bluuebunny/crossref_metadata_2025_split huggingface dataset:
HMG‐CoA reductase mRNA in the post‐implantation rat embryo studied by in situ hybridization
Authors: Brewer Linda M. , Sheardown Steve A. , Brown Nigel A. 
Published: June 2005

Abstract3‐Hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase (EC 1.1.1.34) is the rate limiting step in the mevalonate pathway that produces isoprenoids and cholesterol. Inhibitors of HMG‐CoA reductase are teratogenic in vivo and induce neural tube defects in rat embryo culture, effects which appear unrelated to cholesterol deficiency. This study is the first to localize HMG‐CoA reductase mRNA by in situ hybridization (ISH). Expression of reductase mRNA was examined in post‐implantation rat embryos, and for control purposes in rat liver and UT‐1 cells, using a digoxigenin‐11 (dig‐11) labelled cRNA probe. Eighteen‐day fetal liver showed heavy but patchy hybridization, and adult rat liver showed strong hybridization only on some periportal hepatocytes, which was absent in livers of fasted animals. UT‐1 cells stimulated to overexpress HMG‐CoA reductase mRNA were strongly positive with the same probe. Control hybridizations with sense strand RNA probe, or with cRNA probe on pre‐RNased tissue were negative. Strong hybridization signal for HMG‐CoA reductase mRNA was observed in all tissues of the post‐implantation rat embryo, from egg cylinder to 30 somite stages (7 to 12 days). Heavy signal was noted in primitive ectoderm and neural tube. The wide embryonic and extraembryonic distribution and abundance of HMG‐CoA reductase mRNA may reflect developmental requirements for products of the mevalonate pathway, e.g., isoprenoids for post‐translational farnesylation of p21ras. © 1993 Wiley‐Liss, Inc.
Skeletal development following heat exposure in the rat
Authors: Kimmel C. A. , Cuff J. M. , Kimmel G. L. , Heredia D. J. , Tudor N. , Silverman P. M. , Chen J. 
Published: June 2005

AbstractThe effects of gestation day (GD) 10 heat exposure in the rat were studied to determine the temperature‐response relationship for the induction of skeletal and other defects. Conscious pregnant rats (Experiment 1) were exposed to various temperatures in a warm air chamber. Body temperature was measured using a rectal probe, and these measurements were confirmed as representing core body temperature in separate animals using telemetric procedures. Those animals whose core body temperature was raised to 41–41.9°C had over 90% malformed pups (examined at postnatal day (PND) 3), and a 25% reduction in the percent of live pups per litter. Animals whose temperature was raised to 39.2–40.9°C had a low incidence of pups with similar types of malformations. The primary types of malformations were of the axial skeleton, consisting of fusions and other abnormalities of the ribs and vertebral elements, and a decrease in the total number of ribs and centra. The acute maternal effects of these temperature increases were signs of heat exhaustion during and 1–2 hr after exposure, but there were no permanent changes in weight gain or other signs. When temperatures were raised to ⩾42°C, all maternal animals died. In a second study (Experiment 2), pregnant rats (from a different supplier) were anesthetized to determine the effect of reducing maternal stress and were exposed to heat as in Experiment 1. Those animals whose core body temperature was raised to 42–42.5°C for 5 min had pups with similar responses to those in Experiment 1 at 41–41.9°C, although the reduction in litter size was not as great. Animals whose temperature was raised to 41°C had a much lower incidence of pups with similar defects, and animals whose temperature was raised to 43°C did not survive. A more detailed analysis of the skeletal defects in Experiment 2 showed rib and vertebral malformations that appear to be related to the stage of somite development at the time of exposure. © 1993 Wiley‐Liss, Inc.
Acardius acephalus after induced ovulation: A case report
Authors: Haring D. A. J. P. , Cornel M. C. , van der Linden J. C. , van Vugt J. M. G. , Kwee M. L. 
Published: June 2005

AbstractAn excess of structural defects occurs in monozygotic twins compared to dizygotic twins or singletons. Among these defects the acardius acephalus or chorangiopagus parasiticus is one of the most rare and severe and a possible cause of pathology to the other twin. Ovulation induction by clomiphene causes an increased frequency of multiple gestation and possibly of monozygotic multiple pregnancy. In the present report, we describe a prenatally diagnosed and autopsied case of acardius acephalus from a pregnancy established after ovulation induction by clomiphene. Approximately 1.4% of pregnancies are accomplished after use of ovulation inducing medication in the Netherlands. A possible etiological role of clomiphene justifies close monitoring of future cases. © 1993 Wiley‐Liss, Inc.
Effects of 5‐Fluorouracil on embryonic rat palate in vitro: Fusion in the absence of proliferation
Authors: Abbott B. D. , Lau C. , Buckalew A. R. , Logsdon T. R. , Setzer W. , Zucker R. M. , Elstein K. H. , Kavlock R. J. 
Published: June 2005

