teratological evaluation. Administration of 1,2,3,4‐ and 1,2,3,5‐TCB failed to alter maternal body weight, organ weights, hematological, or the biochemical parameters studied. The highest dose level of 1,2,4,5‐tetrachlorobenzene caused maternal death in nine of ten animals. In addition it induced mixed function oxidases and increased serum cholesterol values at 50 and 100 mg/kg. There was a decrease in the number of fetuses at the highest dose levels of 1,2,3,4‐ and 1,2,3,5‐TCB and at the lowest dose level of the 1,2,4,5‐ congener. None of the congeners produced any anomalies. There were no treatment‐related histopathological changes in either the mothers or fetuses. Residues of all three congeners were found in maternal and fetal tissues but generally the amounts of the 1,2,4,5‐ isomer were about 100 times higher than the other two.
Elevated blood pressure in the embryonic chick induced by a teratogenic dose of dextroamphetamine sulfate
Authors: Cameron Ray H. , Kolesari Gary L. , Rajala Gregory M.
Published: June 2005

Previous work has demonstrated the cardiovascular terato genicity of dextroamphetamine sulfate (0.25 mg/egg) in the 4‐day (stage 24) chick embryo. Our current studies indicate that embryos treated with this teratogenic dose of d‐amphetamine exhibit a mean ventricular blood pressure (MVBP) elevation for 1 hour at 4 hours after treatment. The mean MVBP value 4 hours after d‐amphetamine treatment significantly exceeded the mean MVBP value for combined untreated and saline controls by 30%. Furthermore, d‐amphetamine significantly decreased heart rate relative to controls by 6–9% at 2, 3, and 5 hours after administration. Elevation of embryonic blood pres sure (measured by a water manometer system) during a critical period of aortic arch and ventricular septal morphogenesis is suggested as an etiological factor in the genesis of malformations of these structures.
The anatomy of a congenitally short limb with clubfoot and ectrodactyly
Authors: Hootnick D. R. , Packard D. S. , Levinsohn E. M. , Lebowitz M. R. , Lubicky J. P.
Published: June 2005

Previous studies have shown an association between an abnormal arterial pattern and bony malformations of the human lower limb. We have dissected and performed arteriography on a congenitally short limb with ectrodactyly in order to examine the relationship between arterial pattern and bony anomalies in another type of deformity. The bony anomalies were a combination of short femur, tibia and fibula, clubfoot with tarsal synostoses, metatarsal absence, ectrodactyly, and a bifid hallux. The arterial pattern was characterized by deficiency of the anterior tibial artery and absence of the plantar arch. Major muscular anomalies were noted in the foot only; the muscles of the missing toe were absent and any muscles that normally cross the midventral line were either missing or failed to cross the midline. The superficial peroneal nerve failed to enter the dorsum of the foot and its sensory distribution was assumed by an extra branch of the sural nerve. The most severe abnormalities of the bones, muscles, arteries, and nerves occurred near the midventral line of the foot. We hypothesize that the abnormal arterial pattern put the limb at risk of teratogenic damage by reducing the number of collateral blood supply routes. We suggest that some event, such as extravasation of blood or embolization, compromised the blood flow in the remaining blood vessels and that this event resulted in both a general shortening of the limb and the specific defects observed in the foot. We interpret the anatomy to be consistent with the vascular teratogenic event occurring near the midline of the foot during the fifth week of embryonic development.
Lateral cephalothoracopagus: A case report
Authors: Merwin Michael C. , Wright John
Published: June 2005

A case of lateral cephalothoracopagus with posterior auricles is presented and compared with similar cases previously reported. This case is the first, to our knowledge, which exhibits both unequivocal lateral juncture of the faces and posterior auricles. Thus, it may represent a pattern of juncture intermediate between janiceps and lateral cephalothoracopagus.
Retardation of brain growth of guinea pigs by hyperthermia: Effect of varying intervals between successive exposures
Authors: Edwards M. J. , Gray C. H. , Beatson Jenny
Published: June 2005

