bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exogenous sex hormone exposure and the risk for VACTERL association
Authors: Lammer Edward J. , Cordero Jose F. , Khoury Muin J. 
Published: June 2005

AbstractIn several studies investigators have suggested that maternal use of exogenous sex hormones during early pregnancy may be associated with various congenital malformations. A group of malformations, the VACTERL (vertebral, anal, cardiac, trachea, esophageal, renal, limb—acronym) association, has been statistically associated with maternal exposure to exogenous sex hormones during the first trimester of pregnancy. The VACTERL association is a nonrandom group of major malformations that occur together more often than would be expected on the basis of chance. To assess this association, we conducted a case‐control study of first‐trimester exposure to sex hormones among mothers of 34 infants with the VACTERL association and of 1,024 comparison infants with one or more of ten major malformations or Down syndrome. The study subjects were malformed infants born between July 1970 and June 1979 and registered in a population‐based birth defects registry. Information concerning the use of exogenous sex hormones during pregnancy was obtained by systematically interviewing the mothers of the malformed infants. Most of the mothers were interviewed within 6 months of their children's births. Each mother was interviewed within a year of her child's birth. We found an odds ratio of 0.98 (90% confidence limits 0.40, 2.38) for the relationship between VACTERL association and use of any sex hormone in the first trimester of pregnancy. Our study had adequate statistical power to detect a true relative risk of 2.8 or greater.
Teratogen concentration changes as the basis of the heat stress enhancement of arsenate teratogenesis in hamsters
Authors: Hanlon David P. , Ferm Vergil H. 
Published: June 2005

AbstractHamster dams dosed continously with arsenate and exposed to short‐term hyperthermia produced a greater percentage of malformed offspring than did hamster dams dosed with arsenate alone. Hamsters receiving both treatments possessed elevated arsenic concentrations in the maternal blood and placentas immediately after cessation of the hyperthermic insult. Blood levels of arsenic were the same as those of animals not receiving the heat treatment within several hours post‐hyperthermia; however, arsenic concentrations remained elevated in placentas, the duration being dependent on the dose of arsenate. We suggest that the rise in placental arsenic concentrations is the basis of the increase in the production of fetal malformations for hamsters treated continuously with arsenate and heat stressed during critical organogenesis.
Strain differences in response of Sprague‐Dawley and Long Evans Hooded rats to the teratogen nitrofen
Authors: Kang Y. J. , Zolna L. , Manson J. M. 
Published: June 2005

AbstractAdministration of nitrofen (2,4‐dichloro‐4′‐nitrodiphenyl ether) during organogenesis in rodents produces neonatal lethality accompanied by lung hypoplasia, diaphragmatic hernias, heart anomalies, and hydronephrosis. Different strains of rats, Long Evans Hooded (LEH) and Sprague‐Dawley (SD), are reported to have different malformation responses to prenatal exposure, which could be due to true strain differences, to different levels and times of exposure, or to the use of different methods for detecting visceral malformations. In the present study, LEH, SD, and „virus‐antibody‐negative”︁ SD (VAN‐SD) rats were identically exposed to 0, 6.25, 12.5, or 25 mg/kg/day of nitrofen by gavage in corn oil on days 6–15 of gestation. At term, half of the litter was examined by the Wilson method of razorblade sectioning and the remainder by a modified Staples method of fresh visceral examination. The two methods were equally sensitive for detecting diaphragm, kidney, and lung anomalies, whereas heart malformations were more frequently identified with fresh visceral examination. The frequency of total malformations did not vary across strains at any dose, but there were substantial differences in the pattern of malformations in each strain. SD and VAN‐SD rats responded similarly for all malformations, but had significantly higher incidences of diaphragm and lung anomalies than LEH rats. Conversely, LEH rats had significantly elevated levels of kidney anomalies compared to SD and VAN‐SD rats, whereas frequency of heart malformations was low and comparable across strains. These results suggest that true strain differences exist in the pattern of malformation produced by prenatal exposure to nitrofen that may be based on genetic differences in embryonic susceptibility.
Teratogenicity of paraxanthine (1,7‐dimethylxanthine) in C57BL/6J mice
Authors: York Raymond G. , Randall Joan L. , Scott William J. 
Published: June 2005

