bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of developmental stage and tissue type on embryo/fetal DNA distributions and 5‐fluorouracil‐induced cell–cycle perturbations
Authors: Elstein Kenneth H. , Zucker Robert M. , Andrews James E. , Ebron‐McCoy Marian , Shuey Dana L. , Rogers John M. 
Published: June 2005

AbstractCell‐cycle analysis of nuclei obtained from the circulating erythroblasts (gestational day [GD] 11–16), livers (GD 14–19), and whole embryos (GD 10–13) or remaining (extrahepatic) tissues (GD 14–16) of rat embryos/fetuses revealed age‐ and tissue‐dependent variations in the relative percentages of cells in the G0/G1, S, and G2/M phases of the cell cycle. With development, the rate of cell proliferation declined resulting in decreases in the relative percentage of S‐phase cells and increases in the G0/G1 percentage, while the percentage of G2/M‐phase cells remained relatively constant. Comparing tissue cell‐cycle profiles during development, erythroblasts exhibited the most rapid age‐dependent decline in S‐phase percentage (from 75% at GD 11 to 8% by GD 14), embryos/extrahepatic tissues exhibited a more gradual reduction (from 55% at GD 10 to 14% by GD 15), while the hepatic isolates exhibited a relatively constant S‐phase percentage of approximately 40% from GD 14 to GD 18 before decreasing to 23% at GD 19. These age‐dependent variations suggest that cellcycle distribution may be useful in staging embryogenesis and in detecting abnormal development.To determine how these developmental and organ‐specific cell‐cycle variations affect toxic response, we sampled GD 11–13 embryos 6 hr after maternal administration of a teratogenic dose of 5‐fluorouracil (5‐FU), a thymidylate synthetase inhibitor that induces S‐phase accumulation. The results indicate that, on a relative basis, the amount of induced S‐phase accumulation in erythroblasts and whole embryos 6 hr postdosing increased with development. In contrast, a time course of hepatic cell‐cycle distributions from GD 14 embryos after maternal dosing revealed that S‐phase accumulations occurred at an earlier time, possibly as a consequence of a higher proliferative rate. These findings suggest that the extent of observed toxicant‐induced cell‐cycle perturbations depends on gestational age, tissue type, and the time of sampling. © 1993 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
Developmental toxicity of gemcitabine, an antimetabolite oncolytic, administered during gestation to CD‐1 mice
Authors: Eudaly J. A. , Tizzano J. P. , Higdon G. L. , Todd G. C. 
Published: June 2005

AbstractGemcitabine was given intravenously to female mice on gestation days (GD) 6–15 at doses of 0, 0.05, 0.25, or 1.5 mg/kg/day (0, 0.15, 0.75, or 4.5 mg/m2/day, respectively). Animals assigned to the teratology segment (25/group) were killed on GD 18 for examination of maternal hematologic parameters and organ weights, as well as fetal viability, weights, and morphology. The postnatal segment females (20/group) were allowed to deliver, and offspring physical, behavioral, and reproductive parameters were monitored. After offspring weaning, these dams were killed for hematologic and organ weight evaluations. At necropsy, 3 days after the final dose, the teratology segment dams showed dose‐related increases in spleen and thymus weights. These changes were accompanied by a dose‐related decrease in leukocytes and modest increases in mean corpuscular volume (MCV) and hemoglobin (MCH) at the two higher doses. On postpartum day (PPD) 21, the dams in the postnatal segment showed no treatment‐related effects on these organ weights or hematologic parameters, indicating recovery of these maternal parameters within 3.5 weeks following termination of treatment. The decreases in maternal body weight and food consumption observed during gestation, and in liver and uterine weights at term in the 1.5 mg/kg/day group, were considered to be secondary to a high rate of prenatal mortality, evidenced by increased resorptions in the teratology segment and decreased live litter size in both segments of the study. Additional indications of developmental toxicity in this dose group were an increased incidence of malformations, primarily cleft palate, decreased fetal weights in the teratology segment, and decreased neonatal survival in the postnatal segment. Other indications of offspring toxicity were decreased startle amplitude in the 0.05 and 1.5 mg/kg/day treatment‐derived males, and decreased ovarian weights in all F1 females compared to controls. However, offspring growth, appearance of physical landmarks, F1 activity levels, active and passive avoidance, and reproductive performance were not affected adversely in the surviving offspring of the 1.5 mg/kg/day treatment‐derived group or in mice from either of the two lower dose groups. These results indicate that maternal effects related to the antiproliferative actions of gemcitabine may be detected at doses below those which result in overt developmental toxicity, i.e., malformations, weight changes, and decreased prenatal and neonatal survival. © 1993 Wiley‐Liss, Inc.
Clinical teratology counseling and consultation case report: Two distinct anterior neural tube defects in a human fetus: Evidence for an intermittent pattern of neural tube closure
Authors: Busam Klaus J. , Roberts Drucilla J. , Golden Jeffrey A. 
Published: June 2005

