bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemically induced alterations in maternal homeostasis and histology of conceptus: Their etiologic significance in rat fetal anomalies
Authors: Khera K. S. 
Published: June 2005

AbstractPossible relationships between maternal acid‐base‐electrolyte imbalance, histological changes in the maternal/extraembryonic tissues (decidua, placenta, membranes enclosing cavities), and fetal anomalies induced by maternotoxic doses of ethylene glycol, sodium salicylate, and cadmium chloride in rats were investigated. Acid‐base‐electrolyte, histologic and, teratologic studies were conducted concurrently with, as far as feasible, a similar protocol. Ethylene glycol caused 1) maternal homeostatic changes including metabolic acidosis and hyperosmolality, 2) extraembryonic lesions with degeneration of allantois and reduced villigenesis being more prevalent, and 3) materno‐fetal effects such as decreases in fetal and maternal body weights, decreased maternal food intake, and fetal abnormalities (vertebral, rib, and sternebral defects). Few of these changes occurred when NaHCO3, an endogenous agent known to correct metabolic acidosis, was coadministered with ethylene glycol. Ethylene glycol‐induced maternal metabolic acidosis, concurrent with hyperosmolality, was suspected to contribute toward reduction in villigenesis and fetal anomalies, including body weight reductions. Sodium salicylate induced the following: 1) mild maternal acidosis, hypokalemia, and hypophosphatemia with no significant change in pH; 2) maternal hemorrhage in extraembryonic cavities, papillary proliferation of the visceral yolk sac endoderm, and failure to form the chorioallantoic labyrinth; and 3) resorptions, hydrocephaly, rib defects, and fetal body weight reduction. Upon simultaneous treatment with sodium salicylate, NaHCO3 significantly reduced, and NH4Cl enhanced the incidence of the above histologic and teratologic effects, without significantly altering acid‐base values. An etiologic association between the above salicylate‐induced maternal and extraembryonic lesions and teratogenicity was likely. Cadmium chloride, whether administered by the intraperitoneal (ip) or intravenous (iv) route, caused 1) hydrocephaly, anophthalmia, vertebral and rib defects, reduction in fetal body weight, resorptions and maternal toxicity (acute peritonitis by the ip route only), and 2) extensive necrosis and hemorrhage in the decidua basalis, hemorrhage in the ectoplacental cone and around Reichert's membrane, and absence of chorioallantoic labyrinth. An etiologic relationship between these teratologic and histologic effects seemed probable, since both were dose‐related. From the above studies, it was hypothesized that maternal factors—metabolic acidosis, hyperosmolality, hemorrhages in the ectoplacental cone, extraembryonic cavities, and around Reichert's membrane, and necrosis of decidua basalis—may have, directly or indirectly, reduced fetal nutrition and materno‐embryonic gaseous exchange, which ultimately altered fetal development.
Comparisons of the effects of TCDD and hydrocortisone on growth factor expression provide insight into their interaction in the embryonic mouse palate
Authors: Abbott B. D. , Harris M. W. , Birnbaum L. S. 
Published: June 2005

