bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lectin teratogenesis II: Demonstration of increased binding of concanavalin a to limb buds of rabbit embryos during the teratogenically sensitive period
Authors: DeSesso John M. , Niewenhuis Robert J. , Goeringer Gerald C. 
Published: June 2005

AbstractThe plant lectin concanavalin A (con A) causes malformations of rabbit embryos when 160μg (in 40 μl) are injected into the exocoelom on gestational days 12–15 but does not cause malformations on days 10–11. The purpose of this study was to investigate the mechanism for increased susceptibility of day 12–15 embryos to con A teratogenicity. Light microscopy of day 11 embryos 15–20 hr after treatment with con A revealed no observable difference from controls. Day 13 embryos at similar times exhibited limb buds with large areas that were denuded of ectoderm. Concurrent addition of α‐methyl‐D‐mannoside (αMM), a specific inhibitor of con A, to the injection solution of day 13 embryos resulted in limb buds that appearded normal. The regions of con A binding to day 11 and day 13 embryos were visualized through epifluorescent microscopy of untreated embryos stained with fluorescein‐labelled con A. Day 11 embryos exhibited moderate fluorescence on the surface of limb buds and the pericardial region. Day 13 embryos exhibited strong fluorescence of limb bud surfaces; the pericardial region remained moderately fluorescent. Addition of αMM to the incubation medium resulted in no fluorescence above background. Visualization of con A receptors was accomplished by ultrastructural analysis of forelimb buds stained with ferritin‐labelled con A. Ferritin label was observed only on the surfaces of the ectoderm and was sparse over all regions of day 11 limb buds. In contrast, ferritin label was moderately heavy in all regions of the day 13 limb buds. No labelling occurred when the ferritin‐labelled con A was preincubated with αMM. These observations indicate that the number of exposed con A receptors on limb buds of teratogenically sensitive embryos (day 13) is increased, compared with the number of exposed receptors on limb buds of younger, insensitive (day 11) embryos. The increased number of exposed con A receptors on limb buds during the teratogenically sensitive period provides not only increased binding of the lectin to sensitive embryos but also a potential mechanism for the anomalous attachment of distal regions of the limb buds to the body wall.
Unique anomalies in cephalothoracopagus Janiceps conjoined twins with implications for multiple mechanisms in the abnormal embryogenesis
Authors: Baron Beverly W. , Shermeta Dennis W. , Ismail Mahmoud A. , Ben‐Ami Tamar , Yousefzadeh David , Carlson Nancy , Amarose Anthony P. , Esterly John R. 
Published: June 2005

AbstractThe anatomic features of female conjoined twins with the Janiceps type of cephalothoracopagus are described. Abnormalities included bilateral clefts of the alveolar arches, shared rudimentary mandible, high, arched clavicles, multiple rib deformities, single shared foregut and small intestine, absent large intestines, omphalocele, multicystic kidneys, hypoplastic lungs, interconnected aortas and neck vessels, single ovary with elongated uterus in each twin, displaced labia, abnormal segmentation of the vertebrae, spinal dysraphism, diastasis of the symphysis pubis, malrotated lower extremity, bilateral posterior dislocation of the hips, and club feet. There were two hearts with internal anomalies. Both spinal cords had a myelocele in the lumbar region. The abnormalities noted in previous reports of conjoined twins of this type are reviewed and compared. We propose that factors associated with conjoining, dysgenetic (developmental) defects, and deformations resulting from crowding in utero all may have been important in the abnormal development in this case.
Amelia: Incidence and associated defects in a large population
Authors: Froster‐Iskenius Ursula G. , Baird Patricia A. 
Published: June 2005

