bluuebunny/crossref_metadata_2025_split huggingface dataset:
Etiology of retinoic acid‐induced cleft palate varies with the embryonic stage
Authors: Abbott B. D. , Harris M. W. , Birnbaum L. S. 
Published: June 2005

AbstractRetinoic acid (RA) has been shown to be teratogenic in many species, and 13‐cis‐RA is teratogenic in humans. Exposure to RA during embryonic morphogenesis produced a variety of malformations including limb defects and cleft palate. The type and severity of malformation depended on the stage of development exposed. The purpose of this study was to compare the effects of RA exposure in vivo on different stages of palate development. These results were compared to effects observed after exposure in organ culture. The vehicle used in RA dosing was also shown to be a major factor in the incidence of RA‐induced cleft palate. For the in vivo studies, RA (100 mg/kg) in 10 ml corn oil/kg was given p.o. on gestation day (GD) 10 or 12, and the embryos were examined on GD 14 and 16. Exposure to RA in an oil:DMSO vehicle resulted in much higher incidences of cleft palate than were observed after dosing with RA in oil only. After exposure on GD 10, to RA, small palatal shelves formed which did not make contact and fuse on GD 14. The medial cells did not undergo programmed cell death. Instead, the medial cells differentiated into a stratified, squamous, oral‐like epithelium. The RA‐exposed medial cells did not incorporate 3H‐TdR on GD 14 or 16, but the cells expressed EGF receptors and bound 125I‐EGF. In contrast, RA‐induced clefting after exposure on GD 12 did not involve growth inhibition. Shelves of normal size formed and made contact, but because of altered medial cell differentiation did not fuse. Medial cells differentiated into a pseudostratified, ciliated, nasal‐like epithelium. This response was produced in vivo at exposure levels which produced cleft palate, and after exposure of palatal shelves to RA in vitro from GD 12–15. The medial cells exposed on GD 12 incorporated 3H‐TdR on GD 14, expressed EGF receptors, and bound 125I‐EGF. The responses to RA which lead to cleft palate differed after exposure on GD 10 or 12, and the pathways of differentiation which the medial cells followed depended on the developmental stage exposed.
Chloride transport in embryonic cells: Effect of ethanol and GABA
Authors: Zimmerman Ernest F. , Collins Michael 
Published: June 2005

AbstractEthanol and GABA (γ‐aminobutyric acid) and their interaction on 36Ci−influx were analyzed in cultured embryonic palate and limb mesenchymal cells in order to determine whether ethanol exerts its teratogenic action through a GABA receptor involved in embryogenesis. Cl−transport in secondary cultures of C57BL/6 palate mesenchymal cells was shown to consist of three systems including the electroneutral Cl−HCO3− exchange (50%) and Na+ /K+/Cl− cotransport (30%) pathways and the voltage‐dependent Cl− channel (20%). Treatment with DIDS (4,4′‐diisothiocyanostilbene 2,2′‐disulfonic acid) or SITS (4‐acetamido‐4′‐isocyano‐stilbene‐2,2′ disulfonic acid) in SWV palate cells inhibited the Cl−HCO3− exchange pathway, while treatment with DIDS and bumetanide inhibited both the exchange and cation cotransport pathways, the residual Cl− influx inferred to be the electrogenic pathway. Inhibition of Cl− transport by anthracene‐9‐carboxylic acid confirmed the presence of the electrogenic Cl− pathway. It was observed that the rate of Cl− transport was significantly greater in palate cells of C57BL/6 mice than those of SWV mice. Also the rate of Cl− transport was significantly greater in secondary cultures of palate cells from C57BL/6 mice than from primary cultures of limb cells from the same strain. No evidence could be obtained that ethanol (10 to 100 mM) or GABA (3 × 10−5 M) or their combination stimulated total Cl− influx in either C57BL/6 or SWV palate mesenchymal cells, putative voltage‐dependent Cl− influx in C57BL/6 palate cells, or total Cl− influx in primary cultures of C57BL/6 limb mesenchymal cells.
Maternal diabetes and cardiovascular malformations: Predominance of double outlet right ventricle and truncus arteriosus
Authors: Ferencz Charlotte , Rubin Judith D. , McCarter Robert J. , Clark Edward B. 
Published: June 2005