AbstractHuman neural tube closure is believed to be a continuous process that begins in the cervical region and progresses both rostrally and caudally. In contrast, an intermittent pattern of anterior neural tube closure has been demonstrated in rodents. Based on individual case photographs, a similar pattern of anterior neural tube closure, with multiple sites of closure, may also exist in humans. We report a human fetus with two distinct anterior neural tube defects separated by a cutaneous and mesenchymal bridge. The two defects occurred within distinct closure sites predicted by the murine model, one falling within closure II and the second within closure IV. Although one defect had adherent amniotic bands, evidence is presented to support a primary dysraphy rather than disruption from an amniotic band. This case provides further evidence supporting an intermittent pattern of anterior neural tube closure in human embryogenesis. © 1993 Wiley‐Liss, In.
Histological study of the cranial neural folds of mice genetically liable to exencephaly
Authors: Gunn T. M. , Juriloff D. M. , Vogl W. , Harris M. J. , Miller J. E. 
Published: June 2005

AbstractThe SELH/Bc (SELH) inbred stock of mice has a high liability to the neural tube closure defect, exencephaly. All SELH embryos close their cranial neural tubes by an abnormal mechanism, lacking elevation and initiation of fusion in the posterior prosencephalon/anterior mesencephalon region. Most embryos complete closure of the cranial neural tube by extension of a more rostral site of fusion, but in 10–20% this process fails, and the embryos are subsequently exencephalic.In this study, transverse histological sections of the cranial neural folds of SELH embryos at the 3–5, 6–8, and 9–11 somite stages were compared to those of two strains with normal neural tube closure, ICR/Bc and LM/Bc. At all stages, consistent morphological differences were observed between SELH and the two normal strains. In 3–5 somite SELH embryos, the divergence of the folds from the neural groove is more angular, the folds are flatter, and their lateral tips appear “hooked” downward. In 6–8 somite SELH embryos, the lateral tips of the folds appear more elongated and in the prosencephalon they are less elevated than in the normal strains. The boundary between neuroepithelium and mesenchyme or surface ectoderm tends to be less clear than normal in SELH lateral tips. In 9–11 somite SELH embryos, divergence of the folds from the neural groove continues to be angular and the lateral folds are splayed horizontally. In addition, the lateral surface ectoderm is abnormally indented and the neuroepithelium/surface ectoderm boundary is more ventral and lateral in SELH than in ICR/Bc and LM/Bc.The hypothesis that the defect in SELH cranial neural folds might involve the cytoskeleton was tested using a fluorescent probe for filamentous actin in 7 somite SELH and ICR/Bc embryos. The actin staining pattern in SELH embryos was like that of normal ICR/Bc embryos, with a strongly staining apical concentration in the neuroepithelium. This suggests that there is no gross cytological abnormality within the neuroepithelium, but does not rule out more subtle defects, such as those involving cytoskeletal function. © 1993 Wiley‐Liss, Inc.
Induction of a heat shock response (HSP 72) in rat embryos exposed to selected chemical teratogens
Authors: Mirkes Philip E. , Doggett Barbara , Cornel Leanne 
Published: June 2005

AbstractA monoclonal antibody to the 72 kD heat shock protein (HSP 72), Western blot analysis and 2‐D gel electrophoresis/autoradiography were used to determine whether selected chemical teratogens induced the synthesis and accumulation of HSP 72 in postimplantation rat embryos exposed in vitro. The chemical teratogens studied include N‐Acetoxy‐2‐acetylaminofluorene (N‐Ac‐AAF), cadmium chloride (CAD), cyclophosphamide (CP), sodium arsenite (AS), and sodium salicylate (SAL). Exposures to test chemicals were selected that produced obvious embryotoxicity characterized by abnormal development and growth retardation. Of the five chemical teratogens studied, AS and SAL induced the synthesis and accumulation of HSP 72 in day 10 rat embryos. The kinetics of HSP 72 accumulation, however, differed between AS‐ and SAL‐treated embryos. Maximal levels of HSP 72 were observed 24 hours after AS exposure and 10 hours after SAL exposure. N‐Ac‐AAF, CD, and CP induced obvious embryotoxicity; however, none of these chemical teratogens induced HSP 72 at any of the timepoints assayed. Although only a small sample of chemical teratogens was studied, our results suggest that the heat shock response, characterized by the synthesis and accumulation of HSP 72, is not a general biomarker for chemical teratogens. © 1994 Wiley‐Liss, Inc.
Teratologic evaluation of rats prenatally exposed to pulsed‐wave ultrasound
Authors: Fisher J. Edward , Acuff‐Smith Karen D. , Schilling Mary A. , Vorhees Charles V. , Meyer Richard A. , Smith Nadine B. , O'Brien William D. 
Published: June 2005

