bluuebunny/crossref_metadata_2025_split huggingface dataset:
Early postimplantation embryolethality in mice following in utero inhibition of adenosine deaminase with 2′‐deoxycoformycin
Authors: Knudsen T. B. , Gray M. K. , Church J. K. , Blackburn M. R. , Airhart M. J. , Kellems R. E. , Skalko R. G. 
Published: June 2005

AbstractAdenosine deaminase (ADA) catalyzes the hydrolytic deamination of adenosine (or 2′‐deoxyadenosine) to inosine (or 2′‐deoxyinosine). Previously, we have shown that ADA activity is subject to strong cell‐specific developmental regulation in placental tissues of mice between days 6 and 11 of gestation (Knudsen et al.:Biology of Reproduction 39:937–951, 1988). In the present study, we examined the effects of intrauterine exposure to 2′‐deoxycoformycin (dCF; pentostatin), a potent irreversible inhibitor of ADA, on early postimplantation development. Deoxycoformycin was administered to pregnant ICR mice as a single intraperitoneal injection at a dose of 5 mg/kg on one of days 6 through 11 of gestation (plug day 0). A marked increase in the incidence of implantation site resorptions was observed following treatment specifically on days 7 (61% resorbed) or 8 (78% resorbed). No effect was observed following treatment on days 6, 9, 10, or 11. ADA‐immunoreactive protein was shown, by ABC‐immunoperoxidase staining on days 7 or 8 of gestation, to be present at high levels in decidual cells of the antimesometrial region but at below‐detectable levels in the embryo. Treatment of pregnant dams with dCF on day 7 produced a complete (>99%) inhibition of ADA activity in the antimesometrial decidua by 30 min, induced excessive cell death in the prospective neural plate and primary mesenchyme of the trilaminar disc by 6 h, and arrested embryonic development at an early somite stage. These results suggest that the antimesometrial decidua plays a protective role in preventing an inappropriate accumulation of endogenous ADA substrates in the implantation site.
Defects of skeletal morphology, density, and structure in mouse fetuses with trisomy 16
Authors: Sterz H. , Buselmaier W. , Bacchus C. , Gromier L. , Eppler E. 
Published: June 2005

AbstractSkeletal anomalies present in trisomy 16 in the mouse—an animal model of human trisomy 21—are described. Altogether 27 fetuses with trisomy 16 and 118 chromosomally balanced siblings were examined radiographically and by alizarin staining on day 20 of gestation; the radiographs were analyzed by computer‐aided densitometry and structural differentiation. Extensive asymmetry or abnormal fusion of the vertebral centers and alterations of the vertebral arches were observed along with rib malformations (rib‐vertebra syndrome). The skull primarily exhibited anomalies of the occipital bone. Ossification of the humerus, femur, and tibia was characterized by reduced mineralization. Typical, fracture‐like alterations affecting only the tibia were also observed. Measurement of the lengths of the humeri of fetuses of comparable weight revealed a growth retardation not correlatable with the degree of mineralization. The significance of these skeletal abnomalies with regard to the trisomy 21 syndrome is discussed.
Effects of phorone and/or buthionine sulfoximine on teratogenicity of 5‐fluorouracil in mice
Authors: Naya Masato , Mataki Youichi , Takahira Hiroshi , Deguchi Takashi , Yasuda Mineo 
Published: June 2005

AbstractEmbryotoxicity and teratogenicity of 5‐fluorouracil (5‐FU) and modulation of its effect by the depletors of glutathione (GSH) were evaluated in mice. Pregnant ICR mice were intraperitoneally (i.p.) injected with 25 mg/kg of 5‐FU on day 11 of gestation (vaginal plug = day 0). Mice were pretreated i.p. with 250 mg/kg of phorone, a GSH depleting agent and/or 200 mg/kg of buthionine sulfoximine (BSO, an inhibitor of GSH biosynthesis) 4 hours before dosing with 5‐FU. Dams were killed on day 17 of gestation. Fetuses were examined for external malformations, especially limb malformations. Pretreatment with phorone or BSO decreased fetal weight and increased the frequency and severity of oligodactyly induced by 5‐FU, as well as the reduction of maternal GSH levels. Combined use of 125 mg/kg phorone and 100 mg/kg BSO i.p. augmented growth retardation induced with 5‐FU. Cotreatment with exogenous GSH, at a dose of 300 mg/kg injected intravenously, could not suppress the augmentative effects of phorone and/or BSO on 5‐FU teratogenicity under these experimental conditions. These results indicate that the level of endogenous GSH is one of the factors which significantly affects teratogenicity of 5‐FU.
Teratogenicity of carbamazepine in rats
Authors: Vorhees Charles V. , Acuff Karen D. , Weisenburger Walter P. , Minck Daniel R. 
Published: June 2005