AbstractMost studies on the relationship of maternal diabetes to cardiovascular malformations (CVM) have been prospective investigations of pregnancy outcome and therefore could not identify associations with rare cardiac lesions. The results of a retrospective study shed new light on the risks of specific cardiac defects in diabetic pregnancies.The Baltimore‐Washington Infant Study, a population‐based case‐control investigation of CVM, provides information on maternal diabetes reported in personal interviews. Among 2259 mothers of cases, 35 (1.5%) reported diabetes present before pregnancy (called “overt”) and 95 (4.2%) reported diabetes only during pregnancy (called “gestational”). Among 2,801 mothers of controls, 14 (0.5%) had overt diabetes and 83 (3.0%) had gestational diabetes. Malformationspecific risks were expressed as odds ratios (OR) with 99.5% confidence intervals (CI). The strongest associations with overt maternal diabetes were found with double outlet right ventricle (OR 21.33; 99.5% CI 3.34, 136.26), and truncus arteriosus (OR 12.81; 99.5% CI 1.43, 114.64). No significant diagnosis‐specific associations were found with gestational diabetes. Non‐cardiac malformations were present in 23% of infants with CVM whose mothers had overt diabetes and in 26% of infants with CVM whose mother had gestational diabetes, in 32% of infants with CVM whose mothers did not have diabetes, and in 4% of controls. Double outlet right ventricle and truncus arteriosus are malformations dependent upon neural‐crest‐cell‐derived ectomesenchymal tissues; these are precisely the conotruncal abnormalities that result from experimental ablation of the neural crest in chick embryos. The association with diabetes suggests a further etiologic link between these two lesions.
Examination of a rodent limb bud micromass assay as a prescreen for developmental toxicity
Authors: Wise L. D. , Clark R. L. , Rundell J. O. , Robertson R. T. 
Published: June 2005

AbstractThe mouse limb bud micromass assay is one of many short‐term tests proposed as preliminary screens for potential developmental toxicity. Previous efforts to validate this assay have used too few “nonteratogens.” The purpose of this study was to examine additional compounds, most of which, based on the literature, were perceived to have low potential for developmental toxicity in vivo. In addition, a method of data analysis was sought that would identify selective developmental toxins in the micromass assay, i.e., those that are effective at dosages not maternally toxic. The concentration of each of 23 compounds that produced a 50% inhibition (IC50) of radiolabeled thymidine (T) and sulfate (S) incorporation was determined and used to calculate a T/S ratio. The T/S ratio may be a useful measure of developmental hazard, since T incorporation measures toxicity toward a general cell function (DNA synthesis) and S incorporation measures mainly toxicity toward a developmentally specific cell activity (chondroitin sulfate synthesis). All compounds tested produced T/S ratios of <2.0. Since 22 of these 23 compounds are classified as “nonteratogens” or nonselective developmental toxins in vivo, a low T/S ratio in this in vitro assay system may be capable of discriminating potential for developmental hazard in vivo.
Risk factors for birth defects: Data from the Atlanta Birth Defects Case‐Control Study
Authors: Erickson J. David 
Published: June 2005

AbstractThe Atlanta Birth Defects Case‐Control Study data comprises information obtained from interviews with parents of 4,900 babies born with major birth defects and with the parents of 3,000 babies born without defects. The source of cases is the Centers for Disease Control's Metropolitan Atlanta Congenital Defects Program; the case‐control study is population‐based. Birth defects are classified into 92 groups and cross‐tabulated by 105 exposure/risk factor variables; data from selected cross‐tabulations are presented. The associations of each of the 105 exposure variables with all types of defects combined are presented, as are the associations of each of the 92 defect groups with the specific exposure variable, maternal diabetes. These data can be used to evaluate hypotheses arising from other sources, and for the purpose of “generating” hypotheses. The data describing all 92 × 105 cross‐tabulations are available to other investigators on floppy disk; write to Chief, Birth Defects and Genetic Diseases Branch, Centers for Disease Control, Atlanta, Georgia 30333.
Exposure to ionizing radiation during pregnancy: Perception of teratogenic risk and outcome
Authors: Bentur Y. , Horlatsch N. , Koren G. 
Published: June 2005

