bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of the biguanide class of oral hypoglycemic agents on mouse embryogenesis
Authors: Denno Kelly M. , Sadler Thomas W. 
Published: June 2005

AbstractThe incidence of birth defects among offspring of mothers with non–insulin dependent diabetes mellitus (NIDDM) is 2–3–fold higher than among infants of non diabetics. Since mothers with NIDDM are frequently given oral hypoglycemic agents, including sulphonylureas and biguanides, to control their disease and since these agents have been associated with the occurrence of congenital malformations in humans and animals, the embryotoxic effects of the most commonly employed biguanides, metformin and phenformin, were evaluated in whole embryo culture. Neurulating mouse embryos were exposed to therapeutic concentrations (metformin 500–2,550 mg per day; phenformin 50–400 mg per day, respectively) of the compounds for 24–48 h. Concentrations of metformin in culture ranged from 0.15 to 1.8 mg/ml and phenformin from 2.5 × 10−5 to 0.4 mg/ml. Cultures were terminated and scored for gross morphological alterations and total protein content. Metformin produced no alterations in embryonic growth and no major malformations. Approximately 10% of all embryos exposed to metformin regardless of dose, exhibited open cranial neuropores after 24 h of culture. However, this anomaly appeared to represent a delay in closure as opposed to an overt defect, since no embryos exposed to the highest concentration of the drug and cultured for 48 h showed open neural tubes. In contrast, phenformin produced dose dependent changes in incidence of malformations, protein content, and embryolethality. Malformations included neural tube closure defects, craniofacial hypoplasia, and reduction in size of the first and second visceral arches. Doses above 0.1 mg/ml produced embryolethality and all embryos were killed at the 0.4 mg/ml concentration. Thus, of the two biguanides phenformin has a greater toxicity in whole embryo culture, suggesting that metformin may be safer for use during pregnancy. © 1994 Wiley‐Liss, Inc.
Effects of the class III Antiarrhythmic, Dofetilide (UK‐68,798) on the heart rate of midgestation rat embryos, in vitro
Authors: Spence Stanley G. , Vetter Christine , Hoe Chao‐Min 
Published: June 2005

AbstractGestation day 11 (GD11) and 14 (GD14) embryos were cultured for up to 4 hours in the presence of Dofetilide (0.01–0.50μg/ml), a potent Class III Antiarrhythmic which selectively inhibits the rapid component of the time dependent outward potassium current (IKr). Significant (P < 0.05) reductions in heart rate (HR) as measured over a 4 hour period were dose dependent and reversible. The sensitivity of the GD11 embryos was greater than GD14 embryos (14–64% decrease in HR vs. an 11–43% decrease in HR, respectively) at the same concentrations tested. These in vitro results support the hypothesis that the embryo‐lethality of Class III Antiarrhythmics observed in vivo may be a class effect of the IKr subtype potassium channel blockers. The data suggest a possible mechanism of embryotoxicity is to lower embryonic HR resulting in subsequent hypoxia and death. Dofetilide's effects on GD11 HR were partially reversible by the sequential addition of Isoproterenol or Theophylline. © 1994 Wiley‐Liss, Inc.
Effect of coniine on the developing chick embryo
Authors: Forsyth C. S. , Frank A. A. , Watrous B. J. , Bohn A. A. 
Published: June 2005

AbstractConiine, an alkaloid from Conium maculatum (poison hemlock), has been shown to be teratogenic in livestock. The major ter‐atogenic outcome is arthrogryposis, presumably due to nicotinic receptor blockade. However, coniine has failed to produce arthrogryposis in rats or mice and is only weakly teratogenic in rabbits. The purpose of this study was to evaluate and compare the effects of coniine and nicotine in the developing chick. Concentrations of coniine and nicotine sulfate were 0.015%, 0.03%, 0.075%, 0.15%, 0.75%, 1.5%, 3%, and 6% and 1%, 5%, and 10%, respectively. Both compounds caused deformations and lethality in a dose‐dependent manner. All concentrations of nicotine sulfate caused some lethality but a no effect level for coniine lethality was 0.75%. The deformations caused by both coniine and nicotine sulfate were excessive flexion or extension of one or more toes. No histopathological alterations or differences in bone formation were seen in the limbs or toes of any chicks from any group; however, extensive cranial hemorrhage occurred in all nicotine sulfate‐treated chicks. There was a statistically significant (P ≤ 0.01) decrease in movement in coniine and nicotine sulfate treated chicks as determined by ultrasound. Control chicks were in motion an average of 33.67% of the time, while coniine‐treated chicks were only moving 8.95% of a 5‐min interval, and no movement was observed for nicotine sulfate treated chicks. In summary, the chick embryo provides a reliable and simple experimental animal model of coniine‐induced arthrogryposis. Data from this model support a mechanism involving nicotinic receptor blockade with subsequent decreased fetal movement. © 1994 Wiley‐Liss, Inc.
Fetal anemia following maternal exposure to 5‐fluorouracil in the rat
Authors: Shuey Dana L. , Zucker Robert M. , Elstein Kenneth H. , Rogers John M. 
Published: June 2005

