bluuebunny/crossref_metadata_2025_split huggingface dataset:
Study of the mechanisms of BUdR‐induced cleft palate in the mouse
Authors: Bannigan John G. , Cottell David C. , Morris Aisling 
Published: June 2005

AbstractThis study was designed to examine the pathogenesis of bromodeoxyuridine (BUdR)‐induced clefts of the secondary palate in the LACA mouse. Intraperitoneal injections of BUdR (500 mg/kg body weight) were given at various days and combinations of days between E11 and E15 (plug day = E1). Treatment on E11 alone resulted in approximately 22% of fetuses with cleft palate when the latter were examined either on E16 or E19. Treatment on E11 and E12 approximately doubled the above incidence, and treatment on E11, 12 and 13 raised it to 100%. However, no treatment, either single or multiple, caused cleft palate when given later than E11. This suggests that the cellular changes caused by BUdR that lead to cleft palate must be inflicted during E11 and that such damage can be repaired in about 80% of embryos. All fetuses with cleft palate had severe micrognathia on E16 and E19, which skeletal staining showed to be the result of a bilateral sigmoid buckling of Meckel's cartilage. Studies with the scanning electron microscope (SEM) on E15, 16, and 19 suggested strongly that the micrognathia caused a relative macroglossia and hence mechanical interference with palatal shelf reorientation. Histological studies with the light microscope showed that BUdR caused cellular necrosis in many embryonic tissues during the 24 hours after its administration. This necrosis was strikingly more severe in the mandibular rudiment of the first branchial arch than in the maxillary. The latter observation accords well with findings by other workers that cell proliferation is more rapid in the mandibular blastema than in the maxillary. Transmission electron microscope (TEM) studies of the buckled region of Meckel's cartilage failed to reveal any ultrastructural differences from control Meckel's cartilage. Hence BUdR had only interfered with the shape of the cartilage but not with its histiogenesis. We conclude that BUdR, by its cytotoxicity or antidifferentiative effects, interfered with the formation of the anterior end of Meckel's cartilage, initiating a chain of events leading through micrognathia and relative macroglossia to failure of palatal shelf reorientation and cleft palate.
Expression of Veratrum alkaloid teratogenicity in the mouse
Authors: Omnell M. L. , Sim F. R. P. , Keeler R. F. , Harne L. C. , Brown K. S. 
Published: June 2005

AbstractJervine, a steroidal alkaloid found as a minor constituent in the teratogenic range plant Veratrum californicum, has produced similar terata in sheep, rabbit, hamster, and chick, although the sensitivity to the alkaloid varies in the different species. Sprague Dawley rats and Swiss Webster mice are relatively insensitive. The aim of this study was to determine the teratogenic potential of jervine in three strains of mice and to ascertain if the response is strain dependent. One strain, Swiss N:GP(S), was retested since a Swiss Webster strain had been found previously to be jervine‐resistant. In addition, we tested C57BL/6J and A/J, which are known to differ in their response to the teratogenic action of steroids and vitamin A. Mice were treated by gavage with single doses of jervine (70, 150, or 300 mg/kg body weight) on either day 8, 9, or 10 of gestation. Jervine was teratogenic to C57BL/6J and A/J mice but not to N:GP(S). The induced terata included cleft lip with or without cleft palate, isolated cleft palate, mandibular micrognathia or agnathia, and limb malformations. Fetal teratogenicity and maternal and fetal toxicity were highly correlated. The prevalence of each defect and fetal death was a function of strain, dose, and time of treatment. Maternal death was higher in C57BL/6J than in A/J mice. Although some of the terata were similar, the response pattern between strains was different from corticosteroids and vitamin A for both sensitive period and the strain dose response. An effect on differentiation of chondrocyte precursors may account for many of the defects, but an earlier lethal effect on differentiation of neural crest cells or precordal mesenchyme may also occur.
Embryonal disposition of salicylate: In vivo‐in vitro comparisons
Authors: Daston George P. , Francis William R. , Baines Donald , Poynter James I. , D'Souza Richard W. 
Published: June 2005