Abstract5‐Fluorouracil (5‐FU) inhibits the enzyme thymidylate synthetase (TS) which results in inhibition of DNA synthesis. 5‐FU is teratogenic in many species, inducing cleft palate, limb, and tail defects. In the present study, gestation day (GD) 14 embryonic rat craniofacial explants were exposed to 5‐FU in organ culture with increasing concentrations and durations of exposure. Palates exposed to 5‐FU were morphologically abnormal and craniofacial shape, size, and palatal fusion pattern were affected with the severity of effects dependent on concentration and duration of exposure. Cleft palate was induced in vitro as opposing palates overlapped in a narrowed oral cavity. Palates exposed to higher levels of 5‐FU were growth inhibited, but fused even though proliferation ceased and few cells were available to participate in elevation and fusion. This was demonstrated as a biphasic concentration‐response profile for palatal fusion in which 0.05 to 0.15 μg 5‐FU/ml produced decreasing rates of palatal fusion, while exposure to 0.15 to 3.0 μg/ml resulted in progressively increasing rates of fusion. The effects of 5‐FU were detected biochemically as a reduction in TS activity which was concentration and time dependent during the first 12 hours, with a return to control levels by 24 hours. During the first day, 5‐FU did not alter protein levels, but DNA levels significantly decreased at the high concentration, 2.0 μg/ml. After 5 days in culture, both DNA and protein decreased with increasing 5‐FU concentration and duration of exposure. Also by the end of the culture period, 3H‐TdR incorporation had decreased in a concentration dependent manner. It is concluded that progressive inhibition of proliferation and growth in organ culture results in two different morphological outcomes: cleft palate resulting from a narrowed oral cavity and increased incidence of anterior palatal fusion under conditions of strong growth reduction. This study demonstrates that elevation and fusion can occur in the absence of growth and proliferation. Based on these observations, severe inhibition of growth or proliferation would not necessarily be sufficient to induce cleft palate. © 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.
Risk factors for coarctation of the aorta
Authors: Tikkanen Jorma , Heinonen Olli P. 
Published: June 2005

AbstractTo test the hypothesis that environmental factors during early pregnancy may cause coarctation of the aorta (CoA), 50 cases of CoA and 756 controls were studied. The cases represented all verified CoAs in Finland during 1982–1983 and controls were randomly selected from all babies born during the same period. Both case and control mothers were interviewed by midwives approximately 3 months after delivery. In these data 18 patients had pure CoA only and the remaining 32 at least one other cardiac anomaly. Three CoA patients had a chromosomal anomaly. The relatives of CoA babies had more congenital anomalies than those of the control babies. Maternal overall exposure to chemicals at work was slightly more prevalent among the CoA group (32.0%) than the control group (26.2%). Maternal exposure to mineral oil products at work during early pregnancy was more common among CoA cases (8.0%) than controls (1.4%) [odds ratio (OR) = 5.9, 95% confidence interval (CI95) = 1.8–19.2]. The risk of CoA was also associated with previous miscarriages (OR = 2.3, CI95 = 1.2–4.4) and twin birth (OR = 16.3, CI95 = 4.0–67) of the child. The risk of CoA was not associated with seasonal variation, maternal smoking, alcohol consumption, or use of deodorants. It is concluded that genetic factors explain only a small fraction of the causes of CoA and that many common environmental exposures during early pregnancy are unlikely to be real risk factors for CoA. However, the power of this study was weak for testing the teratogenicity of specific chemicals. © 1993 Wiley‐Liss, Inc.
Penetrance and expressivity of acetazolamide‐ectrodactyly provide a method to define a right‐left teratogenic gradient that differs between the C57BL/6J and WB/ReJ mouse strains
Authors: Biddle Fred G. , Mulholland Lynda R. , Eales Brenda A. 
Published: June 2005