AbstractPrevious studies from our laboratory have shown that maternal 5‐fluorouracil (5‐FU) exposure on day 14 of gestation (GD14) in the rat results in dose‐dependent retardation of both cell cycle progression and growth of embryonic liver. At this developmental stage, hepatic erythropoiesis is the primary source of new circulating fetal erythrocytes. This study examined dose‐dependent hematological changes in the fetus after maternal 5‐FU exposure (0, 20, 30, 40 mg/kg on GD14) to assess 1) hematopoiesis as a potential target for 5‐FU developmental toxicity and 2) the role of the observed 5‐FU‐induced fetal anemia in adverse developmental outcome. Standard clinical hematological parameters, including hematocrit, hemoglobin content, and erythrocyte counts, were measured in fetal blood drawn by cardiac puncture. Dose‐related deficits were observed in all of these parameters within 48 hr of 5‐FU administration. Calculation of various red cell indices revealed a concomitant increase in mean cell volume and mean cell hemoglobin. These changes were preceded by depletion of hepatic precursor populations which was evident by 24 hr after maternal exposure to 30 or 40 mg/kg. At doses of 20 and 30 mg/kg there was full and moderate recovery, respectively, in these endpoints by 72 hr after dosing, but persistent deficits were observed at 40 mg/kg. Fluorescence microscopy of Hoechst‐stained fetal blood smears revealed that at both 48 and 72 hr after dosing, the proportion of nucleated yolk sac‐derived erythrocytes was increased relative to control. These data suggest that inhibition of proliferation of hepatic erythroid precursors by 5‐FU results in depletion of these populations and subsequent deficiency of liver‐derived reticulocytes in the fetal circulation, leading to fetal anemia. Since morphological changes are detectable within embryonal target tissues (e.g., hind limb buds) prior to the onset of significant hematological changes, fetal anemia is not involved in the pathogenesis of 5‐FU‐induced malformations. However, the persistence of hematological deficits at 40 mg/kg was correlated with fetal growth retardation during late gestation, suggesting that fetal anemia may be an important factor contributing to the developmental toxicity of 5‐FU. c 1994 Wiley‐Liss, Inc.This article is a US Government work and, as such, is in the public domain in the United States of America.
Teratogenesis by retinoic acid analogs positively correlates with elevation of retinoic acid receptor‐β2 mRNA levels in treated embryos
Authors: Jiang Heng , Iii Michael Gyda , Harnish Douglas C. , Chandraratna Roshantha A. , Soprano Kenneth J. , Kochhar D. M. , Soprano Dianne Robert 
Published: June 2005

AbstractRetinoic acid (RA) plays an important role during normal embryogenesis, however high doses of RA are teratogenic. Retinoic acid receptor‐β2 (RAR‐β2) mRNA and protein levels were previously demonstrated to undergo rapid elevation in susceptible tissues after treatment with teratogenic doses of RA. In this report we compared the effects of a number of retinoids, which represent a wide variety of chemical structures and which differ in their teratogenic potencies, on RAR‐β2 mRNA levels in mouse embryos 6 hr after treatment. Retinoid treatments which result in a high incidence of limb defects elevated RAR‐ β2 mRNA levels similarly (10–14 fold in the limb buds, 4–8 fold in the head, and 2–4 fold in the remainder of the body). On the other hand, retinoid treatments which cause a low or no incidence of limb defects resulted in minor changes in RAR‐ β2 mRNA levels in each embryonic region. Therefore, a strong positive correlation was found between the elevation of RAR‐β2 mRNA levels and the retinoids which produce limb defects. This provides further evidence that an elevation of RAR‐β2 mRNA levels and subsequently protein levels, is an important event involved in mediating the effects of RA during dysmorphogenesis. © 1994 Wiley‐Liss, Inc.
Ebstein's malformation of the tricuspid valve: Genetic and environmental factors
Authors: Correa‐Villaseñor Adolfo , Ferencz Charlotte , Neill Catherine A. , David Wilson P. , Boughman Joanne A. 
Published: June 2005