AbstractCleft palate (CP) can be induced in embryonic mice by a wide range of compounds, including glucocorticoids and 2,3,7,8‐tetrachlorodibenzop‐dioxin (TCDD). Hydrocortisone (HC), a glucocorticoid, retards embryonic growth producing small palatal shelves, while TCDD exposure blocks the fusion of normally sized shelves. TCDD induction of CP involves altered differentiation of the medial epithelial cells. Recent studies indicate that growth factors such as EGF, TGF‐α, TGF‐β1, and TGF‐β2 are involved in palatogenesis, regulating proliferation, differentiation, and extracellular matrix production. A synergism has been observed between HC and TCDD in which doses too low to induce CP alone are able to produce >90% incidence when coadministered. In the present study a standard teratology protocol was performed in C57BL/6N mice to examine the synergism at doses lower than those previously published. Data from this study indicate synergistic interactions at doses as low as 3 μg TCDD/kg + 1 mg HC/kg. This extreme sensitivity suggests the involvement of a receptor‐mediated mechanism possibly resulting in altered regulation of gene expression. Mechanisms of interaction were further studied by comparing growth of the shelves, fate of the medial epithelium, and expression of growth factor mRNAs and peptides. Pregnant mice were dosed on GDs 10–13 with HC (100 mg/kg sc) or with HC (25 mg/kg sc) + TCDD (3 μg/kg orally), doses producing 30% and 99% CP, respectively. The interaction between HC and TCDD results in a small HC‐like palate, rather than the morphology typical of TCDD‐induced clefting. Both compounds inhibited programmed cell death of the medial epithelium, which instead differentiated into an oral‐like epithelium. The alterations in growth factor expression after HC or HC + TCDD were similar. Expression of EGF, TGF‐β1, TGF‐β2, and EGF receptor increased in specific palatal regions. Increased levels of mRNA were observed only for TGF‐β1. The effects of TCDD alone on growth factor expression differ from those seen with HC or HC + TCDD. These divergent effects on growth factor expression may contribute to the differences in shelf size and thus to the different mechanisms of HC and TCDD clefting. Thus the synergism between HC and TCDD may involve similar and potentially additive effects on regulators of proliferation and differentiation in the palate, but additional contributing factors cannot be excluded.
The functional importance of the oviduct in neonatally estrogenized mouse females for early embryo survival
Authors: Halling Anders , Forsberg John‐Gunnar 
Published: June 2005

AbstractEight‐week‐old virgin untreated female mice were induced to ovulate using equine chorionic gonadotropin (eCG) and human chorionic gonadotropin (hCG), and were then caged with males overnight. Females with a vaginal plug on the following morning were killed 24 hours later and 2‐cell embryos were flushed from the oviduct. These embryos were transferred to the oviduct of 8‐week‐old control females, to females of the same age treated with 5 μg diethylstilbestrol (DES) sc in olive oil for the first 5 days after birth, or to females treated with 1 μg estradiol‐17β for 2 days before and 2 days after transfer (estrogen dominated/ED/females). Two days after transfer, a significantly lower number of embryos were recovered from oviducts of DES females compared to control females and a still lower number from ED females. The recovered embryos were cultured in vitro for 4 days testing trophoblast outgrowth (“implantation stage”). The incidence of embryos reaching this stage after development in DES‐exposed oviducts was only half of that for embryos passing control oviducts or ED oviducts. It is concluded that the adult oviductal environment in neonatally DES‐treated females significantly decreases early embryo developmental potential. The oviductal factor(s) harmful to the embryo may be related to a persistent and possibly increased level of circulating estrogen level in DES females.
Valproic acid‐induced spina bifida: A mouse model
Authors: Ehlers Katharine , Stürje Helga , Merker Hans‐Joachim , Nau Heinz 
Published: June 2005

AbstractPrenatal exposure to the antiepileptic drug valproic acid (VPA) has been associated with the formation of spina bifida aperta, meningocele, and meningomyelocele in the human. Until now, a direct relationship between VPA application and spina bifida has not been experimentally demonstrated. VPA was known only to induce exencephaly in mice, a defect of the anterior neural tube. Maximal sensitivity toward production of this defect was on day 8 of gestation (plug day = day 0). The closure of the posterior neuropore occurs later in the development of mice than the closure of the anterior neuropore. To investigate whether there is a direct relationship between VPA application during pregnancy and induction of spina bifida in mice, we administered various doses of the drug on day 9 of gestation, at three time intervals (at 0, 6, and 12 hr). This administration of VPA produced spina bifida aperta and spina bifida occulta in mice. High doses of VPA (3 × 450 and 3 × 500 mg/kg) induced a low rate of spina bifida aperta in the lumbosacral region. High incidences of spina bifida occulta, a less serious form of spina bifida, were induced with lower doses. This malformation was demonstrated in double‐stained fetal skeletons by measurements of the distance between the cartilaginous ends of each vertebral arch. The occurrence of this defect and its localization was dose‐dependent. The lumbar region was affected by all doses investigated (3×300, 3×350, 3×400, 3×450, and 3×500 mg/kg). The sacral/coccygeal region was affected additionally, but with higher doses (3×400, 3×450, and 3×500 mg/kg). A comparison of the results obtained with day 16 and 17 control fetuses showed that the pattern of gaps present in the lumbar and sacral region of the spinal cord in treated groups was drug‐specific and not related to a developmental delay. Our results indicate that multiple administrations of VPA on day 9 of gestation in mice result in a low incidence of spina bifida aperta and a high incidence of spina bifida occulta, and provides a relevant model for the study of human spina bifida defects.
Morphological changes in long bone development in fetal akinesia deformation sequence: An experimental study in curarized rat fetuses
Authors: Rodríguez José I. , Palacios José , Ruiz Antonio , Sanchez Miguel , Alvarez Ignacio , Demiguel Enrique 
Published: June 2005