AbstractAmelia, or complete absence of a limb, is a very rare congenital anomaly. The incidence of amelia in a population of 1,213,913 consecutive livebirths in British Columbia during the period 1952–1984 was studied using the records of a population‐based registry with multiple sources of ascertainment. There were 18 cases of amelia, giving a minimal incidence rate of 0.15 per 10,000 livebirths for this birth defect. Amelia occurred equally frequently in upper and lower limbs, and 11 of 18 (61%) liveborn cases also had malformations of other organ systems. In the group with lower limb amelia a specific pattern of associated malformations, which included omphalocele and diaphragmmatic defects, was identified. There was no evidence for familial recurrence of amelia. Conditions to be considered in differential diagnosis are discussed.
Influence of maternal dietary zinc intake on in vitro tubulin polymerization in fetal rat brain
Authors: Oteiza Patricia I. , Cuellar Susana , Lönnerdal Bo , Hurley Lucille S. , Keen Carl L. 
Published: June 2005

AbstractThe hypothesis that one of the biochemical lesions underlying zinc deficiency‐induced teratogenicity is altered microtubule formation was tested. Day 19 fetuses from zinc‐deficient Sprague‐Dawley dams were characterized by low brain supernate zinc concentrations and slow brain tubulin polymerization rates compared to controls. Brain supernate tubulin and protein concentrations were similar in zinc‐deficient and control fetuses. In vitro brain tubulin polymerization rates were increased following addition of zinc to either control or zinc‐deficient brain supernates; however, the stimulatory effect of added zinc on polymerization was significantly higher in brain supernates obtained from zinc‐deficient fetuses compared to controls. These results support the idea that one effect of fetal zinc deficiency is a reduction in tubulin polymerization, which in turn may result in altered microtubule function.
Comparison of the incidence of 5‐azacytidine‐induced exencephaly between MT/HokIdr and Slc:ICR mice
Authors: Matsuda Motoko 
Published: June 2005

AbstractThe incidence of 5‐azacytidine‐induced exencephaly was compared between MT/HokIdr strain (MT) and Slc:ICR strain (ICR) mice. MT mice have a genetic predisposition for exencephaly, but ICR mice do not. Pregnant mice were given 5‐azacytidine (1 mg/kg to 100 μg/kg) injected intraperitoneally on Day 7.5 of gestation (vaginal plug day = Day 0.5), and fetuses were observed for external malformations on Day 18.5 of gestation. One hundred μg/kg 5‐azacytidine induced exencephaly in MT mice but not in ICR mice, and 1 mg/kg 5‐azacytidine resulted in resorptions in MT mice but caused exencephaly in ICR mice. These results indicated that MT mice had 10‐fold more sensitivity to 5‐azacytidine than ICR mice. It seems likely that less than effective doses of teratogens for animals without genetic predispositions are still effective in inducing malformations in animals with a genetic predisposition for malformations. When 4‐somite‐stage embryos of both MT and ICR mice were cultured in rat serum supplemented with 5‐azacytidine, 0.02 μg/ml 5‐azacytidine induced the failure of closure of cephalic neural tube in MT embryos but not in ICR embryos, and 0.2 μg/ml 5‐azacytidine induced severe growth retardation in MT embryos but in ICR embryos it only induced embryos with smaller heads and fewer somites than in control. These results indicated that MT mouse embryos in culture also had a 10‐fold‐increased sensitivity to 5‐azacytidine compared with ICR mouse embryos, suggesting maternal effects play no significant role in their increased sensitivity to 5‐azacytidine.
Correlation between the birth prevalence of isolated hypospadias and parental subfertility
Authors: Czeizel A. , Tóth J. 
Published: June 2005

AbstractFactors associated with the occurrence of isolated hypospadias have been studied. We previously reported a secular trend association between hypospadias occurrence and progestagen use by the Hungarian population. Further study does not support that secular trend association. The use of progestagens for the treatment of reproductive problems is a very complex issue, and there are other factors relating to male and female fertility that differentiate the hypospadias families from the controls. It appears that families with problems of subfertility are at increased risk for the occurrence of hypospadias. Our data support more recent studies, which do not demonstrate an association between the occurrence of hypospadias and the administration of progestagens in humans.
Relationship of DNA damage and embryotoxicity induced by 4‐hydroperoxydechlorocyclophosphamide in postimplantation rat embryos
Authors: Little Sally A. , Mirkes Philip E. 
Published: June 2005