AbstractWe quantified the perception of teratogenic risk in women attending the Motherisk program for counseling about diagnostic radiation in pregnancy (n = 50) and compared it with a control group of women exposed to nonteratogenic drugs and chemicals (n = 48). Before receiving known information about the specific exposure, women exposed to radiation assigned themselves a significantly higher teratogenic risk compared with the control group (25.5 ± 4.3% versus 15.7 ± 3.0% for major malformations, P < 0.01). The post‐consultation perception of teratogenic risk did not differ between the two groups. Special consideration and attention should be given when counseling pregnant women exposed to low‐dose ionizing radiation, as their misperception of teratogenic risk may lead them to unnecessary termination of their pregnancy.
Morphological differences elicited by two weak acids, retinoic and valproic, in rat embryos grown in vitro
Authors: Seegmiller Robert E. , Harris Craig , Luchtel Daniel L. , Juchau Mont R. 
Published: June 2005

AbstractWe compared in rat whole‐embryo culture the morphological changes elicited by valproic acid (VPA) with those elicited by trans‐retinoic acid (RA). Rat embryos explanted on day 9.5 of gestation were treated on day 10 with RA or VPA at concentrations producing equivalent reductions in embryonic protein. The concentrations selected for morphological assessment by scanning and transmission electron microscopy, 2.3 and 800 μM, respectively, for RA and VPA, produced approximately a 50% incidence of abnormally open anterior neuropores in initial range‐finding experiments in the culture system. Protein and DNA analyses were also performed on corresponding groups of embryos at three different doses. With concurrent control groups used as reference standards, the two treatment groups were compared for differences in external and internal morphology, protein and DNA contents, and growth indices. While certain variables responded similarly in the two treatment groups, e.g., the growth variables, protein and DNA contents, each drug produced selective morphological effects. Whereas treatment with RA produced underdeveloped branchial arches, symmetrically cleft cranial defects resulting in openings in rhombencephalic and prosencephalic regions, and exteriorized neural tissue in the caudal neuropore region, VPA produced irregular clefts with wavy margins along the entire length of the neural tube, and an open caudal neuropore without eversion of the neuroepithelium, while producing no detectable effect on the branchial arches. The similar effects of these two drugs on protein and DNA contents suggest comparable degrees of overall toxicity; however, the dissimilar effects on neural tube and branchial arches, coupled with the large difference in concentration of the drug required to produce the effects, add to the evidence that their mechanisms for elicitation of abnormal development are qualitatively different.
Effects of lysosomal proteinase inhibition on the development of the rat embryo in vitro
Authors: Daston George P. , Baines Donald , Yonker Julie E. , Lehman‐McKeeman Lois D. 
Published: June 2005

AbstractAltered lysosomal function in the visceral yolk sac can result in abnormal development. As proteolysis is an important function of the rodent visceral yolk sac during early and mid‐gestation, we characterized the lysosomal proteolytic enzyme activity of this extraembryonic membrane and determined the effects of inhibitors of protein degradation on embryonic development. Constituent activities of cysteine and aspartic acid proteinases were measured in rat visceral yolk sac on gestation day 12, and the effects of the cysteine proteinase inhibitors leupeptin, E‐64 [trans‐epoxysuccinyl‐l‐leucylamido(4‐guanido)butane] and N‐ethylmaleimide and the aspartic acid proteinase inhibitor pepstatin were determined in Sprague–Dawley rat embryos cultured in vitro from gestation days 10–12. It was determined that only cysteine proteinases, primarily cathepsins B and L, are active in the mid‐gestation visceral yolk sac. The cysteine proteinase inhibitors leupeptin and E‐64 both produced a concentration‐related decrease in embryonic growth, as measured by crown–rump length, somite number, and embryonic protein content, and a concentration‐related increase in incidence of abnormalities. A characteristic pattern of abnormalities was produced which involved a decrease in neural tube volume and the formation of a subectodermal blister opposite the point of attachment of the vitelline vessels. At high concentrations, anophthalmia was also observed. The decreased neural tube volume was associated with increased osmolality of the exocoelomic fluid, the major extraembryonic fluid compartment. It is possible that the osmotic change decreased neural tube volume by causing water to move to the compartment with a higher solute concentration, out of the embryo. Leupeptin and E‐64 treatment increased yolk sac protein content, and produced histologically observable protein droplets (probably secondary lysosomes), indicating that lysosomal protein degration was inhibited. N‐Ethylmaleimide was a potent embryotoxin, but had none of the effects of the other cysteine proteinase inhibitors at concentrations which were not embryolethal. However, it should be noted that N‐ethylmaleimide was embryolethal at a concentration which is 1,000‐fold lower than that which inhibits cysteine proteinase activity in a lysosomal lysate. Pepstatin, an aspartic acid proteinase inhibitor, was without effect at any concentration tested (up to 300 μg/ml). These results indicate that inhibition of lysosomal proteolysis in the visceral yolk sac, specifically by cysteine proteinase inhibitors, is developmentally toxic to rats. The effects produced may be attributable both to lack of substrates (amino acids) for growth, and altered osmolality in the extraembryonic fluid compartment.
Effects of lithocholic acid exposure throughout pregnancy on late prenatal and early postnatal development in rats
Authors: Zimber A. , Zusman I. , Bentor R. , Pinus H. 
Published: June 2005