AbstractIn order to investigate the transverse growth of the long bones during intrauterine development in the fetal akinesia deformation sequence (FADS), we studied curarized rat fetuses. Curarization was performed by daily subcutaneous administration of D‐Tubocurarine from day 17 of gestation until term. Experimental fetuses were compared with a sham‐operated control group. The total area and perimeter, the absolute and relative amount of periosteum and bone trabeculae, the major and minor axes, and the elongation factor were measured from histological cross‐sections of the femoral metaphysis and diaphysis using an IBAS 1 image analysis system. Curarized rat fetuses showed growth retardation, a short umbilical cord, and multiple articular contractures, a phenotype consistent with FADS. Alterations in femoral shape and transverse growth that affected the diaphysis were noted in these fetuses. These included a decrease of total cross‐section area and reduction of the absolute and relative amounts of bone trabeculae with marked thinning of the periosteum. Femoral cross‐sections was rounder than controls. These results evidenced an impairment of the membranous (periosteal) ossification of long bones produced by immobilization and/or decrease of muscular strength, and support our previous clinical findings of bone hypoplasia and osteopenia in FADS.
Inositol deficiency increases the susceptibility to neural tube defects of genetically predisposed (curly tail) mouse embryos in vitro
Authors: Cockroft D. L. , Brook F. A. , Copp A. J. 
Published: June 2005

AbstractCurly tail (ct/ct) mouse embryos, which have a genetic predisposition for neural tube defects (NTD), were grown in culture from the 2‐5 somite stage, before the initiation of neurulation, up to the 22‐24 somite stage, when closure of the anterior neural tube is normally complete. The embryos were cultured in whole rat serum or in extensively dialysed serum supplemented with glucose, amino acids, and vitamins, with inositol omitted or added at concentrations of 2, 10, 20, and 50 mg/1. Two strains were used as controls; CBA mice, which are related to curly tails, and an unrelated PO stock. It was found thatct/ctembryos were particularly sensitive to inositol deficiency; both they and the CBA embryos showed a similar high incidence of cranial NTD after culture in inositol deficient medium (12/17 and 11/18, respectively). Furthermore, the lowest dose of inositol had no effect on the frequency of head defects inct/ctmice, though it halved the incidence in CBA embryos. With higher inositol concentrations, the majority of ct/ct embryos completed head closure normally, and their development was generally similar to that obtained in whole serum. PO embryos showed a lower proportion (5/19) of cranial NTD in the inositol deficient medium than the other two strains, and this was further reduced by even the lowest inositol dose.
Identical phalangeal defects induced by phenytoin and nifedipine suggest fetal hypoxia and vascular disruption behind phenytoin teratogenicity
Authors: Danielsson Bengt R. G. , Danielson Margaretha , Rundqvist Eva , Reiland Sven 
Published: June 2005