AbstractPenetrance or the frequency of embryos with any degree of forelimb ectrodactyly is the usual method to describe the forelimb ectrodactyly response of mouse embryos to acetazolamide. A digit score for number of small or absent digits for the separate right and left forelimb response to acetazolamide provides a measure of expressivity or the severity of response. We examine the relationship between expressivity and penetrance using right and left forelimb data from a previously reported dose‐response analysis of the C57BL/6J and WB/ReJ strains to acetazolamide. The data show that expressivity and penetrance are highly correlated for the separate right and left forelimbs for both strains. In C57BL/6J, the dose‐response analyses of both expressivity and penetrance of the separate right and left forelimbs demonstrate a teratogenic gradient, decreasing from right to left, that depends on the symmetrical ectrodactyly response of the right and left forelimbs. In WB/ReJ, the right forelimb is also more sensitive than the left, but the dose‐response analyses of both penetrance and expressivity show the two forelimbs are asymmetrical in their ectrodactyly response and that there is not a simple teratogenic gradient in this strain. In WB/ReJ, the left forelimb is resistant at even the highest non‐lethal doses. The high correlation between expressivity and penetrance for the separate forelimbs of both C57BL/6J and WB/ReJ suggests that this right‐left difference between the two strains may not be a property of the limbs themselves but may be an intrinsic genetic difference between the two types of embryos perhaps in the amount of teratogen to which the embryos are exposed. The right and left forelimbs of the embryo may simply provide a biological assay of this intrinsic embryonic difference. © 1993 Wiley‐Liss, Inc.
Report of national institute of child health and human development workshop on chorionic villus sampling and limb and other defects, October 20, 1992
Authors: de la Cruz Felix 
Published: June 2005

AbstractA Workshop on Chorionic Villus Sampling (CVS) was convened by the National Institute of Child Health and Human Development (NICHD) and the American College of Obstetricians and Gynecologists at the National Institutes of Health on April 17, 1992, to discuss recent reports of an increased occurrence of malformations of the upper and lower limbs and oral structures among CVS‐exposed infants. We summarize here the defects described in the CVS‐exposed infants, the retrospective reassessments of published studies of the safety of CVS, the prevalence of limb deficiencies in infants not exposed to CVS, the status of the 7–9 week (conception or fertilization age) embryo, and the relevant human and animal experimental models of how CVS might be harmful to the embryo or fetus. © 1993 Wiley‐Liss, Inc.
A case of a closed partial cloacal septation defect with a patent urachus
Authors: Stoler Joan M. , Doody Daniel P. , Holmes Lewis B. 
Published: June 2005

AbstractA boy with a closed partial cloacal septation defect with a patent urachus is reported. He had an intact abdominal wall, a patent urachus, a colovesical fistula, intact genitalia and urethra, imperforate anus, and a lipomyelocystocoele. Patients with similar constellation of findings have been reported as cloacal exstrophy variants. What distinguishes this case from the other reported variants is the intact abdominal wall with the patent urachus, the small and normally formed phallus and urethra, and the presence of a lipomyelocystocoele.We discuss the possible embryologic mechanism responsible for this boy's findings and possible relationship with the cloacal exstrophy spectrum. We also discuss new terminology for the epispadias‐exstrophy spectrum. Furthermore this case reminds us that there is considerable variability within the epispadiasexstrophy spectrum. © 1993 Wiley‐Liss, Inc.
Effects of sodium bicarbonate and ammonium chloride on the incidence of furosemide‐induced fetal skeletal anomaly, wavy rib, in rats
Authors: Nakatsuka Toshio , Fujikake Noboru , Hasebe Miki , Ikeda Hisataka 
Published: June 2005

AbstractFurosemide produces fetal wavy ribs when administered to pregnant rats during late gestation. The compound is also known to produce metabolic alkalosis in laboratory animals and man. In order to evaluate the effect of furosemide on maternal blood pH, Crj:CD(SD) female rats received an oral administration of 150 or 200 mg/kg of furosemide by gavage on day 16 of gestation and were bled at 4 hr post‐dose. Compared to an average pH of 7.39 in control females, there was a significant elevation in blood pH in these furosemide‐treated females (average pH of 7.44 to 7.48). When 2% sodium bicarbonate was provided in the drinking water for females treated with 150 mg/kg of furosemide, there was a further rise in maternal blood pH (7.52) compared to females treated with furosemide alone. Associated with this elevation in maternal blood pH was a marked increase in the incidence of fetal wavy ribs (87.6% compared to 27.6%). When females treated with 200 mg/kg of furosemide were provided with 0.5% ammonium chloride, furosemide‐induced maternal alkalosis was corrected (pH decreased to 7.35) and there was a reduction in the incidence of fetal wavy ribs (7.0% compared to 37.2%). In addition, maternal blood pH among individual females was positively correlated with the incidence of fetal wavy ribs (r = 0.714). These results suggest that maternal metabolic alkalosis is involved in the pathogenesis of furosemide‐induced wavy ribs. © 1993 Wiley‐Liss, Inc.
Teratogenicity and developmental toxicity of carbon monoxide in protein‐deficient mice
Authors: Singh Jarnail , Aggison Lee , Moore‐Cheatum Linda 
Published: June 2005