AbstractThe distribution of salicylate to embryonal compartments for in situ and in vitro rat embryos under equivalent exposure conditions, and salicylate disposition in the in vivo mid‐gestation embryo and late gestation fetus, were compared. Pregnant Sprague‐Dawley CD rats were exposed to steady‐state blood levels of salicylate by infusing 14C‐salicylic acid iv for a 24 hour period from gestation day 11.5 to 12.5. Cultured Sprague‐Dawley rat embryos (in medium consisting of 100% male rat serum) were exposed to the steady‐state 14C‐salicylate concentration achieved in maternal serum in vivo for the same 24 hour developmental period. At the end of the exposure period radioactivity in visceral yolk sac, extra‐embryonic fluid and embryos, and in maternal tissues, was measured. The distribution of salicylate to embryonal tissues was statistically comparable in vivo and in vitro, although the embryos in vitro accumulated slightly (but not significantly) less of the chemical. There was considerable binding of salicylate by maternal serum and culture medium proteins: less than 20% of the chemical was free at the 40 μg/ml concentration used in this experiment. Consequently, the salicylate concentration in embryonal compartments appeared to be quite low when compared to the surrounding serum/medium, but was actually equal to or greater than the concentration of unbound salicylate in serum or culture medium. The proportion of free salicylate in serum increased at concentrations higher than 40 μg/ml, resulting in somewhat higher concentrations of salicylate in in vitro embryos and extra‐embryonic fluid (as compared to medium) when cultured in the presence of 200 or 400 μg/ml salicylate. Salicylate pharmacokinetics in the fetus were determined by infusing 14C‐salicylic acid iv into pregnant rats from gestation day 19.5 to 20.5 and concentrations in fetuses and dams on gestation day 20.5 were compared to those from gestation day 12.5 rats. There was significantly more salicylate distributed to gestation day 20.5 fetal tissues than to gestation day 12.5 embryos. This appeared to result from a higher percentage of unbound salicylate in maternal serum in late gestation, but may also be due to other factors such as different placental characteristics or binding within embryo/fetal compartments. In summary, under the conditions of this study the disposition of salicylate to embryonal compartments was statistically comparable in vivo and in vitro. Disposition is influenced considerably by developmental stage and concentration of salicylate.
Induction of malformations in the cynomolgus monkey with 13‐cis retinoic acid
Authors: Hummler Hans , Korte Rainhart , Hendrickx Andrew G. 
Published: June 2005

AbstractThe embryotoxic and teratogenic potential of 13‐cis retinoic acid was assessed in the cynomolgus macaque (Macaca fascicularis). A total of 41 animals was orally administered 13‐cis retinoic acid in four sequential experiments. In Exp. 1 three dose levels, 2, 10, and 25 mg/kg, were administered on gestational day (GD) 18–28; 5 mg/kg was administered as an equally divided dose twice daily in Exp. 2 and 3 on GD 21–24 and on GD 25–27, respectively; in Exp. 4 the drug was administered at 2.5 mg/kg once daily from GD 10 to 25 and twice daily (2 × 2.5 mg/kg) on GD 26 and 27. Maternal death and toxicity, manifested as reduction in maternal weight and food consumption, and diarrhea, was observed in Exp. 1 in all three dose groups. No significant maternal toxicity was observed in the treatment groups in Exp. 2, 3, and 4 or in the control group. The primary manifestation of developmental toxicity was embryolethality in Exp. 1 and 2. The incidence of embryonic deaths in Exp. 3 was comparable to the historical controls. No malformations in GD 100 fetuses were observed in Exp. 1, 2, and 3. In Exp. 4, five of seven fetuses (71%) had malformations of both external ears, four of seven fetuses (57%) exhibited hypo‐ or aplasia of the thymus, and two of seven (29%) had malformations (transposition of the great vessels, ventricular septal defect) of the heart. The teratogenic dose for the cynomolgus monkey in the present study was lower than that reported for all other experimental species. Although central nervous system and craniofacial defects were not observed, the incidence of ear and thymus defects was similar to that reported for the human. The cardiovascular defects resembled those reported clinically, but the incidence was lower in the cynomolgus monkey. The similarity in teratogenic sensitivity to humans supports the use of the monkey as a model for developmental toxicity studies of vitamin A‐related compounds.
Effects of pulsed ultrasound and temperature on the development of rat embryos in culture
Authors: Angles J. M. , Walsh D. A. , Li K. , Barnett S. B. , Edwards M. J. 
Published: June 2005