Guinea pigs were exposed to a temperature of 42.5–43.5°C on three occasions between days 20 and 23 of pregnancy. In the first experiment, groups of mothers were exposed at intervals of 18–30 hr. Each exposure ended when the deep rectal temperature had been over 43°C for 6 min and mean temperatures were 43.2–43.4°C. Micrencephaly was found in 78% of heated newborn offspring, the mean brain weights of all groups being significantly less than controls. In the heated groups, the brain weights were reduced significantly as the interval between exposures decreased. Abnormalities other than micrencephaly were found in 10% of heated offspring and included exomphalos, clubfoot, and hypodactyly. In the second experiment, groups of mothers were exposed for 1 hour at intervals of 6–20 hr. The mean temperatures of heated groups were 42.6–42.9°C. The mean brain weights of all groups of heated newborn were significantly reduced and micrencephaly was found in 61% of newborn. Brain weights were reduced significantly as mean maternal temperature increased. There was a significant interaction between the level of temperature elevation and the interval between exposures. Intervals of 6, 8, and 12 hr induced large deficits in brain growth even when temperature elevations were small. We hypothesize that the initial exposure might partially synchronize the brain cell generation cycle, causing abnormally large numbers of cells to be in mitosis 6–8 hr later and thus at risk to lethal damage by a second or third hyperthemic exposure.
Epidemiological study of gastroschisis and omphalocele in Spain
Authors: Martínez‐Frías M. L. , Salvador J. , Prieto L. , Zaplana J.
Published: June 2005

We report an epidemiological study of gastroschisis and omphalocele performed through the Spanish Collaborative Study of Congenital Malformations. Among 264,502 live births analyzed from April 1976 to September 1981, 12 gastroschisis and 40 omphaloceles were identified. The overall incidence of gastroschisis was 0.4 per 10,000 live births and 1.5 for omphalocele.

The incidence of gastroschisis showed a significant secular trend with a mean annual increase of 0.38 per 10,000 livebirths. The mean maternal age was 21.42, which is significantly lower than the control group (p < 0.01). Among isolated omphaloceles the maternal ages showed a U‐shape distribution. Maternal vaginal bleeding, gestational age, and birth weight were significantly different between gastroschisis and omphaloceles and the controls. Mortality within the first 3 days of life was significantly higher in gastroschisis, syndromic omphaloceles, and those associated with other malformations when compared to controls. No significant consanguinity or familial cases were observed for either gastroschisis or omphaloceles.
Hyperthermia and the induction of neural tube defects in mice
Authors: Webster William S. , Edwards Marshall J.
Published: June 2005

The aim of this study was to examine some parameters determining the teratogenicity of hyperthermia. Pregnant inbred (C57B1/6J and CBA/Ca/T6) and outbred (QS) mice were partially immersed in a water bath at 43–43.5°C until their core temperature, monitored by a rectal thermister probe, was elevated to 43°C for the inbred mice and 43.5°C for the outbred mice. The procedure was repeated 6 h later. The regimen of 2 heatings was performed over a range of development from pregastrulation to about the 24 somite stage. The mice were killed on day 19, and the fetuses were examined.

Exencephaly was the common malformation seen in each strain. It occurred at a maximum incidence of 34% in the QS mice, 14% in the CBA strain, and 20% in C57B1 mice. For the CBA and QS mice 4 to 11–15 somites was the most heat sensitive stage of development for the induction of exencephaly while in the C57B1 mice the preceding 24 hr of development were most sensitive.

Control mice were exposed to the same experimental procedure in a water bath at body temperature at the most sensitive stage of development for the strain. There were no instances of exencephaly in the controls.

The sex of all fetuses was determined and revealed a high female/male ratio among the fetuses with exencephaly (2.1 for the QS mice, 1.7 for the CBA mice, and 3.1 for the C57B1 mice) compared with a ratio of approximately 1.0 for all fetuses. Analysis in the QS mice indicated that the predominance of female exencephalics was probably due to prenatal loss of male embryos.
Enhanced visualization of soft tissues in the study of aborted fetuses through the use of xeroradiography
Authors: Graham John M. , Crow Harte C. , Rawnsley Eileen F. , Simmons G. Millard , Hoefnagel Dick
Published: June 2005