AbstractExperiments were carried out to determine the teratogenicity and developmental toxicity of carbon monoxide (CO) in mice fed protein‐deficient diets. Pregnant CD‐1 mice were fed 27 (control), 16, 8, or 4% protein diets throughout gestation and each group was exposed to 0 (control), 65, 125, 250, or 500 ppm of CO from gestation days 8–18. The CO exposure was continuous except for daily watering, feeding or cage changing. The animals were killed on gestation day 18. Pregnancy status of the dams was examined. Fetuses were examined for gross and skeletal malformations. The percentages of dead or resorbed fetuses and of grossly malformed fetuses per litter were related to the CO exposure levels and inversely related to the dietary protein levels. All levels of CO and 8 or 4% protein diets significantly decreased the fetal weight of normal fetuses. The most commonly seen gross malformations were brachygnathia accompanied by protruding tongue, microstomia, microcephaly, open mouth, or open eyes. Most of the grossly malformed fetuses also had dry, bleached and wrinkled skin. An increased incidence of skull (interparietal or supraoccipital), and jaw (mandible or premaxilla) malformation; wavy ribs and scoliosis of spine; and limb unossifications were observed in the litters of dams fed protein‐deficient diet and all levels of CO exposure. Malformed litters in each protein diet were related to CO exposure levels. The data suggest that CO is teratogenic under protein‐deficient conditions. Protein deficiency had additive effect on CO teratogenicity and synergistic effect on fetal mortality. Special groups at risk may include cigarette or marijuana smokers and malnourished or undernourished populations. © 1993 Wiley‐Liss, Inc.
Evidence that spontaneous situs inversus in cultured neural plate staged rat embryos is additive with and not mediated through adrenergic mechanisms
Authors: Flynn Thomas J. , Gibson Regina R. , Johannessen Jan N. 
Published: June 2005

AbstractApproximately 50% of untreated presomite rat embryos in culture have demonstrated inversions of cardiac looping (laeval instead of dextral) or tail flexure (left‐sided instead of right‐sided), or both. This spontaneous situs inversus (SI) was not accompanied by growth inhibition or any other observable defects. The incidence of SI was directly related to the stage at dissection, and all heart defects and most flexure defects were eliminated by delaying explantation to the early somite stage. The incidence of SI was not lowered significantly either by removal of endogenous catecholamines from the culture serum by dialysis or by inclusion of α‐ or β‐adrenergic antagonists in the medium. However, the α‐adrenergic agonist L‐phenylephrine (50 μg/ml) increased the incidence of SI to 73%. These findings appear to rule out adrenergic mechanisms as a cause of spontaneous SI in cultured, neural plate‐staged rat embryos but suggest a mechanism, yet unknown, that is additive with SI induced by α‐adrenergic agonists. The low incidence of non‐SI‐related defects suggests that the high incidence of SI is not an artifact of suboptimal culture conditions. The virtual absence of SI in embryos cultured in bovine serum; a medium in which overall embryonic growth and development were retarded, provides further evidence against nonspecific artifacts. © 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.
Effects of cadmium on reproduction, an epizootologic study
Authors: Kreis I. A. , de Does M. , Hoekstra J. A. , de Lezenne Coulander C. , Peters P. W. J. , Wentink G. H. 
Published: June 2005