AbstractThe teratogenicity of carbamazepine (CBZ) was investigated in Sprague‐Dawley CD rats at doses of 0, 200, 400, and 600 mg/kg administered by gavage in corn oil on days 7–18 of gestation in a dosage volume of 2 ml/kg. The CBZ‐600 dose was maternally toxic in that dams in this group weighed 30.6% less than controls by E20. This group had significantly increased resorptions, reduced live fetal weight (51.6% less than controls), and increased skeletal and visceral abnormalities. The CBZ‐400 dose also significantly reduced maternal weight gain during gestation to 26.6% less than controls by E20. No significant increase in resorptions occurred in this group; live fetuses weighed 42.9% less than controls and showed an increase in visceral, but not skeletal, abnormalities. The CBZ‐200 dose did not significantly affect maternal weight gain or increase resorptions or fetal abnormalities but did reduce fetal body weight (20.3% less than controls). Maternal serum total CBZ concentrations 1 hr after the final dose were 22.9, 27.9, and 34.4 μg/ml for the 200, 400, and 600 mg/kg groups, respectively. These levels were little changed 6 h post‐treatment. CBZ was 65–70% serum protein bound across dose groups. Human therapeutic levels of CBZ are 4–12 μg/ml and the drug is typically 80% serum protein bound. This suggests that abnormalities in rats occur at concentrations well above the human therapeutic range. However, a no‐effect level was not found for fetal body weight. Further experiments will be required to determine how much lower doses will need to be in order to find a no‐effect level for fetal body weight. Nevertheless, the present data suggest that CBZ is not potent at inducing malformations in rats.
Morphogenesis of retinoic acid‐induced postaxial polydactyly in mice
Authors: Bynum S. V. 
Published: June 2005

AbstractPrevious experiments have demonstrated that oral administration of retinoic acid to ICR mice on day 10 of gestation results in an enhanced expression of postaxial polydactyly of the forelimbs. In the present investigations, the development of the limbs from the time of treatment until the appearance of the defect on day 14 were studied at 12‐ to 24‐hr intervals with histological and vital staining technics. A diffuse cytotoxicity in the central proximal mesoderm was noted with a safranin–toluidine blue stain 12 h after treatment which then peaked 24 hr after treatment. Treated limbs stained with Nile blue sulfate showed a significant increase of necrotic mesodermal cells in the foyer preaxial primaire, foyer marginal I and foyer marginal V when compared to the respective control group. The treated postaxial ectoderm was more hyperplastic than was the control ectoderm on day 12. The treated group developed a squarish bulge on the postaxial boundary of the fifth digital ray on day 14 that was larger than those of the controls. Most of the controls had bulges that were completely necrotic. The treated group also had some completely necrotic bulges but a large number of the treated fetuses had bulges characterized as being less than 60% necrotic.
Teratogenic effect of cocaine and diazepam in CF1 mice
Authors: Mehanny Sherif Z. , Abdel‐Rahman Mohamed S. , Ahmed Yehia Y. 
Published: June 2005

AbstractThis study was conducted to determine the teratogenic effect of cocaine hydrochloride, alone or in combination with diazepam. Pregnant mice were administered cocaine hydrochloride at 10 and 20 mg/kg body weight intravenously (tail), and/or diazepam at 20 or 40 mg/kg b.w. by gavage. Combinations of diazepam and cocaine (20/10 and 40/20, respectively) were used. Significant reductions of fetal weight and length were found in the group treated with diazepam and cocaine (40/20). The incidences of incomplete ossification of sternebrae and skull bones, as well as delayed ossification of the paws, were significantly increased in the combination groups. Hydronephrosis and cryptorchidism were observed in the cocaine‐treated groups, with the incidence of these malformations increasing significantly when diazepam was co‐administered.
Physiological consequences of early neonatal growth retardation: Effects of α‐difluoromethylornithine on renal growth and function in the rat
Authors: Gray Jacqueline A. , Kavlock Robert J. 
Published: June 2005