AbstractEbstein's anomaly is a specific structural deformity of the tricuspid valve, and its rarity has hampered etiologic evaluation. Cases of Ebstein's anomaly registered in the Baltimore Washington Infant Study (BWIS), a regional case‐control study of cardiovascular malformations (CVM) in infancy, are reviewed. Between 1981 and 1989 a total of 4, 390 CVM cases, including 47 Ebstein cases, and 3, 572 controls were registered. The prevalencxe of Ebstein's anomaly was 5.2 per 100, 000 livebirths. Additional cardiac anomalies were present in 38. 3% of Ebstein cases. Non‐cardiac malformations were present in 19. 1% of Ebstein cases vs. 25.5% of other CVM, and 1.7% of controls. Case‐fatality by 1 year of age was 23. 4% in Ebstein cases, vs 18. 1% in other CVM. Interviews of parents of Ebstein cases, other CVM, and controls (n = 44, 3,335, and 3,572, respectively) elicited information on family history of malformations, maternal illnesses, reproductive history, therapeutic drugs, parental lifestyle, and environmental exposures during the periconceptional period. Case‐control analyses suggest genetic, reproductive, and environmental risk factors: twins [odds ratio (OR) 8.2, 95% confidence interval (CI) 2.6–25.3]; family history of CVM (OR 6.4, 95% CI 1.8–22.2); white race (OR 2.9 with non‐whites as reference, 95% CI 1.2–7.0); previous miscarriages (OR 2.0, 95% CI 1.2–3.3); maternal exposure to benzodiazepines (OR 3. 4, 95% CI 1.3–9.1); and varnishing (OR 3.4, 95% CI 1.3–9.1). Additional multicenter investigations are warranted to elucidate the role of genetic, reproductive, and environmental factors in the etiology of this anomaly. © 1994 Wiley‐Liss, Inc.
A fetus with sirenomelia, omphalocele, and meningomyelocele, but normal kidneys
Authors: McCoy M. Cathleen , Chescheir Nancy C. , Kuller Jeffrey A. , Altman Georgia C. , Flannagan Lisa M. 
Published: June 2005

AbstractSirenomelia, which has been reported for more than 450 years, is the most severe form of caudal dysplasia. This disorder is classically associated with agenesis or severe dysplasia of the Urinary tract.A 27‐year‐old gravida 3 para 0020 presented at 19 weeks′ gestation with monoamniotic twins, one normal and one with sirenomelia. The pregnancy miscarried following invasive diagnostic testing. Autopsy confirmed the findings of sirenomelia, meningomyelocele, omphalocele, persistent cloaca, and two normal kidneys.The abnormalities accompanying sirenomelia appear as a spectrum. The pathogenic theories of sirenomelia are reviewed in light of this case with normal kidneys. © 1994 Wiley‐Liss, Inc. © 1994 Wiley‐Liss, Inc.
Deaths associated with renal agenesis: A population‐based study of birth prevalence, case ascertainment, and etiologic heterogeneity
Authors: Cunniff Christopher , Kirby Russell S. , Senner John W. , Canino Carole , Brewster Marge A. , Butler Becky , Hassed Susan J. , Murphy Pam 
Published: June 2005

AbstractWe report on deaths associated with renal agenesis among 211,704 consecutive births. Sources included birth and death certificates and an active birth defects surveillance system. Medical review and classification of cases were performed for 1985–1990 events. Sixty‐one cases of renal agenesis were identified, and review of records was possible for 59 of the 61 cases. Of these 59 cases, 36 (61%) were confirmed, 5 (8%) were questionable, and 18 (31%) were incorrectly coded. The prevalence of confirmed cases is thus estimated at 17/100,000 births (14.2/100,000 births, excluding elective terminations and fetal deaths). Records incorrectly coded were most of ten those with multicystic dysplasia. Approximately one‐third of cases was found by the birth defects surveillance system alone, confirming the utility of this data source for prevalence estimates. Isolated renal agenesis accounted for 44% of confirmed cases; other diagnoses included VATER association (19%), unrecognized multiple malformation syndromes (17%), exstrophy of the cloaca sequence (14%), and chromosome disorders (6%). Based on these data, prevalence rates for ICD code 753.0 and death include overascertainment of cases from erroneous coding of multicystic dysplasia and underascertainment of cases with unilateral renal agenesis associated with other malformations. Population‐based ascertainment of cases by active surveillance methods and rigorous diagnostic coding standards are required to improve the accuracy of these rates. Targeted investigations of distinct subclassifications will be necessary to identify specific etiologic factors. © 1994 Wiley‐Liss, Inc.
Alcohol‐induced brain growth restrictions (microencephaly) were not affected by concurrent exposure to cocaine during the brain growth spurt
Authors: Chen Wei‐Jung A. , Andersen Kathleen H. , West James R. 
Published: June 2005