As part of the diagnostic workup following an episode of fetal loss, it is generally recommended that fetal tissue be submitted for chromosome analysis and that the fetus be photographed and radiographed. Our recent clinical experience has suggested that, in those fetuses where size is compatible, xeroradiography may be superior to standard radiography. Xeroradiography utilizes principles similar to those in film radiology, with low‐energy photon beams and relatively long exposure times. The physical characteristics of the beam and imaging system provide optimal soft tissue visualization. We have found this technique to be of use in studying a broad variety of abortuses with abnormalities. Examples of fetal abnormalies in which we have used this technique include acardia, neural tube defects, nuchal cystic hygroma, and arthrogryposis. In fetuses weighing 500–1,000 gm, the exposure settings are 25 MA, 1 second, 40 KVP. For larger fetuses the KVP should be increased by 1 or 2. This technique has not been useful for a complete body view of large fetuses due to the size limitations of the xeroradioraphic cassette itself.
Decreased placental monooxygenase activities associated with birth defects
Authors: Manchester David , Jacoby Elizabeth
Published: June 2005

We have measured monooxygenase activities in placentas from 82 women who smoked throughout their pregnancies and correlated these with the presence or absence of major somatic anomalies. Monooxygenase activities toward benzo(a)pyrene and ethoxyresorufin in placentas from 18 abnormal infants were compared with activities in placentas from 64 concurrently studied normal infants. Placentas from normal infants were found to have high levels of monooxygenase activities and low apparent Kms toward ethoxyresorufin (10−7 M), reflecting induction of cytochrome P‐450 enzymes usually associated with maternal cigarette smoking. Placentas from the abnormal infants, however, had significantly lower monooxygenase activities and higher apparent Kms toward ethoxyresorufin (10−5 M), indicating that induction of specific cytochrome P‐450 systems occured less frequently among placentas from abnormal infants. The reasons for this association are unclear. Apparent lack of induction of monooxygenase activity occurred most frequently in placentas from anencephalic infants but was neither exclusively nor consistently found with this defect. No specific maternal condition or environmental exposure associated with lack of monooxygenase induction was identified.
Glucocorticoid teratogenesis in mouse whole embryo culture
Authors: Pratt Robert M. , Perry Everett L. , Chapman Lisa M. , Goulding Eugenia H.
Published: June 2005

Glucocorticoids, such as triamcinolone acetonide (TAC‐A) and triamcinolone hexacetonide (TAC‐HA), are potent inducers of cleft palate in vivo in various mouse strains when administered on day 11 of gestation, whereas they are poor or ineffective inducers of cleft lip when given on day 7. The purpose of the present study was to determine whether glucocorticoids are capable of interfering with early embryonic development in culture. CD‐1 mouse embryos were cultured for 48 hours starting either on day 8 (plug day 0) with the embryo inside the yolk sac, or on day 10 with the embryo exteriorized from its functional yolk sac. At the end of the culture period, embryos were examined grossly for malformations and biochemically for altered DNA and protein levels. With the day 8 cultures, TAC‐A produced a dose‐dependent inhibition of growth along with malformations consisting of cardiac irregularities, abnormal rotation, and irregular neural tube closure. With the day 10 cultures, these malformations were not observed, presumably due to the advanced stage of development when the embryos were exposed to TAC‐A; however, TAC‐A did produce growth inhibition along with cleft lip. When TAC‐HA was administered in vivo to pregnant donor females on day 7, in combination with TAC‐A added on day 10 to the culture medium, there was a dramatic increase in the frequency of cleft lip along with other alterations in craniofacial appearance. Our results demonstrate that glucocorticoids are capable of directly affecting embryonic growth and development during the early stages of organogenesis.
Humoral immune dysfunction as a result of prenatal exposure to diphenylhydantion: Correlation with the occurrence of physical defects
Authors: Chapman John R. , Roberts Dean W.
Published: June 2005

The effect of prenatal exposure to diphenylhydantoin (DPH) on postnatal immune function of offspring was studied using a longitudinal experimental design and in vivo immunoassays. Maternal Balb/c mice were dosed by gavage on gestation days 9 through 18 with 0, 20, 40, or 60 mg/kg DPH. Humoral immune function was assessed by measuring the serum antibody levels to type III pneumococcal polysaccharide 5 days after immunization by radioimmunoassay. Cell‐mediated immune function was assessed by measuring the delayed‐type hypersensitivity response to the contact allergen oxazolone using a micrometer method. A dose‐related suppression of humoral immune function was observed in male and female offspring at 25 days but not at 15 weeks of age. Cell‐mediated immunity was not affected by prenatal DPH exposure at 25 days or 15 weeks of age. Offspring developed purulent eye exudates at 12 days of age; the incidence and persistence was related to DPH dose. The immunosuppressive effect of DPH on humoral immune function was significantly greater in offspring born with open eye defect than in similarly treated but physically normal offspring. The results suggest that prenatal exposure to DPH may adversely affect the normal development and expression of humoral immune function, particularly in those offspring with other manifestations of DPH's developmental toxicology.
Gene‐teratogen interaction and its morphological basis in retinoic acid‐induced mouse spina bifida
Authors: Kapron‐Brás Carolyn M. , Trasler Daphne G.
Published: June 2005