AbstractThe physiological consequences of early neonatal growth retardation in the kidney were investigated using α‐difluoromethylornithine (DFMO), a specific irreversible inhibitor of ornithine decarboxylase (ODC), a key enzyme in the biosynthesis of polyamines. We administered by s.c. 500 mg/kg/day DFMO, or saline, to Sprague‐Dawley rat pups from the day of birth through postnatal day (PD) 6 and evaluated renal function on PD 4, 7, 10, and 13 using tests of basal renal clearance and urinary concentrating ability. Kidney weights and gross pathology were also obtained. On PD 39, serum chemistries and organ weights were determined. In a second experiment, we evaluated concentrating ability on PD 7–10, and basal renal function, concentrating ability, diuretic response, serum chemistries, and organ weights on PD 132–140. DFMO selectively inhibited renal growth but did not inhibit glomerular and tubular functional maturation. In fact, the rates of filtration and reabsorption (per g renal tissue), and concentrating ability were increased in treated pups. These changes were associated with long‐term effects on renal function, including uremia, glucosuria, and male‐specific concentrating deficits in adulthood. Several hypotheses can be developed concerning the physiological mechanisms underlying these changes (e.g., altered renal urea metabolism), which in turn may reflect either a direct role of ODC in the regulation of maturation or secondary consequences of inhibition of ODC. In conclusion, the renal growth retardation induced by neonatal administration of DFMO (PD 2–6) was associated with an apparent precocious maturation of function in the early postnatal period (PD 4–13) and dysfunction in adulthood, thus demonstrating that the physiological consequences of growth retardation are not always obvious and predictable, and must be evaluted on a case by case basis.
Conceptus viability, malformation, and suspect mutagens or teratogens in humans. The Yule–Simpson paradox and implications for inferences of causality in studies of mutagenicity or teratogenicity limited to human livebirths
Authors: Hook Ernest B. , Regal Ronald R. 
Published: June 2005

AbstractIf a genetic disorder or a congenital malformation is associated with embryonic or fetal death, then this may distort reported associations of environmental or biological factors with genetic and congenital disorders. We illustrate how such distortion may occur in humans as a manifestation of the Yule–Simpson (or Simpson) statistical paradox. We analyze the reported negative association of maternal smoking and Down syndrome in livebirths and demonstrate that under plausible conditions, valid negative associations both in livebirths and in embryonic or fetal deaths can occur, despite the fact that in all conceptuses there may be no association whatsoever. A similar analogous manifestation of the Yule–Simpson paradox may hold for positive associations. That is, positive relative risks may occur for an alleged mutagen or teratogen in separate studies both of livebirths, and of embryonic and fetal deaths, despite the absence of any effect in all conceptuses. These considerations illustrate the need for data on genetic disorders and malformations in embryonic and fetal deaths, and the need for a synthesis of such data with those from studies in livebirths before valid inferences may be made about mutagenic or teratogenic effects of environmental or biological factors.
Prenatal exposure to gamma/neutron irradiation: Sensorimotor alterations and paradoxical effects on learning
Authors: Di Cicco Daniela , Antal Sara , Ammassari‐Teule Martine 
Published: June 2005

AbstractThe effects of prenatal exposure on gamma/neutron radiations (0.5 Gy at about the 18th day of fetal life) were studied in a hybrid strain of mice (DBA/Cne males × C57BL/Cne females). During ontogeny, measurements of sensorimotor reflexes revealed in prenatally irradiated mice (1) a delay in sensorial development, (2) deficits in tests involving body motor control, and (3) a reduction of both motility and locomotor activity scores. In adulthood, the behaviour of prenatally irradiated and control mice was examined in the open field test and in reactivity to novelty. Moreover, their learning performance was compared in several situations. The results show that, in the open field test, only rearings were more frequent in irradiated mice. In the presence of a novel object, significant sex × treatment interactions were observed since ambulation and leaning against the novel object increased in irradiated females but decreased in irradiated males. Finally, when submitted to different learning tasks, irradiated mice were impaired in the radial maze, but paradoxically exhibited higher avoidance scores than control mice, possibly because of their low pain thresholds. Taken together, these observations indicate that late prenatal gamma/neutron irradiation induces long lasting alterations at the sensorimotor level which, in turn can influence learning abilities of adult mice.
A new method for explanting early postimplantation rat embryos for culture
Authors: Fujinaga Masahiko , Baden Jeffrey M. 
Published: June 2005