AbstractIn previous experimental studies in rabbits, we have shown that vasodilating drugs (including nifedipine) cause distal digital defects. These defects were preceeded by edema, hemorrhage, and finally necrosis of the developed cartilage in the phalanges. The underlying mechanism is most likely a fetal hypoxic response, secondary to maternal hypotension and decreased uteroplacental blood flow. Since phenytoin is known to cause distal digital defects both in man and rabbits, we decided to compare the defects provoked by oral administration of phenytoin (100 mg/kg) versus nifedipine (8.3 mg/kg) to New Zealand White rabbits on days 6‐18 of gestation. In order to investigate phasespecificity, phenytoin (150 mg/kg) was given on days 14‐17. The result of single dose administration on day 16 of phenytoin (300 mg/kg) versus nifedipine (33.2 mg/kg) was also studied. In this latter experiment maternal heart rate was measured up to 21 hours after phenytoin administration. Phenytoin induced digital defects identical with those produced by nifedipine and caused marked maternal cardiodepression. The defects consisted of a reduction, absence, or abnormal structure of the distal phalanges. The distal phalanx of the fourth digit on the hindpaw was the first to be affected, with inclusion of other phalanges, both on the hind‐ and forepaws, with increasing dose. The sensitive period for induction and histological appearance of these defects was identical for phenytoin and nifedipine. These results suggest that vascular disruption due to a fetal hypoxic response lies behind phenytoin teratogenicity, as has been shown for vasodilators. A cardiodepressive action on the maternal and fetal hearts, possibly in combination with decreased uteroplacental blood flow, is discussed as a probable factor behind phenytoin teratogenicity.
Birth prevalence of down syndrome in a predominantly Latino population: A 15‐year study
Authors: Wilson Miriam G. , Chan Linda S. , Herbert William S. 
Published: June 2005

AbstractThe birth prevalence of Down syndrome (DS), although decreasing in parts of the world, is not known in many specific subpopulations. The rate of DS for live births was determined for a 15‐year period (1974‐1988) at the Los Angeles County‐University of Southern California Medical Center, which is a large public hospital serving a predominantly Latino population. DS was ascertained primarily by clinical monitoring of newborn infants. The overall rate of DS was 1.60/1,000 live births and had minimal fluctuation throughout the 15 years. The rate of DS for Latino births was 1.69/1,000 live births, 1.67 when adjusted for maternal age, and 1.75 when corrected for prenatal diagnosis. The high rate of DS in the Latino population was associated with advanced maternal ages and increased maternal‐age specific rates for DS, especially in the age ranges of 30 to 34 and 40 to 44 years, when compared with other studies.
Thyroid hormone differentially regulates cellular development in neonatal rat heart and kidney
Authors: Slotkin T. A. , Seidler F. J. , Kavlock R. J. , Bartolome J. V. 
Published: June 2005

AbstractThe role of thyroid hormone in the control of cardiac and renal cell development was examined in neonatal rats made hyperthyroid by administration of triiodothyronine (T3, 0.1 mg/kg s.c. on postnatal days 1‐5) or hypothyroid by administration of propylthiouracil (PTU, 20 mg/kg s.c. given to dams on gestational day 17 through postnatal day 5 and to pups on postnatal days 1‐5). Indices of total cell number (total DNA per tissue), cell packing density (DNA per g tissue), and relative cell size (protein/DNA ratio) were evaluated from birth through young adulthood. PTU administration led to primary shortfalls in cell number that were of similar magnitude in both tissues, but persisted somewhat longer in the kidney than in the heart. Deficits in cell packing density and cell size in the hypothyroid animals were secondary to the effect on cell number, displaying smaller magnitudes of effect and a lag in appearance and disappearance of the deficits compared to that for total DNA; indeed, the phase in which tissues were restoring their cell numbers was accompanied by increased cell packing density, reflecting a more rapid restitution of cell numbers than tissue weight or cell size. In contrast to the relatively similar effects of PTU on developing cardiac and renal cells, the effects of T3 were selective for the heart. Although T3 caused general growth impairment, it evoked marked cardiac overgrowth that was accompanied by a striking increase in cell number and a small increase in cell size. The cardiac hyperplasia is unique to the developing animal, as post‐replicative heart cells in adult animals show only hypertrophy in response to thyroid hormone. The time course of appearance and disappearance of the effects of T3 on the indices of cardiac cell development suggested that the hormone shifted maturation such that cell replication was initiated and terminated earlier than in control animals. The results obtained in this study thus indicate that thyroid hormone plays two distinct and separable roles in modulation of cellular development: basal levels of hormone are required to maintain cell acquisition in all tissues but, in addition, there is a more specific role in cardiac cells in setting the timing of onset and disappearance of cell replication.
First trimester maternal medication use in relation to gastroschisis
Authors: Werler Martha M. , Mitchell Allen A. , Shapiro Samuel 
Published: June 2005