AbstractRat embryos in culture were exposed to pulsed ultrasound at SPTA intensity of 1.2 W/cm2 for 5, 15, and 30 min on day 9.5 of development. The whole embryo culture system allowed precise temperature control for directly examining the effects of ultrasound on the developing neural plate. After exposure, embryos were maintained in culture for a further 48 hr. No major morphological abnormalities were observed but a reduction in somite number occurred in the group insonated for 30 min, which was equivalent to a 2 hr delay in embryonic development. Similar delay in growth and “blistering” in the prosencephalon region of some embryos were observed after insonation for 15 min at 40.0°C, an elevation of 1.5°C over the temperature used for controls. Exposure to ultrasound for 15 min at 40°C caused significant reduction in the growth of the head compared with that of control embryos. Heat shock genes for hsps 71/73 and 88 kD were induced after insonation for 30 min at 38.5°C. Insonation did not cause any temperature changes in the culture medium. However, when the temperature of the culture medium was increased during insonation, defective development occurred. The results of these in vitro experiments suggest that ultrasound if resulting in significant hyperthermia could affect the development during early organogenesis of the neural plate and in particular they suggest that the embryo is at greater risk of damage during hyperthermic conditions. These results should provoke discussion of the concept that ultrasound in the febrile patient may present an increased embryonic risk which should be considered when deliberating on the use of diagnostic ultrasound procedures in the pregnant patient.
Trisomy 22 with holoprosencephaly: A clinicopathologic study
Authors: Isada Nelson B. , Bolan Jean C. , Larsen John W. , Kent Stephen G. 
Published: June 2005

AbstractTrisomy 22 (47, XY, +22) was found at 17 weeks gestation in one fetus of a twin gestation. The karyotypes of both parents and of the other twin were normal. Abnormal prenatal findings included maternal pre‐eclampsia, fetal growth retardation, and progressive intracranial sonolucency of the trisomic fetus. Delivery by cesarean section at 36 weeks gestation yielded a normal healthy female weighing 2,822 grams and a markedly macerated dysmorphic male weighing 642 grams. Holoprosencephaly was found in the trisomic fetus, an unusual feature in trisomy 22. Additional findings in this case are compared to other findings in the literature.
Growth failure in second‐trimester fetuses with trisomy 21
Authors: Fitzsimmons Jack , Droste Sabine , Shepard Thomas H. , Pascoe‐Mason Julie , Fantel Alan 
Published: June 2005

AbstractGrowth failure in the Down syndrome is common postnatally, but is thought to be less consistent in fetuses and newborns. We describe the growth of individual organs in 53 second‐trimester abortuses with trisomy 21 and compare the organ weights to organ weights from 432 spontaneously aborted, but otherwise normal control specimens. Using multiple regression analysis, we found body weight to be the most significant predictor of all organ weights in normal fetuses; therefore, this variable was used to generate the regression lines to which the organ weights of trisomic specimens were compared. All trisomic fetal organs were found to be small, with an abnormal karyotype being a significant predictor of low organ weight. However, the effect on individual organs was variable, with some organs differing only minimally from the controls. Placental weights were not affected by fetal trisomy. This study demonstrates the presence of well‐established, although variably severe, growth retardation in second‐trimester fetuses with Down syndrome.
Effect of prenatal N2O exposure on startle reflex reactivity
Authors: Rice Susan A. 
Published: June 2005

AbstractThe teratogenic effect of N2O is of interest because thousands of pregnant women are exposed to this gaseous anesthetic each year. The effects of repeated N2O exposures were investigated for offspring of mice exposed to air or N2O (5%, 15%, or 35%) for 4 hours per day on days 6 through 15 of pregnancy. Ten litters per exposure group were studied. Exposures did not affect reproductive indices, survival, or physical milestones of development. Body weights showed significant exposure effects that could not be isolated to specific exposure groups; however, N2O‐exposed mice tended to weigh more than air‐exposed animals. Brain weights measured on postnatal day (PND) 126 or 127 were not different among exposure groups or between genders. Ability to stay on a rotating rod was not affected by prenatal N2O exposure. Prenatal exposure to N2O resulted in hyporeactivity of the startle reflex in response to acoustic or tactile stimuli. On PND 95 the results were statistically significant for all N2O‐exposed groups compared with the air‐exposed group. On PND 60, although not statistically significant, there was a definite trend toward hyporeactivity for the N2O groups. There was a significant age‐related difference in startle response; control animals were significantly more reactive at 95 than at 60 days of age. Of the N2O‐exposed groups, only the 15% group showed a statistically significant increase in reactivity from 60 to 95 days of age. The risk of behavioral or functional abnormalities for humans following in utero N2O exposure is unknown and cannot be directly extrapolated from the present study. The 4 hour duration of exposure is not unusual for surgical patients, but exposure throughout the period of organogenesis is unusual. Daily exposure to N2O more closely resembles the pattern of occupational exposure, although the concentrations used in this study are much higher than those measured in surgical or dental operatories. The effects of N2O on reactivity observed in mice are worthy of further investigation because both the mechanism of action and the no‐effect exposure for mice and humans has yet to be determined.
Methionine and neural tube closure in cultured rat embryos: Morphological and biochemical analyses
Authors: Coelho Caroline N. D. , Klein Norman W. 
Published: June 2005