AbstractRat embryos were explanted either on day 8, 3 PM (primitive streak stage) or on day 9, 8 AM (presomite stage) and divided randomly into two groups (plug day = day 0). In one group, Reichert's membrane was removed starting from the side opposite to the ectoplacental cone which was left intact (standard method). In the second group, Reichert's membrane was removed starting from the same side as the ectoplacental cone after the latter structure was excised and the proamniotic cavity (day 8) or the ectoplacental cavity (day 9) destroyed (new method). Embryos were then cultured and examined at 10 AM on day 11. All embryos developed normally in size and general morphology. However, there was a high incidence of inverted heart, allantoic placenta and tail in all groups, except for day 9, new method group; this was the only group in which the ectoplacental cavity did not expand abnormally during culture. The new method, which is quick and easy to perform even when Reichert's membrane does not protrude well, lessens the chances of damaging embryonic ectoderm during the removal of Reichert's membrane. Furthermore, the absence of ectoplacental cone decreases embryo aggregation during culture. We hypothesize that the abnormally expanded ectoplacental cavity generates abnormal physical forces within the egg cylinder that disrupt the control of body asymmetry.
Sirenomelia associated with a “vanishing twin”
Authors: Kapur Raj P. , Mahony Barry S. , Nyberg David A. , Resta Robert G. , Shepard Thomas H. 
Published: June 2005

AbstractA case is presented of twin gestation in which one gestational sac was completely resorbed and the remaining twin was subsequently found to be sirenomelic. First‐trimester prenatal ultrasound examination demonstrated a second gestational sac that disappeared 2 weeks later. The sonographic features that led to the diagnosis of sirenomelia in the remaining fetus included severe renal dysgenesis, persistently apposed lower extremities, and absence of fibulae. Postmortem examination, including angiographic studies of the fetus, revealed caudal dysgenesis and a single umbilical artery that arose from the abdominal aorta. Sirenomelia occurs more frequently in twin gestations than in singletons. This case suggests that the association between twinning and sirenomelia may be greater than is currently recognized. Two hypotheses are given to explain this association.
TCDD exposure of human embryonic palatal shelves in organ culture alters the differentiation of medial epithelial cells
Authors: Abbott B. D. , Birnbaum L. S. 
Published: June 2005

AbstractThe highly toxic, polychlorinated aromatic compound 2,3,7,8‐tetrachlorodibenzo‐p‐dioxin (TCDD) occurs as a contaminant throughout the environment. Epidemiology studies of populations accidentally exposed to TCDD have failed to identify TCDD as a human teratogen, but these studies are limited by the small numbers of exposed pregnancies and imprecise estimates of exposure. TCDD is highly teratogenic in mice, inducing cleft palate and hydronephrosis. TCDD exposure in vivo of embryonic mice alters the differentiation and expression of growth factors in the medial epithelial palatal cells. These alterations also occur in rat and mouse palates exposed to TCDD in organ culture. In the present study, human embryonic palatal shelves were cultured in the rodent organ culture system. In order to achieve in vitro the developmental stage at which fusion would normally occur, GD 52 shelves were cultured for 4 days, GD 53 shelves were cultured for 3 days, and GD 54 shelves were cultured for 3 days. Three of four palatal shelves exposed to 5 × 10−11 M TCDD were identical to their homologous controls (right shelf cultured with control medium; left shelf cultured with TCDD‐containing medium). TCDD at 1 × 10−7 M produced cytotoxicity detected by transmission electron microscopy (TEM). Exposure to 1 × 10−8 M TCDD resulted in continued incorporation of thymidine ([3H]‐TdR detected autoradiographically) by palatal medial cells, failure of the medial peridermal cells to degenerate as observed by scanning electron microscopy (SEM), and differentiation into a stratified, squamous epithelium. These alterations are identical to those induced by TCDD in vitro in rat and mouse palatal cells. The main difference between these species is the level of TCDD required to elicit the responses. Cultured mouse palates respond to 5 × 10−11 M TCDD with altered medial cell differentiation, and 1 × 10−10 M TCDD is cytotoxic. The rat shelves respond with altered differentiation at 1 × 10−8 M and cytotoxicity at 1 × 10−7 M. All the human shelves respond at 1 × 10−8 M TCDD with altered differentiation, 1 out of 4 responded at 5 × 10−11 M, and cytotoxicity occurred at 1 × 10−7 M. The present data suggest human embryonic palates are less sensitive than those of the C57BL/6N mouse, and that exposure to high levels of TCDD would be required to elicit altered differentiation in the palatal shelf.
Activity profiles of developmental toxicity: Design considerations and pilot implementation
Authors: Kavlock Robert J. , Greene Jacqueline A. , Kimmel Gary L. , Morrissey Richard E. , Owens Elizabeth , Rogers John M. , Sadler Thomas W. , Stack H. Frank , Waters Michael D. , Welsch Frank 
Published: June 2005