AbstractWhile there are no known risks associated with diagnostic ultrasound, uncertainty about the safety of prenatal ultrasound exposure remains. The purpose of the present experiment was to evaluate the teratogenic potential of pulsed‐wave (pw) ultrasound in rats, in the absence of maternal anesthesia or restraint. Pregnant CD rats, trained to remain immobile in a waterfilled ultrasound exposure tank, were scanned with 3‐MHz pw ultrasound at levels of 0, 2, 20 or 30 W/cm2 lSPTA (spatial peak, temporal average intensity) on gestational days 4–19 for approximately 10 min/day. Examination of fetuses on E20 revealed no increase in skeletal or visceral malformations in groups exposed to pw ultrasound in utero. The number of implantations/dam was significantly increased in all pw ultrasound exposure groups compared to sham‐exposed animals and, in a possibly related finding, resorptions were increased in the two highest exposure groups. Although significantly increased compared to controls, resorption frequencies in these groups were low (<10%). No exposure‐related changes in fetal weights were observed in offspring of rats scanned with pw ultrasound during gestation. The results indicate that, under the conditions described, no overt embryotoxicity is associated with gestational exposure to pw ultrasound intensities of up to 30 W/cm2. © 1994 Wiley‐Liss, Inc.
The teratogenic effects of valproic acid in human chondrogenesis in vitro
Authors: Aulthouse Amy Lynn , Hitt Daron C. 
Published: June 2005

AbstractThe anticonvulsant drug valproic acid (VPA) is a known teratogen in humans. In general, anticonvulsants effect major systems in the embryo causing craniofacial, cardiovascular, neurological, urogenital, and major and minor skeletal defects. The limb defects associated with in utero VPA exposure include digital hypoplasia, ectrodactyly, radial ray aplasia, and proximal phocomelia. Human studies are limited to case reports and to retrospective and/or prospective studies. Although animal studies have demonstrated a teratogenic effect of VPA on skeletogenesis, these doses were well above the human therapeutic dose which makes extrapolation from these studies to humans difficult. The purpose of this research was to evaluate the potential deleterious effects of VPA on chondrogenesis, a process that occurs in human limb formation. To accomplish this goal, human chondrocytes were cultured in a three dimensional agarose gel and treated with VPA. The use of this model system was a novel approach to evaluate the teratogenic potential of VPA during chondrogenesis. The influence of VPA on human chondrocytes was monitored using histochemical, immunocytochemical, and morphological techniques. There was a decrease in mitotic activity and the extracellular matrix was modified. At human therapeutic doses, immunofluorescence revealed that type II collagen was reduced, while type I collagen increased. In addition, the alcian blue‐staining matrices (i.e., sulfated proteoglycans) were reduced. Moreover, the Golgi apparatus had swelling in the trans‐face cisternae suggesting that proteoglycan synthesis may be altered. © 1994 Wiley‐Liss, Inc.
D‐mannitol, a specific hydroxyl free radical scavenger, reduces the developmental toxicity of hydroxyurea in rabbits
Authors: Desesso John M. , Scialli Anthony R. , Goeringer Gerald C. 
Published: June 2005