AbstractThe teratogenicity of caffeine, as well as two of its three dimethylated metabolites (theobromine and theophylline), has been established in animal studies. The third metabolite, paraxanthine, has not been reported as being tested for teratogenicity even though it is actually the major demethylated metabolite of caffeine metabolism in man. Pregnant C57BL/6J mice were treated i.p. with 175 or 300 mg/kg/day paraxanthine (1,7‐dimethylxanthine) dissolved in deionized water at 4 p.m. on day 11 and 9 a.m. on day 12 of gestation. All dams were sacrificed on day 18, and fetuses were fixed for Wilson's razor blade sectioning or double‐staining skeletal examination. A dose‐related increase in total malformations, primarily cleft palate and limb malformations, was found. The pattern of malformations was similar to that reported for caffeine, theobromine, and theophylline, i.e., an asymmetric response with the left forelimb most often affected. A 21% resorption and a 46% malformation rate was observed at 300 mg/kg/day of paraxanthine, indicating that paraxanthine was slightly less toxic to the embryo than caffeine. Therefore, the parent compound, caffeine, as well as all three of its dimethylated metabolites—paraxanthine, theophylline, and theobromine—are teratogenic.
In vitro studies on the effect of yolk sac antisera on functions of the visceral yolk sac: I. Pinocytosis and transport of small molecules
Authors: Lerman S. , Koszalka T. R. , Jensen M. , Andrew C. L. , Beckman D. A. , Brent R. L. 
Published: June 2005

AbstractThe production of congential malformations by the administration of teratogenic antisera to pregnant animals has been reported from many laboratories. This work has focused our attention on the importance of the yolk sac placenta in supporting the rat embryo during early organogenesis and the significance of yolk sac dysfunction in rodent teratogenesis. The studies reported in this article deal with the effect of teratogenic antisera on the process of yolk sac transport; specifically pinocytosis (as measured by 14C‐sucrose uptake) and small‐molecule transport utilizing 14C‐α‐aminoisobutyric acid (AIB) and 3H‐2‐deoxyglucose (DOG). We sought to determine whether several different yolk sac localizing antibodies interfere with these transport processes, and, if so, which transport processes were most affected.The results of the experiments indicated that teratogenic antisera interfered with the process of pinocytosis in the yolk sac and that pinocytosis can be reduced as much as 40%. Nonteratogenic antisera, even when they localized in the yolk sac, did not interfere with the process of pinocytosis. Furthermore, the teratogenic antisera did not interfere with the transport of small molecules (either AIB or DOG) in the yolk sac. These results indicated that while fluorescent localization of an antiserum in the yolk sac did not invariably indicate the potential for teratogenicity, it is likely that the reduction in pinocytosis may directly correlate with the teratologic and embryopathic events. This work reaffirms the view that the yolk sac in important during rodent organogenesis and that yolk sac dysfunction can play an important role in the development of congenital malformations. The results from the endocytosis experiments with explanted yolk sacs did identify the embryotoxic antiserum (i.e., whole visceral yolk sac antiserum) and thus this method may have utility as a rapid bioassay for these antisera. The simple measurement of endocytic index as a marker for the determination of teratogenicity of uncharacterized sera would represent a considerable saving in time, effort, and animals.
Dose‐ and stage‐related sex difference in the incidence of cytosine arabinoside induced digit anomalies in the mouse fetus
Authors: Goto Tadashi , Endo Akira 
Published: June 2005

AbstractPregnant mice of the Jc1:ICR strain were injected intraperitoneally with a single dose of 2.5, 5, or 10 mg/kg of cytosine arabinoside (Ara‐C) on day 9.5 or 10.5 of gestation (dg). Mice were killed on 18.4 dg, and the incidences of digit anomalies were compared between male and female fetuses. In the group treated with 10 mg of Ara‐C on 9.5 dg, oligodactyly of the hindlimbs was produced more frequently in male fetuses. In the group treated with 5 mg of Ara‐C on 10.5 dg, oligodactyly of the forelimbs tended to occur more frequently in male fetuses. Also, in this group, oligodactyly of the hindlimbs occurred more frequently in male fetuses, whereas polydactyly occurred more frequently in female fetuses. The observed difference in the incidences of digit anomalies between male and female fetuses may be explained either in terms of the sex‐related time lag in the critical period for digit development or by a probable sex difference in embryonic susceptibility to Ara‐C.
Glycolysis in the mouse uterus during the early post‐implantation stages of pregnancy and the effects of acute doses of ethanol
Authors: Murdoch R. N. 
Published: June 2005