AbstractIn a case‐control surveillance program, first trimester medication use was studied in relation to gastroschisis. There were 76 cases of gastroschisis which were compared with 2,142 controls with other major malformations. For pseudoephedrine use, we found a significantly elevated relative risk of 3.2 (95% confidence interval, 1.3‐7.7), with adjustment for confounding. Multivariate relative risks for analgesic/antipyretics and another decongestant were as follows: salicylates, 1.6 (0.9‐2.7); acetaminophen, 1.7 (1.0‐2.9); ibu‐profen, 1.3 (0.4‐3.7); and phenylpropanolamine, 1.5 (0.4‐5.4). No increases in risk were identified for use of antihistamines, antibiotics, oral contraceptives, or spermicides.Because salicylates, pseudoephedrine, and phenylpropanolamine are vasoactive, the elevated risks for these drugs support the hypothesis of vascular disruption in the etiology of gastroschisis. We therefore examined maternal use of vasoactive medications in relation to a second case group of 416 infants with hetereogeneous defects suspected to have a vascular etiology. Relative risks for salicylates, ibuprofen, pseudoephedrine, phenylpropanolamine, and other decongestants approximated unity.These positive associations must be considered tentative. They have not been reported previously and should be confirmed independently. Also, acetaminophen, which may be taken for the same indications as salicylates and decongestants, but is not thought to be vasoactive, was associated with gastroschisis, suggesting that identified associations may be due to an underlying maternal illness.
Correlation of increased levels of class I MHC H‐2Kk in the placenta of murine trisomy 16 conceptuses with structural abnormalities revealed by magnetic resonance microscopy
Authors: Kornguth Steven , Bersu Edward , Anderson Mark , Markley John 
Published: June 2005

AbstractMurine trisomy 16 (mts16) placentas and fetuses, 17‐day gestation age, were examined histologically and by magnetic resonance imaging at 9.4 T and compared with control littermate tissues. Placentas were studied by immunohistochemical methods, at 15‐days gestational age, for expression of the major histocompatibility complex (MHC) class I H‐2Kk cell surface marker. Immunohistochemical studies revealed a markedly increased expression of the MHC marker H‐2Kk on cells in the labyrinth of the placenta of mts16. There were differences between the magnetic resonance (MR) images of the trisomic and normal placentas, which may be correlated with the increased expression of H‐2Kk in the mts16 placental labyrinth. The decidual and labyrinthine components of the normal placentas showed similar high signal intensities (SI) while in trisomic placentas a marked high SI was characteristic only of the decidual region on proton spin density images. The MRI also revealed a smaller cerebellum in the ts16 fetuses. The potential effects of the compromised structure of the placental labyrinth and the overexpression of the H‐2Kk marker on the mts16 neural and placental dysgenesis are discussed.
Variation in development of rat embryos at the presomite period
Authors: Fujinaga Masahiko , Baden Jeffrey M. 
Published: June 2005

AbstractRat embryos at a single gestational time in the presomite period were studied for their variation in development and their fate after culture. They were explanted at 8 A.M. on day 9 of gestation from timed‐pregnant Sprague‐Dawley rats which were obtained by mating between 8 and 10 A.M. (plug day = day 0). In the first experiment, a total of 203 embryos from 20 litters were examined for their variation in development. Several dimensions of embryo/egg cylinder were measured and development of various embryonic/extraembryonic structures were assessed using a scoring system that we developed for the present study. Embryos were then divided into different stages of development based on their scores using the staging system that we developed previously. A large variation in developmental stage was demonstrated; the youngest embryo was at the early primitive streak stage with no signs of amniotic folds and the oldest one was at the late neural plate stage with a foregut pocket but without visible somites. No strong correlation was demonstrated between developmental stage and size of embryo/egg cylinder, nor between developmental stage and development of the proamniotic tube, ectoplacental cavity, or allantois. In the second experiment, embryos were explanted at the same time and those at different stages were cultured separately in rotating bottles and their outcomes were compared after 49 hours. The difference in mean somites number of embryos cultured from the mid primitive streak and late neural plate stages was 6.1. This difference corresponds to approximately 10 hours based on the known linear increase of somites number on day 11 of approximately 0.6 somites per hour. These results indicate a large variation in development of presomite period embryos supposedly of the same gestational age and suggest the importance of careful staging at the time of explantation if precision is needed for whole embryo culture experiments. © 1992 Wiley‐Liss, Inc.