AbstractHydroxyurea (HU) is a potent mammalian teratogen. Within 2–4 hours after maternal injection, HU causes 1) a rapid episode of embryonic cell death and 2) profound inhibition of embryonic DNA synthesis. A variety of antioxidants delays the onset of embryonic cell death and reduces the incidence of birth defects. Antioxidants do not block the inhibition of DNA synthesis, indicating that early embryonic cell death is not caused by inhibited DNA synthesis. We have suggested that some HU molecules may react within the embryo to produce H2O2 and subsequent free radicals, including the very reactive hydroxyl free radical. The free radicals could cause the early cell death; antioxidants are believed to terminate the aberrant free radical reactions resulting in lessened developmental toxicity. To investigate whether hydroxyl free radicals cause the early episode of cell death, pregnant New Zealand white rabbits were injected subcutaneously on gestational day 12 with a teratogenic dose of HU (650 mg/kg) in the presence or absence of 550 mg/kg of D–mannitol (Man), a specific scavenger of hydroxyl free radicals. Osmotic control rabbits received HU plus 550 mg/kg of xylose (Xyl, a nonactive aldose). At term, the teratologic effects of HU were ameliorated by Man as evidenced by decreased incidences of the expected limb malformations. Xyl exerted no demonstrable effect on HU teratogenesis. Histological examination of limb buds at 3–8 hours after maternal injection, showed that Man delayed the onset of HU–induced cell death by as much as 4 hours. Xyl had no effect. That Man acts within the embryo was shown by performing intracoelomic injections on alternate implantation sites with Man, Xyl, or saline followed by subcutaneous injection of the pregnant doe with HU. Embryos were harvested 3–8 hours later. Limb buds from saline– and Xyl–injected embryos exhibited the typical pattern of widespread HU–induced cell death at 3–4 hours, whereas Man–injected embryos did not exhibit cell death until 5–8 hours. These results are consistent with those reported for antioxidant–mediated amelioration of HU–induced developmental toxicity and with the hypothesis that hydroxyl free radicals are the proximate reactive species in HU–induced early embryonic cell death. © 1994 Wiley‐Liss, Inc.
Dysmorphogenic effects of nitric oxide (NO) and NO‐synthase inhibition: Studies with intra‐amniotic injections of sodium nitroprusside and NG‐monomethyl‐L‐arginine
Authors: Lee Qwihee P. , Juchau Mont R. 
Published: June 2005

AbstractSodium nitroprusside (SNP), a chemical that is readily converted to nitric oxide (NO) in biological systems, was microinjected into the amniotic fluids of cultured whole rat conceptuses on day 10.5 of gestation and dysmorphogenic/embryotoxic effects were evaluated after a 24 hr incubation period. Injections of 217 ng/embryo (∼800 μM) resulted in whitened zones of dead cells in a discretely circumscribed region within the mesencephalon closely associated with the neural tube. These zones were observed with a high incidence after SNP microinjections and were referred to as “white caps” because of their microscopic appearance. At higher concentrations, the whitened zone extended into the rhombencephalon and occasionally appeared to extend the full length of the dorsal midline. The whitened zones of tissue separated readily from the apparently normal underlying tissues upon removal or disturbance of the amniotic membrane. Coinjection of ferrous hemoglobin with SNP selectively prevented the appearance of “white caps” but not other embryotoxic manifestations. Microinjections of the breakdown products of light‐exposed SNP elicited generalized embryotoxicity but “white caps” were not observed. In separate experiments, we found that embryonic enzymes catalyzed significant conversion of arginine to citrulline, indicating expression of NO‐synthase during organogenesis. NG‐monomethyl‐L‐arginine (L‐NMMA), a specific inhibitor of NO‐synthase, was microinjected (50–150 ng/embryo; ∼200–600 μM) on day 10.5 of gestation and produced malformations that differed markedly from those elicited by SNP. Failure of anterior and posterior neural tube closure and profound underdevelopment of the hyoid arch and optic cup were observed at concentrations that produced no apparent growth deficit. These studies with SNP and L‐NMMA indicated that both an excess and a deficiency of NO can be embryotoxic/dysmorphogenic and suggest important roles for optimal levels of NO and NO synthases in normal embryonic development. © 1994 Wiley‐Liss, Inc.
Effects of prenatal exposure to cocaine on heart rate and nonassociative learning and retention in infant rats
Authors: Heyser Charles J. , McKinzie David L. , Athalie Felixia , Spear Norman E. , Spear Linda Patia 
Published: June 2005