AbstractWhen headfold‐stage rat embryos were cultured on cow serum, their neural tubes failed to close unless the serum was supplemented with methionine. Methionine deficiency did not appear to affect the ability of the neural epithelium to fuse as a type of fusion was observed between anterior and posterior regions of the open neural tube in methionine‐deficient embryos. Although methionine deficiency reduced the cell density and mitotic indices of cranial mesenchyme and neural epithelial cells, this did not appear to be a factor in failure of the neural tube to close. For example, embryos cultured on diluted cow serum also had fewer mesenchymal cells yet could complete neural tube closure if provided with methionine. Examination of the tips of the neural folds suggested that microfilament contraction could be involved; in the absence of methionine the neural folds failed to turn in. This possibility was supported by the reductions in neurite extension of isolated neural tubes cultured without methionine and by the reductions in microfilament associated methylated amino acids contained in embryo neural tube proteins.
Cyclophosphamide teratogenesis: Evidence for compensatory responses to induced cellular toxicity
Authors: Francis B. Magnus , Rogers John M. , Sulik Kathleen K. , Alles Ajit J. , Elstein Kenneth H. , Zucker Robert M. , Massaro Edward J. , Rosen Mitchell B. , Chernoff Neil 
Published: June 2005

AbstractCyclophosphamide (CP) administered ip to pregnant mice on day 10 of gestation (day of plug = day 0) is teratogenic (exencephaly, cleft palate, and limb malformations) at 20 mg/kg and embryolethal at higher doses. In the present study, CP was administered at 1, 5, 10, or 20 mg/kg on day 10 of gestation. Embryos were removed at 8 and 28 hr postdosing, and two embryos from each litter were immediately stained with Nile blue sulfate (NBS) to identify areas of cell death. The remaining embryos were frozen and forelimb buds subsequently removed for flow cytometric (FCM) analysis of the cellular DNA synthetic cycle. Additional litters were examined near term (day 17) for morphological abnormalities; these data were correlated with embryonic toxicity as detected by NBS staining and FCM analysis.Only the highest dose produced malformations. In marked contrast, a dose‐related increase in the percentage of limb bud cells in the S (DNA synthetic) phase of the cell cycle was detectable at all doses. Inhibition of DNA synthesis was detected at all doses 8 hr post exposure and persisted through 28 hr for doses ≥10 mg/kg. NBS staining indicated increased cell death in the alar plate of the neural tube 28 hr after exposure to 10 mg/kg CP and generally increased cell death in areas of rapid cell proliferation throughout the embryo at 20 mg/kg. The absence of an overt teratogenic response at dose levels that produced significant perturbation of the cell cycle indicates that a measure of embryonic damage can be compensated for or repaired. The implications of these findings for the existence of thresholds in developmental toxicity are discussed.
External genitalia of the rat: Normal development and the histogenesis of 5α‐reductase inhibitor‐induced abnormalities
Authors: Anderson Charles A. , Clark Robert L. 
Published: June 2005