AbstractThe objective of this study was to assess the possibility that, in mice, alcohol interferes with uterine glycolysis to influence indirectly embryonal development. Glycolysis was found to be a major metabolic process in the mouse uterus and its pattern of activity changed during post‐implantation pregnancy between days 5 and 9. This was evidenced by changes in glycolytic enzymes and intermediates, and in the capacity of endometrial preparations to consume oxygen and produce lactate during incubation in vitro. The intraperitoneal administration of ethanol at 3.0 and 6.0 gm/kg body weight, but not at 1.5 gm/kg body weight, on day 9 of pregnancy modified glycolysis in the uterus after 2 hours, resulting in significant changes in the rates of accumulation of glucose, glucose‐6‐phosphate, fructose‐6‐phosphate, fructose‐1,6‐diphosphate, and citrate. These effects were not mediated by changes in redox state, since the ratio of lactate to pyruvate remained unchanged after injection of ethanol. Citrate was considered to be a major factor involved both in the regulation of uterine glycolysis and in the ethanol‐induced alterations in the levels of hexose phosphates. The elevated levels of uterine glucose registered after treatment with ethanol were related to an acceleration of glycogen degradation in the liver and not in the uterine endometrium. The results suggest that part of the adverse action that these doses of ethanol exert on embryonal development stems from indirect effects that involve uterine functions relating to the nurture of the conceptus via glycolysis.
Assessment of the safety of chemicals administered intravenously in the neonatal rat
Authors: Greener Yigal , Gillies Barbara , Wienckowski David , Schmitt Donald , Woods Eugene , Youkilis Eugene 
Published: June 2005

AbstractA 3‐day‐old neonatal rat model for the safety assessment of various drugs, chemicals, and nutrients administered intravenously is described. This model was used to assess the safety of di(2‐ethylhexyl) phthalate (DEHP), cyclohexanone, and a 3:1 mixture of medium and long‐chain triglyceride emulsions following subchronic administration using the intravenous route. The administration of DEHP at dosage of 164.8 mg/kg for 18 consecutive days resulted in a small but statistically significant increase in liver weight and SGOT activity. However, no conclusive histopathological alternations could be discerned between livers from DEHP and normal saline (control) animals. No effects were observed among neonates treated with cyclohexanone at dosages up to 25 mg/kg for 18 consecutive days. Because of technical difficulties emanating from high dosage volumes, the administration of lipid emulsion mixture lasted 9 consecutive days only. Except for transient ataxia and sedation, no adverse effects were observed among neonates that received 3:1 medium‐ and long‐chain triglyceride emulsion for 9 consecutive days beginning on day 3 postpartum. No adverse effects were observed among neonates receiving the lipid emulsions for 7 consecutive days beginning on day 12 postpartum.
Aspirin and acetaminophen use by pregnant women and subsequent child IQ and attention decrements
Authors: Streissguth Ann Pytkowicz , Treder Robert P. , Barr Helen M. , Shepard Thomas H. , Bleyer W. Archie , Sampson Paul D. , Martin Donald C. 
Published: June 2005

AbstractIn a longitudinal prospective study of 1,529 women pregnant in 1974–1975, aspirin and acetaminophen were the two medications most frequently taken during the first half of pregnancy (46 and 41%, respectively). In a selected cohort of 421 offspring of these women, examined at 4 years of age, maternal aspirin use during the first half of pregnancy was significantly related to IQ and attention decrements in the exposed children. Multiple regression analyses were used to statistically adjust for a variety of potentially confounding factors including demographic characteristics, child characteristics, other exposures, and lifestyle/environmental variables. Continuous doseresponse and step‐function parameterizations of aspirin exposure were both statistically significant and not clearly distinguishable from each other. The estimated aspirin effect is significantly greater, for girls than boys. Aspirin effects on offspring function were found in the absence of effects on physical size both at birth and at 4 years. Maternal acetaminophen use was not significantly related to child IQ or attention. As this exploratory research originated from observations of a data set gathered for other purposes, it would be desirable to have these findings replicated in other studies. Further follow‐up of the children at a later age is planned.
Inhibitory effect of caffeine on 5‐azacytidine‐induced digital malformations in the rat
Authors: Kurishita Akihiro , Ihara Toshio 
Published: June 2005

