bluuebunny/crossref_metadata_2025_split huggingface dataset:
Changes in the reproductive system following acute prenatal exposure to ethanol or methylazoxymethanol in the rat: I. Effects on immunoreactive LHRH cell number
Authors: Gavin Claire E. , Kates Barbara , Hoffman Gloria E. , Rodier Patricia M. 
Published: June 2005

AbstractIt has long been recognized that ethanol (EtOH) interferes with the hypo‐thalamo‐pituitary‐gonad axis in adults of many species, and recent studies have provided evidence for similar effects after prenatal EtOH exposure. Since EtOH is capable of injuring dividing cells, we investigated the possibility that a single acute in utero EtOH exposure during the period of LHRH neuron formation might change the number of immunoreactive LHRH cells in the hypothalamus. Final LHRH cell division in Long‐Evans rats was determined by [3H]thymidine autoradiography to take place over a short period between gestation days 12 and 13. Subsequently, pregnant rats were treated acutely with either EtOH or methyla‐zoxymethanol (MAM), a known neuroteratogen, and the numbers of immunoreactive LHRH cells were counted. On gestation day 22, LHRH‐positive cell numbers were significantly fewer than control numbers in both EtOH‐ and MAM‐exposed offspring. On postnatal day 60, cell numbers in EtOH‐exposed offspring did not differ from control numbers, whereas cells in MAM‐exposed offspring remained significantly reduced. In controls, there were 40% fewer LHRH‐positive cells on postnatal day 4 than in late gestation or at maturity. We conclude that 1) acute exposure to a high dose of EtOH at a critical time in early gestation can alter the expression of LHRH in late gestation; 2) exposure to MAM in the same period alters LHRH expression before birth and in the adult; and 3) in the early postnatal period, LHRH expression decreases profoundly. © 1994 Wiley‐Liss, Inc.
Interactions in developmental toxicology: A literature review and terminology proposal
Authors: Nelson B. K. 
Published: June 2005

AbstractDevelopmental toxicologists have investigated the interactive effects from concurrent exposures to a variety of chemical and physical agents, including therapeutic drugs, industrial agents, and some biological organisms or their toxins. Of approximately 160 reports of concurrent exposures reviewed in this paper, about one third report no interactive effects (including additive effects‐‐usually referring to response‐‐as opposed to dose‐additivity); another one third report antagonistic effects, and the final third report potentiative or synergistic effects. The quality of the studies is highly variable. Frequently, only small numbers of animals were included, and very few dose levels were evaluated. Maternal toxicity was rarely discussed. Time‐effect relationships were examined infrequently. In addition, these studies are also inconsistent in the use of terms to describe interactive effects, and more than 90% of the terms were not in harmony with currently accepted definitions in toxicology. Because interaction studies will continue to be important in the future, this paper proposes uniform usage of terms for additivity and interactions in developmental toxicology: additivity (the combined effect of two or more developmental toxicants approximates the sum of the effects of the agents administered separately); antagonism (the combined effect of two or more agents, one or more of which are present at doses that would be developmentally toxic if given individually, is significantly less than the sum of the effects of the agents administered separately); potentiation (the increased effect of a developmental toxicant by concurrent action of another agent at a dose that is not developmentally toxic); synergism (the combined effect of two or more developmental toxicants is significantly greater than the sum of the effects of each agent administered alone); and, interaction if more precise terminology does not apply. © 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.
A physiologically based pharmacokinetic computer model for human pregnancy
Authors: Luecke Richard H. , Wosilait Walter D. , Pearce Bruce A. , Young John F. 
Published: June 2005