AbstractThe Dutch part of Kempenland has been exposed to cadmium pollution since the last century. Experimental data suggest effects by cadmium on reproduction such as diminished fertility, decreased foetal growth, and specific malformations. Use was made of a historical cohort of dairy cows, ascertained from a surveillance program conducted by the regional Veterinary Health Service between 1976 and 1986. Ten dairy farms in the cadmium region were matched by size with 40 dairy farms from a reference area. Logistic models were used to calculate Odds (OR) and Rate Ratios (RR) and their 95% confidence interval. In total 4,039 exposed and 15,552 reference gestations were compared. The reasons for the slaughter of 574 exposed and of 2,824 reference cows were ascertained. A lower twinning rate [OR = 0.63 (0.47–0.84)] was found and more birth complications, for both calves [OR = 1.50 (1.25–1.80)] and cows [OR = 1.49 (1.24–1.79)]. More inseminations [OR = 1.20 (1.01–1.43)] were needed for conception in the exposed area. Deaths among twins [OR = 1.66 (0.90–3.07)] were not significantly higher. Perinatal death, premature death, age at, or reasons for, slaughter were not consistently different. These results are consistent with those of other observational and experimental studies. Extrapolation from these large domestic animals to humans is problematic, as is the more frequent extrapolation from rodents to humans. It can be concluded that longterm exposure to low levels of cadmium is associated with impaired reproduction in dairy COWS. © 1993 Wiley‐Liss, Inc.
Chloroquine embryotoxicity in the postimplantation rat conceptus in vitro
Authors: Ambroso Jeffrey L. , Harris Craig 
Published: June 2005

AbstractThe embryotoxicity of the antimalarial drug chloroquine (CQ) was evaluated in vitro using the rat whole embryo culture system. CQ was found to be embryotoxic and dysmorphogenic when added directly to the culture media containing gestational day (GD) 10 rat conceptuses. Twenty‐six‐hr exposure to CQ elicited dose‐related decreases in embryonic crown‐rump length, protein and DNA contents and increases in the incidence of morphologically abnormal embryos. At 30 μM CQ, embryonic protein content was decreased to 67% and DNA content to 58% of control while the incidence of morphological abnormalities rose to 100%. Abnormal axial rotation, microophthalmia, and selective cephalic hypoplasia were the most common developmental abnormalities observed. Visceral yolk sac (VYS) vasculature and blood pigmentation were also decreased in a dose‐dependent manner, as was VYS DNA content (80% of control at 30 μM). VYS protein content, however, showed an alternate pattern of response, decreasing to 87% of control at 10 μM CQ but increasing to 125% of control at 30 μM. Histologic evaluation revealed that the cytoplasm of the VYS endoderm epithelium was distended due to vacuolization produced by CQ exposure. In the embryo proper, CQ inhibited cranial neural tube development and altered the morphology of cranial neural crest cells. These observations document the in vitro embryotoxicity of CQ and suggest altered VYS histiotrophic nutrition as well as direct embryonic effects as possible mechanisms of CQ embryotoxicity. © 1993 Wiley‐Liss, Inc.
Changes in dopamine, serotonin and their metabolites in discrete brain areas of rat offspring after in utero exposure to cocaine or related drugs
Authors: Henderson Mark G. , McMillen Brian A. 
Published: June 2005

AbstractThe concentrations of dopamine (DA), serotonin (5HT) and their metabolites were quantified in 5 brain areas of rats exposed to saline, cocaine (15 mg/kg b.i.d.), amitriptyline (10 mg/kg), or amfonelic acid (AFA, 1.5 mg/kg) throughout gestation. Male pups from 3 similarly treated dams were fostered to 2 surrogate dams. The process of breeding and rearing was repeated 4 times with new dams to build the groups to 4–12, since only one pup per litter was used for any one measurement. AFA was used to mimic the dopamine (DA) uptake blockade and stimulant properties of cocaine and amitriptyline was used to mimic the other pharmacological effects of cocaine. At postnatal days (PND)30, 60, and 180, one pup per litter was removed for HPLC analysis of monoamines. A second pup received 0.3 mg/kg haloperidol, catalepsy assessed after 1 hr, and the brain used for analysis. The cataleptic response to haloperidol was unaffected by any prenatal treatment. The striatum from PND 30 cocaine rats had decreased levels of DA without a decrease in DA metabolites. At PND 60 in cocaine exposed rats, DA and DOPAC concentrations were increased, and 5HT levels were decreased in the striatum. The amitriptyline‐exposed group exhibited decreased 5HT and 5‐HIAA levels in the striatum. The hypothalamus of the cocaine group had lower levels of 5‐HIAA, and other brain areas had a trend for lower levels of 5HT and 5‐HIAA. At PND 180, DOPAC was increased in the striatum and prefrontal cortex of the cocaine group. Haloperidol‐induced altered monoamine metabolism was unaffected by any prenatal treatment at any age. These data suggest that age‐related changes in the DA and 5HT neurotransmission systems occur in rats exposed prenatally to cocaine. However, the ability of the dopaminergic system to respond to a challenge by a DA receptor blocker is unaltered by these in utero treatments. © 1993 Wiley‐Liss, Inc.