AbstractThe effect of caffeine on 5‐azacytidine (5‐AC)‐induced digital malformations in rat fetuses was investigated. Caffeine suppressed all types of digital defects in the fore‐ and hindlimbs except for syndactyly induced by 1.0 mg/kg of 5‐AC; it was still effective when administered 24 hours after 5‐AC treatment. However, fetal mortality increased as the frequency of malformations decreased. While the malformation results support the view that caffeine inhibits the processes leading to malformation expression, the relation between its suppressive effect on malformations and its enhancing effect on fetal mortality is unclear.
Uterine trauma and limb defects
Authors: Webster William S. , Lipson Anthony H. , Brown‐Woodman Patricia D. C. 
Published: June 2005

AbstractThe temporary clamping of the uterine blood vessels on one side of the uterus during late pregnancy in the rat (days 14–16) results in hemorrhage and tissue necrosis in the extremities of the fetuses from the experimental side and occasionally from the control side. A further series of experiments showed that similar fetal hemorrhage followed 1) the temporary clamping (45 minutes) of the uterine wall or uterine fat, excluding major uterine vessels; 2) handling the uterus for 5 minutes; and 3) stretching of the uterine blood vessels. A low incidence of fetal hemorrhage was also associated with laparotomy alone, but the fetuses were unaffected by extensive handling of the uterus through the abdominal wall or by intraperitoneal anesthesia. Fetal hemorrhage was also induced by a short episode of severe maternal hyperthermia but not by a high dose of ethanol given by gavage. These results suggest that a range of uterine trauma may result in fetal hemorrhage, perhaps through a common mechanism.
Maternal smoking: Greater effect on males, Fetal Tobacco Syndrome?
Authors: Wertelecki Wladimer , Hoff Charles , Zansky Shelley 
Published: June 2005

AbstractWe tested the recently proposed criteria for a Fetal Tobacco Syndrome (FTS) on a sample of 925 primiparous black women (including 204 smokers) and their neonates. The proposed FTS criteria included proportional growth retardation (ponderal index > 2.26, birth weight < 2,500 g) in term neonates. Only 19 neonates (2%) in our study fulfilled the FTS morphometric criteria, and of these only 8 had smoking mothers. Nonetheless, the negative effect of maternal smoking on fetal growth (birth weight and length) as reported from earlier investigations was clearly evident in our own data (P < .01). Separate analysis by fetal sex revealed that the negative effect of maternal smoking upon fetal growth is more pronounced among males than females. We concluded that fetal sex should be taken into account in studies of maternal smoking effects. As for evidence for the existence of the FTS, it remains to be proven.
Pregnancy outcomes after weekly oral administration of ethanol during gestation in the pig‐tailed macaque (Macaca nemestrina)
Authors: Clarren Sterling K. , Bowden Douglas M. , Astley Susan J. 
Published: June 2005

AbstractEthanol was orally administered once per week to gravid pigtailed macaques (Macaca nemestrina) in doses of 0.3, 0.6, 1.2, 1.8, 2.5, 3.3, or 4.1 g/kg. A control group received a sucrose solution, isocaloric and isovolemic to the highest ethanol dose. Pregnancy was followed after 116 possible conceptions in 54 females. Peak plasma ethanol concentrations (PPECs) ranged from 24 ± 6 mg/dl at the 0.3 g/kg dose to 549 ± 71 mg/dl at the 4.1 g/kg dose. An increased rate of spontaneous abortion was related to ethanol exposure at and above 1.8 g/kg (mean PPEC = 205 mg/dl). Pregnancy failure in the first 30 days of gestation increased at doses above 2.5 g/kg. The effect on pregnancy outcome of weekly exposure to ethanol in this nonhuman primate is comparable to available data on humans. The methodology of this study represents an effective model for studying ethanol teratogenesis in a nonhuman primate.
Developmental anomalies induced by all‐trans‐retinoic acid in fetal mice: II. Induction of abnormal neuroepithelium
Authors: Yasuda Yoshiko , Konishi Hiroyoshi , Kihara Takahide , Tanimura Takashi 
Published: June 2005