AbstractThe prevalence of concomitant use of alcohol and cocaine among drug abusers has raised concern about the possible increased risk of fetal damage. The aim of this study was to assess the interactive effects of alcohol and cocaine on lethality, somatic growth, and brain growth using an animal model system. Sprague‐Dawley rat pups were used as subjects. They were randomly assigned to 1 of the 9 artificially reared groups which varied with respect to the combination treatments of cocaine (0, 40, or 60 mg/kg) and alcohol (0, 3.3, or 4.5 g/kg). All artificially reared pups were given daily cocaine and alcohol treatments during a major part of the brain growth spurt period (postnatal days 4–9). An additional group of suckled control animals raised by their natural dams was included to control for artificial rearing. The results are summarized as follows: (1) Drug‐induced lethality was higher in cocaine‐treated groups when compared with non‐cocaine‐treated groups, and the concurrent administration of high doses of alcohol and cocaine significantly increased the mortality rate. (2) Somatic growth, in terms of body weight, was not affected by alcohol, cocaine, or the combination of both drugs using the artificial rearing technique. (3) Alcohol exposure during this brain growth spurt period significantly reduced whole brain weight, as well as forebrain, cerebellum, and brain stem weights. (4) In contrast to alcohol, cocaine failed to exert a detrimental effect on brain weight measures during this early postnatal period. (5) There were no antagonistic or synergistic effects in inducing brain growth restrictions by concurrent exposure to alcohol and cocaine during the brain growth spurt. The potential involvement of cocaethylene in mediating the observed lethality is discussed. © 1994 Wiley‐Liss, Inc.
Distribution of cellular retinoic acid‐binding proteins I and II in the chick embryo and their relationship to teratogenesis
Authors: Maden M. 
Published: June 2005

AbstractThe distribution of cellular retinoic acid‐binding proteins I and II (CRABP I and II) during the first 6 days of chick development has been investigated using immunoblotting. Since retinoic acid (RA) is teratogenic to some parts of the embryo, stimulatory to other parts, and has no effect on others it may be that the distribution of cytoplasmic proteins such as CRABP I and II plays some role in this differential activity. Neither protein is expressed in the day 2 embryo, but from day 3 onwards both proteins are expressed and CRABP I is in considerable excess over CRABP II. Within the day 4 embryo there is some significant variation in the distribution according to tissue type. Neural tissues, neural crest derivatives, and limb buds most strongly express CRABP I whilst other tissues contain only moderate levels, and heart and epidermis do not express CRABP I at all. CRABP II has a widespread distribution, although at a lower level than CRABP I, with the exception of somites and ectoderm which do not express it at all. In the limb buds, there is a significant variation in CRABP I levels across the anteroposterior axis which suggests that these two CRABPs may have different functions during development. The relationship of these distributions in the embryo to the role of endogenous RA and the teratogenic effects of RA is discussed. © 1994 Wiley‐Liss, Inc.
Developmental toxicity of the HMG‐CoA reductase inhibitor, atorvastatin, in rats and rabbits
Authors: Dostal Lori A. , Schardein James L. , Anderson John A. 
Published: June 2005