AbstractA physiologically based pharmacokinetic (PBPK) model for human pregnancy must incorporate many factors that are not usually encountered in PBPK models of mature animals. Models for pregnancy must include the large changes that take place in the mother, the placenta and the embryo/fetus over the period of pregnancy. The embryo/fetal weight change was modeled using the Gompertz equation for growth which gave a good fit to extensive pooled weight data of the human embryo/fetus from 25 to 300 days of gestation. This equation is based on a growth rate that is proportional to the total weight of the organism with the proportionality factor decreasing exponentially with time. Allometric equations, which are widely used to relate organ weights, blood flow rates and other attributes of mature animals to total weight, were adapted to correlate fetal organ weights with total fetal weight. Allometric relationships were also developed for plasma flow rates and other organ‐related parameters. The computer model, written in FORTRAN 77, included 27 compartments for the mother and 16 for the fetus; it also accommodates two substances allowing representation of a parent compound and a metabolite (or a second drug or environmental substance). Although this model is large, the inherent sparsity in the equations allow it to be solved numerically in a reasonable time on currently available, reasonably priced desktop computers. A nonlinear regression routine is included to fit key model parameters to experimental data. Concentrations of chemicals administered and measured in the mother may be simulated in both maternal and fetal organs at any day(s) between 25 days and 300 days of gestation. Allometric relationships are also utilized to adopt this human model for use with data obtained from animal experiments. © 1994 Wiley‐Liss, Inc.This article is US Government work and, as such, is in the public domain in the United States of America.
Ethyl alcohol reduces cardiac output, stroke volume, and end diastolic volume in the embryonic chick
Authors: Bruyere Harold J. , Stith Charles E. 
Published: June 2005

AbstractIt has been established that ethanol causes both human congenital cardiac malformations and structural intracardiac abnormalities in the embryonic chick. In view of a theory that reduced embryonic tissue hemodynamics are associated with the development of malformations, we attempted to determine whether or not a) ethanol altered cardiac blood flow and b) altered hemodynamics were a function of ethanol dose in the chick embryo. Cardiac function in Hamburger‐Hamilton stage 19 chick embryos was recorded on videotape before and up to 10 hours after exposure to graded doses of ethanol. Parameters of cardiac function, including cardiac output, were determined from videotaped images by means of computer assistance. Cardiac output decreased in a linear fashion with dose for up to 3 hours after exposure to ethanol. The maximum relative percent decrease in cardiac output was directly related to the dose of ethanol administered. Furthermore, the time required after ethanol treatment for mean cardiac output to return to pretreatment and control values was also dose‐dependent‐‐lower doses of ethanol required less time for mean cardiac output to return to pretreatment and control values. Although relatively high doses of ethanol depress cardiac rate, we attribute the significant decrease in cardiac output primarily to parallel dose‐dependent decreases in both stroke volume and end diastolic volume. Our data are consistent with the hypothesis that reduced embryonic cardiac blood flow during cardiogenesis is associated with the development of ethanol‐induced intracardiac defects in chick embryos. © 1994 Wiley‐Liss, Inc.
Effects of methanol on embryonic mouse palate in serum‐free organ culture
Authors: Abbott B. D. , Logsdon T. R. , Wilke T. S. 
Published: June 2005