AbstractAll‐trans‐retinoic acid (RA) in olive oil was given in doses of 0, 40, or 60 mg/kg of body weight to pregnant mice on day 8 of gestation, and 2–6 hr later embryos were fixed in solutions with or without cetylpyridinium chloride (CPC). The neuroepithelium of the presumptive midbrain was processed for light and electron microscopy. Distorted contours of the neuroepithelium were induced by both doses of RA and the incidence and the severity of the disorganized neuroepithelium showed dose‐related results. Abnormal neuroepithelium showed wide intercellular spaces with degenerated cytoplasmic processes or cell debris, separation of the apical side from adjacent cells, retention of mitotic and/or postmitotic cells on the apical side, presence of mitotic cells on the basal side, and detachment of degenerated structures from the neuroepithelium. Ultrastructurally, the affected neuroepithelium showed (1) appearance of degenerating filamentous or tubular coagulating bundles in the cytoplasm and the cytoplasmic process of the neural crest cells, (2) dispersal of polysomes into monosomes especially in the degenerating neural crest cells, (3) and a collecting of microfilament‐like structures at the contact area between the neural crest cell and the presumptive neuroblast. These morphological changes suggest that RA affects the nature of cytoskeletal elements and the protein synthesis of the neuroepithelial cells. The selective susceptibility of neural crest cells to RA causes more degenerating neural crest cells in the neuroepithelium, which causes nonapproximation of the neural folds and scantiness of the migrating neural crest cells; these results lead to neural tube defects and craniofacial anomalies, respectively.
Development of the embryonic trisomy 1 mouse
Authors: Smith Barbara S. , Pettersen James C. 
Published: June 2005

AbstractTrisomic and normal control embryos 9.5 through 12 gestational days were examined externally and on serial section with standard light microsopy techniques. Trisomic embryos showed significant retardation in length, weight, optic angle, and somite numbers at most times (p < .05), and were 1/2 day behind normal animals in overall development. The eye showed the most defects, and these appeared at every period. They included aphakia, large intraretinal space, and dysmorphia of optic cup layers. Brain defects were found at all times. The most common were narrow brain vesicles and folding of the vesicle walls. Some animals showed neural tube defects. The major defect in neural crest derivatives was deficient frontonasal processes in the most defective embryos. The study supports the conclusion of previous investigators that Ts 1 is a syndrome of growth and developmental retardation with a wide range of defects. Definitive evidence, previously lacking, indicates that developmental delay and defective morphogenesis are apparent before 11 days of gestation. In addition, according to our measurements, optic angles are larger in trisomic mice than in normal littermates. This is in contrast to the only previous investigation that included such measurements. Our data do not give definitive support to the suggestion that trisomy 1 belongs to the holoprosencephaly‐cyclopia spectrum. However, the hypothesis that murine trisomy 1 shows a parallel in development to human trisomy 13 is not supported by our data. Possible causal mechanisms for the defects and developmental delay are discussed.
Pathogenesis of median facial clefts in mice treated with methotrexate
Authors: Darab D. J. , Minkoff R. , Sciote J. , Sulik K. K. 
Published: June 2005

AbstractMethotrexate (MTX), administered as a single 20 mg/kg intraperitoneal dose to C57Bl/6 J mice on their 9th day of pregnancy results in high incidences of median facial clefts in the surviving gestational‐day‐18 fetuses. We have shown the presence of dilated and congested blood vessels in the frontonasal prominences (FNP) of embryos from treated mothers as early as 3 hours following drug administration. Within 24 hours, large vascular blebs are located in the FNP and the neural tubes appear somewhat distended. By 32 hours after treatment, distention of the neural tube is marked while blebs have become less evident. Subsequent to these changes, FNP mesenchymal deficiency as well as neural tube distention lead to the formation of median facial clefts. It is hypothesized that, as with a number of other teratogenic agents (especially hypoxia), initial fluid imbalance is the primary teratogenic insult.