Homozygotes for the splotch (SP) mutation in the mouse have spina bifida, whereas the heterozygotes have a white belly spot but otherwise appear normal. Spina bifida can be induced by maternal treatment with retinoic acid. Female SWV strain mice were treated intraperitoneally with retinoic acid suspended in peanut oil 8 days/12 hours after they had been mated to either Sp/+ or +/+ males. Probit analysis of the dose‐response data suggests that the presence of the SP gene causes an increased susceptibility of the embryo to the spina bifida‐causing effects of retinoic acid. To study the nature of this increase litters were obtained on gestation day 9 from untreated SWV females mated as above. The mean length of the posterior neuropore (the length of the posterior neural tube that has not yet closed) was determined for each somite number between 14 and 26 and was found to be significantly greater in embryos from the Sp/ + cross. This delay of closure of the neural tube in Sp/ + cross. embryos could explain the observed increase in their susceptibility to retinoic acid.
Acentric craniofacial cleft in a newborn female prenatally exposed to a high dose of diazepam
Authors: Rivas Fernando , Hernandez Alejandro , Cantu Jose Maria
Published: June 2005

A newborn female with craniofacial clefts, including cleft lip and palate, was studied. The mother had ingested 580 mg of diazepam in a single dose at about the 43rd day of gestation. The synchronism of the drug intake and the embryological development of the affected structures suggests an etiopathogenic relationship.
Vascular abnormalities due to hyperthermia in chick embros
Authors: Nilsen Nils Øhre
Published: June 2005

Intraembryonic vascular abnormalities were studied in chick embryos exposed to temperatures 3°C and 4°C above normal temperature (38°C) from the beginning of incubation. The average duration of hyperthermia was 54 and 53 hours, respectively. Immediately after exposure, the embryos were examined with FITC‐Dextran microangiography in vivo. Following hyperthermia various abnormalities in the heart, ventral aortae, aortic arches, omphalomesenteric arteries, and the distal dorsal aortae frequently occured. There were also significant microvascular changes in the head, in the lateral and caudal parts of the embryos, and in the pellucid area of the yolk sac. In another series incubation at 41°C, hyperthermia of 3°C during the first 3 days of development produced several extraembryonic vascular abnormalities. These included duplication and abnormal branching of the cranial vitelline vein, absence or abnormal course of the omphalomesenteric vessels, aneurysmatic dilatation or abnormal course of the caudal vitelline vein, and aneurysmatic dilatation or occlusion of the abdominal venous sinus. Most frequent findings were blind, congested, and dilated microvascular segments in the pellucid area, commonly associated with an irregular microvascular pattern and perivascular swelling.

The abnormalities described are assumed to be caused by the direct effects of hyperthermia upon the developing vessels resulting in microvascular insufficiencies, pathological leakage, and perivascular oedema. Such disturbances may have serious consequences for embryonic vascular development and microcirculation, which in turn may have adverse effects on further embryonic growth and development.
Threshold for carbon monoxide induced fetotoxicity
Authors: Singh Jarnail , Scott Lou H.
Published: June 2005

Carbon monoxide (CO) is said to be the most widely encountered occupational and environmental contaminant. Threshold for CO‐induced fetotoxicity was studied using mouse as an experimental animal. Pregnant animals of CD‐1 strain were exposed to 0, 65, 125, 250, or 500 ppm CO from gestation day 7 to 18. The animals were sacrificed on gestation day 18, and their uterine horns were examined for live or resorbed fetuses. The data suggest that maternal CO exposure to as low as 125 ppm affects fetal growth and higher levels affect viability. The data also suggest that the developing organism is sensitive to chronic CO exposure, and this sensitivity is dose dependent. The fetal mouse is influenced at levels of exposure below those found transiently for human cigarette smokers and ambient CO concentrations associated with various occupations.
Muscle abnormalities associated with the twin reversed‐arterial‐perfusion (TRAP) sequence (acardia)
Authors: Stephens Trent D.
Published: June 2005