AbstractThe available literature was searched for quantitative test results from both in vitro and in vivo assays for developmental toxicity for five model compounds: cyclophosphamide, methotrexate, hydroxyurea, caffeine, and ethylenethiourea. These compounds were chosen on the basis of their extensive utilization in a variety of assay systems for developmental toxicity as evidenced by their representation in the ETIC database (each generally has 100–500 citations encompassing multiple test systems). Nine cellular‐based assays, six assays using whole embryos in culture, as well as Segment II and abbreviated exposure tests for mammalian test species are included in the database. For each assay, the critical endpoints were identified, each of which was then provided a three‐letter code, and the criteria for extraction of quantitative information were established. The extracted information was placed into a computerized reference file and subsequently plotted such that the qualitative (positive/negative) and quantitative (e.g.), IC50, highest ineffective dose (HID), lowest effective dose (LED)) results across all test systems could be displayed. The information contained in these profiles can be used to compare qualitative and quantitative results across multiple assay systems, to identify data gaps in the literature, to evaluate the concordance of the assays, to calculate relative potencies, and to examine structure‐activity relationships.
Isolated oral cleft malformations: Associations with maternal and infant characteristics in a California population
Authors: Shaw Gary M. , Croen Lisa A. , Curry Cynthia J. 
Published: June 2005

AbstractData on isolated oral cleft malformations from a birth defects registry covering a large population base were examined to describe potential associations with maternal and infant characteristics. Infants with cleft palate (CP) were analyzed separately from infants with cleft lip with or without cleft palate (CLP). The prevalence of isolated CLP per 1,000 births was 0.741, approximately twice the prevalence of isolated CP, which was 0.383. Male infants were more likely to be born with CLP (OR = 1.9) but less likely to be born with CP (OR = 0.56) than were females. Women 39 years or more of age were twice as likely as 25–29 year olds to have a child with either type of cleft. Black, non‐hispanic infants had a lowered risk for CLP compared to white, nonhispanics (OR = 0.40). These risks were found to be independent of each other based on multivariate analyses. Associations with either type of cleft malformation were not observed for plurality, number of previous live births, and maternal birthplace.
Role of glutathione and hsp 70 in the acquisition of thermotolerance in postimplantation rat embryos
Authors: Harris Craig , Juchau Mont R. , Mirkes Philip E. 
Published: June 2005

AbstractStudies were initiated to determine the extent to which reduced glutathione (GSH) may be involved in the capacity of cultured rat embryos to develop heat‐induced tolerance to the deleterious effects of exposure to high temperatures (heat shock). Investigations of the modulation of dysmorpho‐genic responses of embryos to heat shock (43°C, 30 min) as well as to the expression of the hsp70 gene and subsequent formation of hsps indicated that the acquisition of thermotolerance by rat embryos could be significantly influenced by the inhibition of GSH synthesis. Treatment of conceptuses with L‐buthio‐nine‐S,R‐sulfoximine (BSO) reduced intracellular GSH concentrations and compromised the capacity of embryos to mount a thermotolerance response as assessed by alterations in indices of growth and development. Embryonic thermotolerance elicited by preexposure to 42°C for 30 min was accompanied by increases in GSH to levels greater than those measured in control embryos at 37°C just prior to the subsequent 43°C heat exposure. Expression of hsp70 mRNA was detectable soon after elevation of the temperature to 42°C and reached its highest level of accumulation 1.5 hr after the 43°C heat shock. BSO treatment had little if any effect on hsp70 message levels or on the synthesis of hsp70. The fact that BSO‐treatment attenuated the thermotolerance response but did not produce a decrease in hsp70 RNA or the synthesis of hsp70 suggests that hsp70 alone is not sufficient to confer thermotolerance upon cultured rat embryos.