AbstractNonassociative learning and retention were assessed in terms of habitution of a heart‐rate (HR) orienting response (bradycardia) to a tone in 16‐day‐old male and female rats prenatally exposed to cocaine and in control offspring. Offspring were derived from Sprague‐Dawley dams given daily subcutaneous injections of 40 mg/kg/3 cc cocaine HCI (C40) from gestational days 8–20, pair‐fed control dams given saline injections (PF), and nontreated control dams (LC). Each pup was adapted to the test apparatus for 15 min prior to being given 10 presentations of a pulsing tone, each separated by a 65‐sec intertrial interval, with HR measured during a 5‐sec pretone period and throughout the 10‐sec tone for each trial. To assess retention, subjects were given 10 additional tone trials either 1, 2, 4, or 6 hr later. C40 male offspring displayed significantly lower basal HR following the initial 15‐min isolation period than either LC or PF offspring, whereas prenatal treatment had no effect on basal HR among females. Although no differences were seen in rate of habituation, prenatal cocaine exposure was observed to affect retention of the habituated orienting response. Whereas LC and PF offspring retained habituation of the orienting response for less than 4 hr, C40 offspring exhibited no forgetting after a 4‐hr interval, and showed significant loss of the habituation response only after a 6‐hr interval. © 1994 Wiley‐Liss, Inc.
Human fetal somatic and visceral morphometrics
Authors: Barr Mason , Blackburn Will R. , Cooley N. Reede 
Published: June 2005

AbstractBecause of the increasing prenatal use of high‐resolution ultrasonography to assess fetal growth and because growth aberration is one of the principal manifestations of abnormal intrauterine development, a more precise definition of normal growth is desirable. Our data set from autopsies of fetuses/neonates (50–4,000 g), collected with systematic attention to precision of measurement, is analyzed and presented. Previous computations of fetal growth curves appear to overstate the variation about the mean. Through the identification and exclusion of outliers and the use of appropriate curve fitting techniques, the problem of overestimation of variation about the mean has been largely eliminated. The new growth standards we present can be used to assess aberration from proportional growth and correlate it with gestational circumstances and particular morphological features of the fetus. © 1994 Wiley‐Liss, Inc.
Optic nerve hypoplasia: Comparative effects in children and rats exposed to alcohol during pregnancy
Authors: Strömland Kerstin , Pinazo‐Durán Maria Dolores 
Published: June 2005

AbstractChildren with the fetal alcohol syndrome often have ocular anomalies. These include abnormalities of the eyes and adnexa (strabismus, blepharoptosis, epicanthus), as well as intraocular defects (cataract, glaucoma, persistent hyperplastic primary vitreous, retinal and optic nerve anomalies). Based on the clinical results in an ophthalmological study of a group of Swedish children with the fetal alcohol syndrome, in which optic nerve hypoplasia was found in up to one‐half of the group, an experimental study was designed in rats pre‐ and perinatally exposed to alcohol by means of a liquid diet. The optic nerve was seriously affected. Macroglial cells and optic axons were ultrastructurally damaged. The diameter of the optic nerve cross section, glial cell nuclear area, axonal diameter, and the total number of optic axons showed significantly lower values in the alcohol‐exposed group than in the controls. In addition, the retina from the alcohol‐exposed animals displayed significantly lower values of the retinal thickness and ganglion cell nuclear volume, as compared to the controls. Thus, rats exposed to alcohol in utero developed hypoplasia of the optic nerve similar to the findings in children born to alcoholic mothers. This strongly supports the hypothesis that prenatal alcohol exposure may adversely affect the development of the optic nerve. © 1994 Wiley‐Liss, Inc.
Risk factors for hypoplastic left heart syndrome
Authors: Tikkanen Jorma , Heinonen Olli P. 
Published: June 2005

AbstractA case‐control study was performed in Finland to investigate the etiology of the lethal heart malformation, hypoplastic left heart syndrome (HLHS). The cases represented all verified HLHS (n = 34) in Finland during 1982‐1983, and controls (n = 756) were randomly selected from all babies born during the same period. Both case and control mothers were interviewed by midwives approximately 3 mo after delivery. Maternal upper respiratory infection during the first trimester of pregnancy was a significant risk factor for HLHS (OR = 2.5, Cl95 = 1.2–5.4). Maternal exposures at work to factors such as disinfectants, pesticides, dyes, lacquers or paints, and anesthetic gases were rare and failed to indicate any risk for HLHS. Maternal use of deodorants or hairsprays during the first trimester of pregnancy was not a significant rick factor for HLHS (OR) = 1. 8, Cl95 = (0.9–3.6). The risk of HLHS was not associated with seasonal variation, maternal smoking, alcohol or coffee consumption, or use of acetosalicylic acid.Because the study material is limited in size, the power of this investigation or weak for testing the teratogenicity of specific chemicals on the risk of HLHS. Thus, conclusions from the negative findings of this study should be drawn very carefully. © 1994 Wiley‐Liss, Inc. © 1994 Wiley‐Liss, Inc.