AbstractMethanol has widespread applications in industry and manufacturing and is under consideration as an alternative automotive fuel. Human exposure to methanol would be expected to increase if applications expand in coming years. Methanol has been shown to be a reproductive and developmental toxicant in the rodent, producing cleft palate in the CD‐1 mouse. Developmental toxicity has also been demonstrated in vitro for rat and mouse embryos in whole embryo culture. The present study examines the developmental toxicity of methanol in the palate using a serum‐free organ culture model. Gestation day 12 CD‐1 mouse embryos were dissected and mid‐craniofacial tissues were cultured in BGJ medium at 37°C for 4 days with medium changes at 24 hr intervals. Cultures were exposed to methanol from 0–20 mg/ml for 6 hr, 12 hr, 1 or 4 days. Some cultures were exposed to ethanol for 4 days at doses ranging from 0–15 mg/ml. All cultures were gassed with a 50% O2, 5% CO2, and 45% N2 upon addition of fresh medium and prior to the addition of alcohol. Following organ culture the craniofacial explants were examined for effects on morphology, fusion, proliferation, and growth. Incidence and completeness of palatal fusion decreased with increasing exposure. Depending on the concentration and duration of methanol exposure, the medial epithelium either degenerated completely or remained intact in unfused palates and either condition would interfere with fusion. Cellular proliferation appeared to be a specific and sensitive target for methanol as craniofacial tissues responded to methanol with reduction in total DNA content at an exposure that did not affect total protein. However, both DNA and protein decreased with increasing exposure to methanol. Incorporation of thymidine decreased significantly after 4 day exposure and autoradiography of 3H‐thymidine (TdR) demonstrated exposure‐dependent reduction in proliferation of palatal mesenchymal cells. Ethanol decreased fusion score, total protein, and DNA, but 3H‐TdR/DNA was not significantly changed. In general the ethanol was more potent than methanol for inhibition of protein and DNA synthesis and palatal fusion. This study demonstrated that methanol can selectively affect specific sensitive cell populations and has effects on proliferation and cell fate. © 1994 Wiley‐Liss, Inc.This article is US Government work and, as such, is in the public domain in the United States of America.
Cocaine‐induced embryonic cardiovascular disruption in mice
Authors: Fisher J. Edward , Potturi Raju B. , Collins Michael , Resnick Elisabeth , Zimmerman Ernest F. 
Published: June 2005

AbstractThe purpose of this study was to determine whether vascular disruption is a feature of cocaine‐induced teratogenicity in early murine organogenesis. The embryotoxic effects of cocaine were assessed: (1) in vivo, (2) in embryos cultured in the presence of cocaine (in vitro), and (3) after cocaine was administered in vivo and the embryos subsequently cultured in the absence of cocaine (in vivo‐in vitro). When cocaine (78 mg/kg) was administered in vivo on day 8 and embryos were assessed on day 10, significant vascular perturbations, in the form of vasodilation and hemorrhage, as well as neural defects, were observed. In the in vitro system, day 8 embryos were cultured for 48 hr in the presence of 0, 10, 20, 33, and 66 μ/ml cocaine. At 10 and 20 μ/ml, vascular perturbation was not seen, while at higher cocaine concentrations, development of the yolk sac vasculature was inhibited. Hemorrhage was not a feature of in vitro cocaine embryotoxicity. However, significantly increased incidences of neural defects were seen at concentrations of 20 μ/ml or greater. Finally, in the in vivo‐in vitro system, 78 mg/kg cocaine was administered on day 8 in vivo and embryos were dissected after 15 min and cultured for 48 hr. Marked cardiovascular perturbation, as well as neural defects, were produced using this protocol. With cocaine treatment, only 26.6% of embryos had a functioning heartbeat and yolk sac circulation, compared to 85.6% of controls. This cardiovascular disruption was associated with pooling of blood in the embryo, with 59.9% of embryos exhibiting marked vasodilation and hemorrhage compared to 12.5% in controls. Additional manifestations of cardiovascular perturbation were edema and blisters observed in cocaine‐treated embryos. Neural tube defects, including open neural tube (8.3%) and microcephaly/hypoplastic prosencephalon (30.0%), were also significantly increased in cocaine‐treated embryos. The cardiovascular and neural effects produced by cocaine were dose‐dependent (40, 20 mg/kg). Thus, administration of cocaine in the in vivo or in vivo‐in vitro systems produced marked cardiovascular effects, while in vitro treatment did not. These results suggest that cocaine may elicit cardiovascular toxicity through a maternally mediated mechanism. © 1994 Wiley‐Liss, Inc.
Developmental phase alters dosimetry‐teratogenicity relationship for 2‐methoxyethanol in CD‐1 Mice
Authors: Terry Ketti K. , Elswick Barbara A. , Stedman Donald B. , Welsch Frank 
Published: June 2005