AbstractThe effects of lithocholic acid (LCA) on late prenatal and early postnatal development were studied. LCA was given in the diet (0.8% by weight) or administered in the drinking water (0.8%) throughout the entire period of pregnancy. The addition of LCA to the drinking water caused a significant reduction in the weight of 20‐day‐old fetuses as well as their placentas and livers. Feeding LCA to pregnant rats affected postnatal growth of the offspring: their weight was significantly lower than control values until 6 weeks of age. The pattern of postnatal growth was similar in the experimental and control rats. The retardation in growth and development of the offspring was accompanied by microscopic and biochemical changes in their livers.
Sensorineural hearing loss as evidenced by the auditory brainstem response following prenatal cocaine exposure in the long‐evans rat
Authors: Church M. W. , Overbeck G. W. 
Published: June 2005

AbstractPrenatal cocaine exposure has been associated with a variety of adverse neurological effects. Three recent studies found evidence that prenatal cocaine exposure is associated with abnormal auditory electrophysiology, suggesting abnormal processing of auditory information. The present study used the auditory brainstem response to evaluate the effects of prenatal cocaine exposure on hearing in an animal model (Long‐Evans rat). We report that prenatal cocaine exposure can cause elevated ABR thresholds and latency‐intensity curves consistent with a recruitment‐type sensorineural hearing loss.
Selective staining methods for cartilage of rat fetal specimens previously treated with alizarin red S
Authors: Yamada Takashi 
Published: June 2005

AbstractA convenient method for staining cartilage with several basic stains after alizarin red S staining of bone was investigated in rat fetuses. It was found that bromophenol blue was useful and effective for staining of the margin and center areas of cartilage, even in specimens stored in glycerin for over 10 years. The specimens were washed in running tap water for 1 hr, and subsequently were immersed in water or in 70% ethanol at pH 4 for 1 hr or longer. The specimens were then stained with 0.005% bromophenol blue in 40% ethanol adjusted to pH 4 for 2 hr, or with 0.001% bromophenol blue in 40% ethanol adjusted to pH 4 for 24 hr. Furthermore, the bromophenol blue stain color actually faded when the specimens were immersed in water or in 70% ethanol at pH 8. Descending order of the stain‐effective action on fetal rat cartilage for the basic stains tested was bromophenol blue, aniline blue, Evans blue, methyl violet, trypan blue, and water blue.
Marked increase in the teratogenicity of the combined administration of the industrial solvent 2‐methoxyethanol and radiofrequency radiation in rats
Authors: Nelson B. K. , Conover David L. , Brightwell W. Stephen , Shaw Peter B. , Werren Dwight , Edwards Richard M. , Lary Joseph M. 
Published: June 2005