AbstractThe normal histogenesis of the rat genital tubercle and the effect of exposure in utero to the 5α‐reductase inhibitor finasteride (L‐652,931; MK‐0906;Proscar®) on that process were studied. In normal males and females, the genital tubercle was first seen on Day 14.25 of gestation. It contained a urethral plate which extended from the cloaca (and after Day 15.25, from the urogenital sinus) to the tip of the tubercle. On Day 18.25 the glans lamellae, which would separate the glans penis or the clitoris from the prepuce, began to develop in both sexes. Also on Day 18.25 a dense, midline plate of mesenchymal cells was first evident between the urogenital sinus and the rectum in normal males. This plate acted as a wedge, first increasing the separation between the rectum and the urogenital sinus, and subsequently separating the urethral plate from the surface epithelium in the genital tubercle. As a result, by Day 21.25 the urethra in males followed an “S”‐shaped course, extending from the pelvis through the center of the glans penis to an orifice near the tip of the genital tubercle. In females, in which a mesenchymal plate did not develop, the urethral orifice remained at the base of the tubercle, and the clitoris contained the remnants of the urethral plate, extending as an open groove from the urethral orifice to the tip of the tubercle. Finasteride did not affect development of the genital tubercle in females. However, in males exposed to finasteride in utero, there was variable failure of the mesenchymal wedge to develop. As a result, the urethral plate remained in contact with the surface epithelium and eventually opened to form a groove on the ventral surface of the glans penis (hypospadias). Also, the persistence of the urethral plate along the ventral midline in finasteride‐treated male fetuses and its subsequent opening as a groove interfered with development of the glans lamellae, causing displacement of the frenulum distally on the glans penis and the development of a cleft in the prepuce.
Sensitivity, specificity, and positive predictive value of multiple malformations in isotretinoin embryopathy surveillance
Authors: Lynberg Michele C. , Khoury Muin J. , Lammer Edward J. , Waller Kirsten O. , Cordero Jose F. , Erickson J. David 
Published: June 2005

AbstractIsotretinoin causes serious birth defects in about 25% of babies exposed in the first trimester of pregnancy. Despite warnings about the drug's teratogenicity, cases of isotretinoin embryopathy continue to occur; more than 80 such cases have been reported since 1982. The true magnitude of the problem is unknown, however, and case estimates range to more than 1,000. The need for isotretinoin embryopathy (IE) surveillance is therefore great. Sixty‐one known cases were evaluated to determine the sensitivity (proportion of cases with a given defect pattern) of various defect combinations. Using data from the Metropolitan Atlanta Congenital Defects Program for the period before isotretinoin was available, we evaluated the specificity (proportion of malformed infants without exposure who do not have the pattern of defects) for the various defect combinations. Ear malformations (microtia, anotia, absence or stricture of auditory canal, missing pinnae) have an associated sensitivity of 70.5% and a specificity of 99.5%. Ear defects combined with central nervous system (CNS) defects (microcephalus, hydrocephalus, reduction deformities of the brain) and cardiovascular (CVS) defects (conotruncal defects, aortic arch abnormalities) have an associated sensitivity of 19.7% and a specificity of 100.0%. The case definition of ear defects combined with either CNS or CVS defects maximizes both specificity (99.9%) and sensitivity (45.9%). The investigators are now evaluating the feasibility of using this pattern of defects to monitor for IE within a national monitoring program.
Teratogenic effect of the cholesterol synthesis inhibitor AY 9944 on rat embryos in vitro
Authors: Repetto M. , Maziere J. C. , Citadelle D. , Dupuis R. , Meier M. , Biade S. , Quiec D. , Roux C. 
Published: June 2005

AbstractAY 9944 [trans‐1,4‐bis(2‐chlorobenzylaminomethyl) cyclohexane dihydrochloride] is an amphiphilic cationic molecule. This chemical is an established inhibitor of cholesterol synthesis and is teratogenic in rats. The mechanisms of this teratogenicity remain to be clarified. This study used cultured rat whole embryos to ascertain whether AY 9944 had a direct effect on embryos, or whether its action was indirect, via the maternal cholesterol metabolism. Four experimental conditions were investigated: (A) controls; (B) 10 day untreated embryos were cultured in serum of treated rats; (C) 10 day untreated embryos were cultured in serum containing added AY 9944 (0–1,000 μg/ml); and (D) 10 day embryos from females treated on day 4 of gestation were cultured in normal serum. In group B there was no growth retardation; some slight nonspecific abnormalities were not significant. In group C, direct addition of AY 9944 to culture medium retarded growth and differentiation in a dosedependent manner. No malformation was observed, but histological examinations showed numerous areas of cell necrosis, especially in the CNS. In group D, not only was growth retardation observed, but also characteristic malformations of AY 9944 teratogenesis, including pituitary agenesis. These results show that AY 9944 teratogenicity is initiated prior to day 10.