Abstract4‐Hydroperoxydechlorocyclophosphamide (4‐OOHdeCl‐CP) is a preactivated analogue of cyclophosphamide (CP) that undergoes an elimination reaction to yield acrolein and the nonalkylating derivative of phosphoramide mustard (PM), i.e., dechlorophosphoramide mustard. We used this analogue to assess the role of acrolein in CP‐induced embryotoxicity. Embryotoxicity was assessed using day 10 rat embryos cultured in vitro. 4‐OOHdeCl‐CP was embryotoxic over a concentration range of approximately 75–150 μM and produced complete embryolethality at concentrations of 175 μM and above. This analogue induced abnormal development characterized by tail defects at low drug concentrations and microcephaly or prosencephalic hypoplasia at high concentrations. Using the technique of alkaline elution, we also assessed DNA damage induced by embryotoxic concentrations of drug. When embryos were cultured in serum‐containing medium during drug exposure, no DNA damage was detected, even at embryolethal drug concentrations. However, if cellular glutathione (GSH) was depleted with buthionine sulfoximine (BSO) before drug exposure and embryos were cultured in serum‐free medium during drug exposure, DNA damage, primarily DNA single‐strand breaks, was detected, but only at embryolethal concentrations. Using radiolabeled CP, we showed that acrolein does reach the embryo; however, more acrolein is incorporated into the yolk sac. Binding studies revealed that acrolein binds preferentially to cellular protein, whereas PM binds preferentially to DNA. These results suggest that, unlike the case with PM, the embryotoxic target for acrolein is protein and not DNA. Furthermore, our results indicate that acrolein may mediate its effects on the embryo via the yolk sac.
Prevention of unnecessary pregnancy terminations by counselling women on drug, chemical, and radiation exposure during the first trimester
Authors: Koren Gideon , Pastuszak Anne 
Published: June 2005

AbstractAs part of a new approach to counselling pregnant women concerned about antenatal exposure to drugs, chemicals, or radiation, we measured their tendency to terminate their pregnancy by using a visual analogue scale (VAS). Analysis of 78 cases where women had less than 50% tendency to continue pregnancy before they were advised by us reveals that 61 decided to continue their pregnancy after the consultation (57 normal, healthy infants, four miscarriages) and 17 terminated. Women who continued their pregnancy significantly changed their tendency after we discussed relevant information with them (from 34.3 ± 2.5% to 84.5 ± 3.3%, P<0.00001), whereas most of those who eventually terminated pregnancy did not change their tendency to continue pregnancy beyond the 50% mark (from 24.8 ± 5.4% to 45.1 ± 9.8%) (P>0.1). Only two of the women who terminated their pregnancy were exposed to teratogenic drugs; however, in most other cases, other obvious reasons, unrelated to the exposure in question, were identified by the women as leading reasons for termination.An appropriate intervention in early pregnancy can prevent unnecessary pregnancy terminations by correcting misinformation and thereby decreasing the unrealistically high perception of risk by women exposed to nonteratogens.
Teratogenicity of the 13‐cis and all‐trans‐isomers of the aromatic retinoid etretin: Correlation to transplacental pharmacokinetics in mice during organogenesis after a single oral dose
Authors: Löfberg Boel , Chahoud Ibrahim , Bochert Gerd , Nau Heinz 
Published: June 2005

AbstractNMRI mice were treated on day 11 (day 0 = plug day) of gestation with a single oral dose of 100 mg/kg of either all‐trans‐etretin (acitretin) or 13‐cis‐etretin. For teratology studies mice were sacrificed on day 18 of gestation, and the fetuses were examined for malformations. For pharmacokinetic studies, groups of 5 mice were sacrificed after 5, 10, and 30 min and 1, 2, 4, and 8 h. The concentrations of retinoids in maternal plasma and in embryos were determined by a newly developed HPLC gradient method. All‐transetretin induced malformations in 94% of the fetuses, mainly in fore and hind limbs and cleft palate. 13‐cis‐etretin did not show any teratogenic or embryolethal effects at the dose level used. These findings could be explained by a transplacental pharmacokinetic study. The maximum peak level and also the AUC (area under the concentration‐time curve) values of all‐trans‐etretin in the embryos was 7–8 times higher than corresponding values for 13‐cis‐etretin, probably due to extensive transport of the trans‐isomer and limited transport of the cis‐isomer from maternal plasma to the embryos. The concentration quotient between embryo and the maternal plasma was between 0.43 and 1.10 for all‐trans‐etretin, and only 0.16–0.31 for 13‐cis‐etretin over the time period studied. An in vivo isomerization of the compounds was also observed which was more extensive for 13‐cis‐etretin than for all‐trans‐etretin. Our results indicate that the low teratogenic potency of 13‐cis‐etretin is due to a limited placental transfer of this compound; on the other hand, the potent teratogen all‐transetretin is rapidly and extensively transferred to the embryo.
Neural tube defects and first trimester operations
Authors: Källén Bengt , Mazze Richard I. 
Published: June 2005