AbstractLimited published animal research reports synergistic teratogenic effects following combined hyperthermia (induced by elevated ambient temperature) and administration of chemical teratogens. Radiofrequency (RF) radiation is widely used in occupational environments. Since RF radiation also elevates the body temperature of, and is teratogenic to, exposed animals, concurrent RF radiation and chemical agent administration may enhance teratogenicity. The present exploratory study, consisting of preliminary dose‐finding studies and the primary study, was designed to investigate whether concurrent exposure of rats to RF radiation and the industrial solvent 2‐methoxyethanol (2ME) can enhance the developmental toxicity of either agent acting alone. Preliminary dose‐finding studies using small numbers of rats investigated the ability of various RF radiation conditions and doses of 2ME to produce external malformations (primarily of the paws) when administered on gestation day 13. Based on these preliminary studies, RF radiation exposure [sufficient to elevate rectal temperature to 42.0°C (4°C above normal for rats) for 30 min] and 2ME administration (150 mg/kg) were selected for the primary study. In the primary study, groups of 18 to 27 pregnant rats were administered RF radiation exposure and distilled water gavage, 2ME gavage and sham RF exposure, RF radiation exposure and 2ME gavage concurrently, or sham RF exposure and distilled water gavage. Pregnant rats were sacrificed on gestation day 20, and the offspring were examined for external malformations. Combined exposures enhanced the adverse effects produced by either experimental agent alone (no malformations were detected in the double sham group). Mean fetal malformations/litter increased from 14% after 2ME and sham RF (15/26 litters affected, with an average of 2 fetuses/litter malformed) and 30% after RF radiation and water gavage (10/18 litters affected, with an average of 4 fetuses/litter malformed), to 76% after the combined treatment (18/18 litters affected, with an average of 12 fetuses/litter malformed). In addition to a significant increase in the frequency of malformations, the severity of malformations also was enhanced by the combination treatment (on a relative severity ranking scale, the 2ME severity score was less than 1, the RF score was 3, and the combination score was 6). This study provided evidence of synergism between RF radiation and 2ME administration, but additional research will be required to characterize the extent of synergism between these two agents. Potential interactive effects between chemical and physical agents need to be investigated to determine the extent to which such interactions should impact occupational exposure standards.
Hypothermia: Teratogenic and protective effects on the development of mouse embryos in vitro
Authors: Smoak Ida W. , Sadler Thomas W. 
Published: June 2005

AbstractHypothermia often occurs in association with clinical conditions involving severe hypoglycemia, but its effect on embryonic development has not been well evaluated. Thus, the whole embryo culture method was used to expose day 9 (neurulating) and day 10 (early limb bud stage) mouse embryos to physiologic levels of hypothermia (35°C and 32°C) for 4 and 24 hr. Embryos were evaluated after 24 hours for growth and malformations and compared with controls grown at 37°C. Lactate production was measured in embryos cultured for 4 hr at 32°C and compared with those cultured at 37°C. A 4‐hr exposure to hypothermia produced little effect morphologically but reduced the rate of lactate production at both embryonic stages. A 24‐hr exposure to hypothermia at 35°C or 32°C produced growth retardation and dysmorphogenesis in embryos undergoing neurulation. Early limb bud stage embryos were less sensitive to this treatment, with growth retardation produced only at the lower temperature. Since hypothermia is commonly associated with severe hypoglycemia in cases of diabetic insulin overdose, day 9 (neurulating) mouse embryos were exposed concurrently to short periods of hypothermia and hypoglycemia and compared with embryos cultured in hypoglycemic medium at normal temperature. The results demonstrated that hypothermia partially protects embryos against the dysmorphogenic effects of hypoglycemia. A balance of metabolic rate and available substrate is discussed as a possible mechanism for this protective effect.
Potentiating effect of caffeine on the teratogenicity of acetazolamide in C57BL/6J mice
Authors: Beck Sidney L. , Urbano Charissa M. 
Published: June 2005

AbstractPregnant C57BL/6J mice were treated with 0 or 50 mg of caffeine (CAFF) per kg, and 0, 200 mg/kg (L) or 1,000 mg/kg (H) of acetazolamide (ACZM) during day 9 of gestation (9DPC). Individual fetuses were examined for gross morphological abnormalities and skeletal variations. The increase in fetal malformations seen, especially right forelimb electrodactyly, was augmented at both dose levels of acetazolamide by concomitant exposure to caffeine. Both frequency and severity of ectrodactyly were potentiated by caffeine. Skeletal examination revealed a reduction of the number of ossified cervical and caudal vertebral centra among litters exposed to ACZM at either dose. In either case (ACZM‐H, ACZM‐L) that effect was augmented by co‐administration of CAFF. The first cervical vertebra (C1) appeared to provide the most sensitive index of teratogenic exposure.This study provides evidence that a subteratogenic dose of caffeine can potentiate the teratogenic effect of acetazolamide in C57BL/6J mice when dams are treated on day 9 of gestation. In addition, skeletal examination provided evidence that simultaneous treatment with both agents delayed fetal development. Many litters exposed to ACZM or both agents displayed a reduction in skeletal ossification even in the absence of gross morphological abnormalities, suggesting that ossification can be used as an indicator of prenatal exposure to potentially harmful substances in the C57BL/6 mouse strain.