AbstractThe developmental toxicity of the 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitor, atorvastatin, was investigated in pregnant rats and rabbits given daily oral doses during organogenesis. Rats received 0, 10, 100, or 300 mg/kg on days 6–15 of gestation, and rabbits received 0, 10, 50, or 100 mg/kg on days 6–18 of gestation. Maternal and fetal parameters were evaluated on day 20 (rats) or 29 (rabbits) of gestation. Live fetuses were examined for external, visceral, and skeletal malformations and variations. At 300 mg/kg in rats, 1 treatment‐related death occurred on day 12 of gestation, and maternal body weight gain and food consumption were decreased during treatment (43% and 23%, respectively). In addition, 1 animal at 300 mg/kg had total litter resorption. Increased postimplantation loss (not statistically significant) and slightly decreased fetal body weight (statistically significant only in males) were also observed at 300 mg/kg. There were no significant differences between treated and control groups in the incidence of fetal malformations or variations. No maternal or developmental toxicity was observed in rats at 10 or 100 mg/kg. In rabbits, marked maternal toxicity (7 deaths, body weight loss during and after treatment, and decreased food consumption) and abortion occurred at 100 mg/kg. At 50 mg/kg, maternal toxicity (2 deaths and 72% body weight gain suppression) and abortion also occurred. There were no treatment‐related effects on live litter size or sex ratio. At 50 and 100 mg/kg, nonstatistically significant increases in postimplantation loss and decreases in gravid uterine weight were observed, and at 100 mg/kg, decreases in fetal body weight were observed relative to controls. There were no treatment‐related malformations or variations in live fetuses of atorvastatin‐treated rabbits. No maternal or developmental toxicity was observed in rabbits at 10 mg/kg. Thus, these studies demonstrate developmental toxicity at maternally toxic doses of atorvastatin in rats and rabbits, but no evidence of teratogenicity. © 1994 Wiley‐Liss, Inc.
Enhancement of the teratogenicity of all‐trans‐retinoic acid by maternal restraint stress in mice as a function of treatment timing
Authors: Rasco Jane F. , Hood Ronald D. 
Published: June 2005

AbstractIn CD‐1 mice, maternal restraint stress was combined with all‐trans‐retinoic acid (†RA) given during the restraint period (9:00 a.m. to 9:00 p.m.) to determine in what manner and to what degree teratogenesis might be affected by treatment timing within the stress period and to determine the optimum timing for stress‐enhanced production of fetal defects. Eleven groups were treated on gestation day 9 (copulation plug = day 1): group 1, vehicle (corn oil) control (C); group 2, food/water deprived (FWD); group 3, restraint only (R); group 4, †RA plus food/water deprivation (†RA+FWD); groups 5 and 6, †RA at 0 or 4 hr after 9:00 a.m., i.e., †RA(0) and †RA(4), respectively; and groups 7‐11, restraint plus †RA at 0, 2, 4, 8, or 12 hr after 9:00 a.m., (i.e., R+†RA(0), R+†RA(2), R+†RA(4), R+†RA(8), and R+†RA(12), respectively). The †RA dose was 20 mg/kg, PO; mice were restrained in the supine position. FWD mice were deprived for the same 12 hr as the restrained mice. All stated differences were significant (p⩽0.05), based on litter incidences. The incidences of short tails (65%), fused ribs (62%), and fused vertebrae (37%) were elevated in the R+†RA(4) group in comparison with all others, and there appeared to be more exencephalies in R+†RA(2) litters than in any others. The incidence of supernumerary ribs was elevated in the R group in comparison with C and FWD; it was further elevated by †RA at all treatment times. Fetuses from the R+†RA(4) group weighed less than those from all other †RA‐exposed groups; the differences were nonsignificant except for the comparison with †RA+FWD. These results show that timing of teratogen exposure relative to maternal stress can significantly influence the magnitude of effects on the offspring and that this influence is not merely due to the changing developmental susceptibility of the conceptus. © 1995 Wiley‐Liss, Inc.
Heritable oligodactyly occurring only in male rats
Authors: Kaneda Masahiro , Aoyama Hiroaki , Teramoto Shoji 
Published: June 2005

AbstractHeritable oligodactylism in male rats was discovered in Wistar‐derived rats. In this study, external and skeletal features of the limb anomalies were examined to clarify the type of oligodactyly. External observation revealed absence and hypoplasia (with respective percentage incidence) in digits II (100,0), III (87,13), and IV (23,1) of the forefeet and in digits II (26,34), III (34,11), and V (0,3) of the hindfeet. Fusion was also observed in digits IV and V in the forefeet (4%) and in digits I and II in the hindfeet (15%). Skeletal examination disclosed absence of all three (proximal, middle, and distal ) phalanges in digits II (97%), III (93%), and IV (67%) and of the middle phalanx in digit V (12%) of the forefeet. In the hindfeet, the missing pattern of phalanges in digits II and III was similar to, but less severe than that in the forefeet; the incidence of absence of the three phalanges in digits II and III was 43% and 45%, respectively. Digit V was more affected than that in the forefeet; absence of the middle phalanx was found at 30% Although no absence was found in the bones proximal to the phalanges, hypoplasia and/or fusion were detected with various degree and incidences among carpi/metacarpi and tarsi/metatarsi. Based on these observations, the types of limb anomalies in this mutant rat were classified as oligodactyly of digits II–V in the forefeet and II, III and V in the hindfeet with hypoplasia and/or fusion of the carpi/metacarpi and tarsi/metatarsi. © 1995 Wiley‐Liss, Inc.