AbstractSwedish health care registries were used to identify women who had surgery during pregnancy and their offspring. Among the 2,252 infants born to women who had first trimester operations during 1973–1981, six had definite diagnoses of neural tube defects (expected number, 2.5). Scrutiny of the records showed that 572 operations occurred during gestational weeks 4–5, the period of neural tube formation, and that the mothers of five of the six infants with neural tube defects had an operation during that period (expected number of neural tube defects, 0.6) although one of the offspring probably had Meckel's syndrome. The relationship between neural tube defects and operation during pregnancy is discussed including the possibility that the association may be random.
Developmental toxicity of soman in rats and rabbits
Authors: Bates Hudson K. , LaBorde James B. , Dacre Jack C. , Young John F. 
Published: June 2005

AbstractSoman (GD; phosphonofluoridic acid, methyl‐,1,2,2‐trimethylpropyl ester) is an organophosphate compound with potent anticholinesterase activity. To determine developmental toxicity, soman was administered orally to CD rats on days 6 through 15 of gestation at dose levels of 0, 37.5, 75, 150, or 165 μg/kg/day and to New Zealand White (NZW) rabbits on days 6 through 19 of gestation at dose levels of 0, 2.5, 5, 10, or 15 μg/kg/day. At sacrifice, gravid uteri were weighed and examined for number and status of implants. Individual fetal body weights and external, visceral, and skeletal malformations were recorded. Mean maternal weight changes, fetal implantation status/litter, fetal weight, and fetal malformations/litter were compared between dose groups. Monitors for maternal toxicity were net body weight change, treatment weight change, mortality, and clinical signs of toxicity such as lethargy, ataxia, and tremors. Maternal rats and rabbits in the high‐dose groups exhibited statistically significant increases in toxicity and mortality when compared to controls. There were no significant dose‐related effects among dose groups in the prevalence of postimplantation loss, malformations, or in average body weight of live fetuses per litter. There was no evidence of increased prenatal mortality or fetal toxicity in the CD rat or NZW rabbit following exposure to soman, even at a dose that produced significant maternal toxicity.
Teratogenic potential of two neurotropic drugs, haloperidol and dextromoramide, tested on mouse embryos
Authors: Jurand A. , Martin L. V. H. 
Published: June 2005

AbstractPotential teratogenic activity of two neurotropic drugs, haloperidol and dextromoramide tartrate, was tested by using the mouse embryo experimental model. Like numerous other drugs of this class these two are also embryotoxic. After treatment 1 hour into the 9th gestation day they induce the neurotropic syndrome of malformations comprising exencephaly, craniorachischisis, kinking of the spinal cord, brachyury, and dilation of the fourth brain ventricle. In addition, dextromoramide tartrate was found to induce one more, so far unknown, neural tube defect, namely the ectopia of the neural tube. Delay of treatment by 1 or 2 hours tends to displace the location of the neural tube defects along the length of the neural axis towards the anterior and posterior directions. Even after accumulating these results at relatively high doses, it is difficult to estimate human reproductive risks from this animal data for human therapeutic doses.
Variability in the developmental toxicity of bropirimine with the day of administration
Authors: Marks Thomas A. , Black Daniel L. , Terry Roger D. , Branstetter Daniel G. , Kirton Kenneth T. 
Published: June 2005