Even though over 400 acardia (twin reversed‐arterial‐perfusion, TRAP) specimens have been reported in the literature since 1533, few attempts have been made to provide detailed evaluation of anything other than the circulation. The purpose of this study was to evaluate the various limb defects in nine TRAP specimens in light of the presumed etiology and pathogenesis, reversed arterial perfusion, and subsequent degenerative changes in the fetus. Two hypotheses were tested: (1) degeneration of formed tissues should not result in tissue rearrangement and (2) one tissue type should be lost in preference to the others. Neither of these hypotheses were supported by the data. Alternative explanations are discussed as well as the implications of these observations on the concept of reversed arterial perfusion.
Immediate and delayed effects of oligohydramnios on limb development in the rat: Chronology and specificity
Authors: Houben J. J.
Published: June 2005

Experimental oligohydramnios has been induced in pregnant rats on the 15th gestational day. Characteristic features of the amniocentesis syndrome can be observed in the posterior limbs and tail early after the amniotic puncture. Histological studies of the affected limb buds reveal immediate endothelial rupture of the marginal vein in the interdigital areas. General and nonspecific effects of the syndrome appear after 30 minutes: venous congestion, blebs, and periendothelial oedema. Such vascular disturbances can does not occur. Growth and differentiation of the condensed digital rays are often unimpaired. Since the condensed preskeletal rudiments are spared by the haemorrhage, resorption of the hematoma results in limb at the time of experiment. Current hypotheses formulated to explain the amniocentesis syndrome are reviewed on the basis of the new descriptive data. Congenital constriction band syndrome and amniotic ruptures have been observed in rare cases.
Injection of diethylstilbestrol on the first day of incubation affects morphology of sex glands and reproductive behavior of Japanese quail
Authors: Gildersleeve R. P. , Tilson Hugh A. , Mitchell Clifford L.
Published: June 2005

Japanese quail eggs were injected with DES (0.9–1,000 μg) dissolved in 50‐μl of Corn oil on day 1 of incubation. Higher doses of DES (250–1,000 μg) reduced hatchability to 37–33% compared to 61% for corn oil–injected controls. Lower doses of DES (0.9–125 μg) had no effects on hatchability. In a second study, eggs were injected with 0.9 or 1.9μg of DES and the survivors were assessed up to 12 weeks posthatch. DES did not affect hatchability, but did increase mortality during the first 4 weeks posthatch. Females were affected more than males. At 10 days of age, open‐field activity of some birds was examined. The acquisition and reversal of a visual discrimination task was studied at 6 weeks of age. DES had no effect on these measurements. Ten females from each group were chosen randomly to determine egg production over a single 28‐day period beginning at 6 weeks of age. Exposure to DES blocked egg production in these birds. The oviduct weights of 12‐week‐old females were decreased by 50%, but ovarian weights were not affected. Testicular weights were not affected. In a third study reproductive behaviors and social‐dominance behaviors of males were markedly attenuated in birds exposed to 0.48 or 1.9 μg DES in ovo.
Pathologic features of the CHARGE association: Support for involvement of the neural crest
Authors: Siebert Joseph R. , Graham John M. , MacDonald Constance
Published: June 2005

Defects associated with choanal atresia include coloboma, cardiac anomalies (usually involving the conotruncal region), physical or mental retardation, genital hypoplasia, and abnormalities of the ear. This constellation of defects is known as the “CHARGE” association and may be accompanied by other anomalies. Many of these defects seem to result from abnormalities in the development, migration, or interaction of cells of the cephalic neural crest. The range of variation in neural crest development is substantial, as indicated by the rather large number of malformation complexes and syndromes that are related phenotypically to the CHARGE association. The increasingly unwieldy nature of this collection of malformations demonstrates the need for an expanded classification of the “neurocristopathies”.
Critical periods during development as assessed by thalliu‐induced inhibition of growth of embryonic chick tibiae in vitro
Authors: Hall B. K.
Published: June 2005

In ovo application of thallium sulfate has been shown to produce a characteristic shortening and angulation of the tibia of the embryonic chick. The critical period for susceptibility to thallium‐induced inhibition of tibial growth ends at 8⅔ days of incubation, a time when the growth rate of the embryo declines by 55%. The aim of the present study was to expose tibiae to thallium in vitro to determine whether this response was intrinsic to the tibia. A 4‐hour exposure to 400 μg thallium was found to be most effective. Growth of tibiae from 8‐day‐old embryos was inhibited, growth of tibiae from 9‐day‐old embryos was not, and the response of tibiae isolated from embryos of 8⅔ days of incubation was intermediate. Therefore, the response of the tibia to thallium represents an intrinsic property and is not secondary to inhibited nerve growth as has been suggested. The critical period and its termination is also an intrinsic property of the tibia. Tibiae were exposed to thallium for 4 hours at various times after the tibiae had been established in vitro. Susceptibility to growth inhibition was shown to decline as tibiae developed beyond the critical period, a decline that could be correlated with a declining growth rate. Emphasis is placed upon critical events during development as a more useful concept than critical periods for explaining susceptibility to teratogens.
Goldenhar syndrome, anterior encephalocele, and aqueductal stenosis following fetal primidone exposure
Authors: Gustavson Edward E. , Chen Harold
Published: June 2005

Fetal exposure to primidone was associated with Goldenhar syndrome, hemifacial microsomia, tetralogy of Fallot, aqueductal stenosis, and anterior encephalocele in this male infant. No similar cases in anticonvulsantexposed pregnancies were found on literature review, despite the increased incidence of other anomalies following such exposure.

Goldenhar syndrome, especially related to rare central nervous system anomalies, is reviewed. Experimental production of hemifacial microsomia by a folic acid antagonist, triaxene, is mediated via hemorrhage in the fetus. Intraventricular hemorrhage was noted in this infant as were dilated lateral and third ventricles. The hemorrhagic diathesis and/or the folic acid depletion of newborns following fetal anticonvulsant exposure may have been the underlying mechanism.
Developmental toxicity of ethylene glycol monopropyl ether in the rat
Authors: Krasavage Walter J. , Katz Gary V.
Published: June 2005

In order to determine the potential developmental toxicity of ethylene glycol monopropyl ether (EGPE), pregnant rats were exposed to vapor concentrations of 100, 200, 300, or 400 ppm of the compound for 6 hours per day on days 6–15 of gestation. Maternal effects included a slight reduction in red blood cell count and increased mean corpuscular volume and mean corpuscular hemoglobin at the 200‐, 300‐, and 400‐ppm concentrations. Reticulocyte counts and polychromasia of the red blood cells were increased at all exposure levels, while anisocytosis was increased at 300 and 400 ppm and macrocytosis was increased at 200, 300, and 400 ppm. Hematocrit, hemoglobin concentration, platelet, and total and differential white blood cell counts were comparable to those of the controls. Red urine was seen in the females after the first and second exposures to 200, 300, and 400 ppm of EGPE, but not after subsequent exposures. Absolute and relative spleen weights were increased by 200, 300, and 400 ppm EGPE. Histologic changes were seen in the maternal spleen, liver, and thymus, particularly after exposure to 300 and 400 ppm. Kidneys, bone marrow, and mesenteric lymph nodes were normal. Pregnancy rate, number of corpora lutea, implantation sites and viable fetuses per dam, the incidence of resorptions per litter, and the mean fetal body weights were comparable to those of the controls. Gross external, internal soft tissue, and skeletal examinations of the fetuses revealed that EGPE did not produce teratogenicity or significant embryo/fetotoxicity in the rat at vapor concentrations as high as 400 ppm. Variations in the ossification of certain skeletal elements and the incidence of 14th thoracolumbar rudimentary ribs were increased by exposure to 200, 300, and 400 ppm EGPE.
Two massive congenital intracranial immature teratomas with neck extension
Authors: Rostad Steven , Kleinschmidt‐DeMasters B. K. , Manchester David K.
Published: June 2005

In this report we detail two congenital intracranial immature teratomas, noteworthy for their massive intracranial growth and extension through the skull with compromise of neck structures. Cytogenetic studies were done in both cases on the fetuses and their tumors and are the first in the literature. Few previously reported congenital intracranial teratomas have been described with neck extension. In both cases, polyhydramnios was detected by prenatal ultrasonography and was possibly caused by the laryngoesophageal and/or brainstem distortion by neoplasm. Possible reasons for such excessive, unchecked growth of teratomas in the fetal period are discussed.