AbstractThe aim of this study was to determine the mechanism by which bropirimine exerts its developmental toxicity. This drug is an immunomodulator and interferon inducer with antiviral and antitumor activities in experimental models. Timed‐pregnant Upj:TUC(SD)spf (Sprague‐Dawley) rats were given a single oral (gastric intubation) dose of bropirimine at 200 or 400 mg/kg (doses as high as 100 mg/kg/day have been employed in human cancer trials) on days 5, 6, 7, 8, 9, 10, 11, or 12 of gestation and in a second experiment on day 12, 13, 14, 15, 16, 17, 18, or 19 of gestation. The dams were killed 24 hours after dosing and their uterine contents examined. In a third experiment, bropirimine (400 mg/kg) was administered on day 4 of gestation and the uteri of different groups were examined on day 8, 9, 10, 11, or 12 of gestation. Serum progesterone levels were measured at sacrifice. In the first two experiments a battery of hematologic/clinical chemistry assays also were performed. In all three experiments, bropirimine‐related maternal toxicity was observed; such toxicity was characterized by significant decreases in weight gain, relative to the concurrent vehicle controls, as well as significant differences in several blood parameters including platelets, white blood cells, alanine aminotransferase, and aspartate transaminase. In the first experiment, bropirimine treatment on day 11, but not day 12, resulted in significant decreases in the number of live embryos per litter. In the second experiment, significant decreases in the number of live fetuses per litter occurred 24 hours after dosing on day 18 (200 and 400 mg/kg groups) or day 19 (400 mg/kg group). Decreases in serum progesterone appeared to correlate well with the embryolethal effects seen after treatment between days 6 and 11 of gestation, but not with the fetal lethality seen when treatment was given on day 17 or 18. The decreases in serum progesterone levels found most likely were the result of a luteolytic effect, although it is unknown if bropirimine has a direct or indirect effect on the corpora lutea. In the third experiment, bropirimine treatment on day 4 of gestation resulted in only slight preimplantational losses, but significant decreases were found in mean number of live embryos per litter after day 9. Uterine decidual necrosis has been observed in the first experiment where bropirimine was given on day 11; however, treatment on day 4 resulted in an apparent decrease in decidual development but not necrosis.
External genitalia abnormalities in male rats exposed in utero to finasteride, a 5α‐reductase inhibitor
Authors: Clark Robert L. , Antonello Joseph M. , Grossman Scott J. , Wise L. David , Anderson Charles , Bagdon Walter J. , Prahalada Srinivasa , MacDonald James S. , Robertson Richard T. 
Published: June 2005

AbstractA series of studies was conducted to determine the developmental toxicity of the 5α‐reductase inhibitor finasteride (MK‐0906) in rats. This compound was administered orally once daily to pregnant rats during various extended treatment periods during gestation. F1 offspring were evaluated on Day 20 of gestation as well as postnatally through mating to produce an F2 generation. MK‐0906 treatment induced dosage‐related incidences of hypospadias (penischisis) in male offspring with a threshold dosage level near 0.1 mg/kg/day and a 100% effect level of 100 mg/kg/day (with dosing through Day 20 of gestation). MK‐0906 also caused decreased anogenital distance in male offspring. The dosage response for this effect (ranging from a 4.2% decrease at 0.003 mg/kg/day to a 38% decrease at 100 mg/kg/day) was more shallow than that for hypospadias. The decreases in anogenital distance were at least partially reversible postnatally with essentially complete recovery at dosages up to 0.1 mg/kg/day. There was also a dosage‐related, temporary induction of nipples in F1 males. All of these effects were apparent following treatment on Days 6 through 17 of gestation but were more pronounced when dosing extended to Day 20 of gestation. Slight maternal toxicity consisting of minor decreases in body weight gain occurred only at dosages of 3 mg/kg/day and higher, indicating the selective nature of the developmental toxicity. The 5α‐reductase enzyme located in the rat fetal genital tubercle was studied in vitro and compared to that in the adult ventral prostate. The values for Km, Vmax, and IC50 for inhibition by MK‐0906 were similar in the two tissues, suggesting that the enzymatic proteins in the genital tubercle and ventral prostate may be similar.