AbstractThe industrial solvent 2‐methoxyethanol (2‐ME) elicits phase‐specific terata in mice through its primary metabolite and proximate toxicant, 2‐methoxyacetic acid (2‐MAA). Recent pharmacokinetic studies indicate that the incidence and severity of digit malformations induced in CD‐1 mice by 2‐ME exposure on gestation day (gd) 11 (copulation plug = gd 0) correlate better with the total 2‐MAA exposure over time (= area under the curve; AUC) than with its peak concentrations (Cmax) in maternal plasma, embryo and extraembryonic fluid. In this study, the phase specificity of exencephaly induction by 2‐ME was investigated to ascertain whether the 2‐ME/2‐MAA dosimetry‐teratogenicity relationship remains consistent throughout organogenesis. Following a single intravenous (iv) bolus dose of 250 mg 2‐ME/kg given to pregnant mice, exposure on gd 8 was decidedly the gestation day that best balanced low embryo lethality and high malformation incidence as recorded in near‐term fetuses. Concentrations of 2‐MAA were measured during distribution and elimination in maternal plasma and conceptuses following iv bolus doses of 175, 250, and 325 mg 2‐ME/kg, as well as during and after termination of subcutaneous (sc) constant‐rate infusions (4, 6, and 8 hr; 8 μl/hr) of 277,392, and 606 mg 2‐ME/kg total doses. For all administration regimens, exencephaly incidence rates were determined in fetuses on gd 18. Similar plasma 2‐MAA Cmax values (∼5 mmol/l) and fetal malformation frequencies (∼12%) were induced by sc infusion of 392 mg 2‐ME/kg or a bolus dose of 250 mg 2‐ME/kg. However, the AUC produced by infusion was significantly larger than that following the iv bolus dose (38 vs. 26 mmol‐hr/l, respectively). In both maternal plasma and conceptuses, the correlation coefficients between Cmax and exencephaly rates, as well as developmental toxicity, were higher than they were for AUC and those end points. This outcome suggests that dosimetry‐teratogenicity determinants may be quite specific for a distinct developmental phase during which a particular organ differentiates and a specific chemical acts upon the embryo. © 1994 Wiley‐Liss, Inc.
On the use of affected controls to address recall bias in case‐control studies of birth defects
Authors: Khoury Muin J. , James Levy M. , Erickson J. David 
Published: June 2005

AbstractInferences regarding causes of birth defects in humans are often based on results of case‐control studies conducted after birth. To address bias in these studies caused by potential differential recall of past exposures between case and control mothers, many investigators have advocated the use of affected controls (babies with birth defects other than the one of interest). To evaluate whether the use of affected controls is warranted for a wide range of scenarios, we analyzed data from a population‐based case‐control study of birth defects in Atlanta, in which there were 4,918 babies with serious defects ascertained in the first year of life and 3,029 babies without defects. We compared the magnitude of the odds ratios for 10 specific defects–risk factor associations between normal and affected controls. These associations included demographic factors (e.g., advanced maternal age and Down syndrome), chronic maternal illnesses (e.g., diabetes and cardiac defects), chronic exposures (e.g., multivitamins and neural tube defects), and acute exposures (e.g., flu and neural tube defects). In all instances, the use of affected controls did not change etiologic inferences derived from using normal controls and there were only moderate changes in odds ratios. On the basis of theoretical considerations, we show that recall bias can lead to spurious inferences only under extreme conditions. We conclude that concerns about recall bias are overrated in birth defects studies and that the use of normal controls is acceptable unless evidence of substantial recall bias exists. © 1994 Wiley‐Liss, Inc.The article is a US Government work and, as such, is in the public domain in the United States of America.
Trans‐2‐ene‐valproic acid is less behaviorally teratogenic than an equivalent dose of valproic acid in rats
Authors: Fisher J. Edward , Acuff‐Smith Karen D. , Schilling Mary A. , Nau Heinz , Vorhees Charles V. 
Published: June 2005

AbstractAlthough animal experiments have shown the trans‐2‐ene metabolite (t‐2‐ene‐VPA) of valproic acid (VPA) to be pharmacologically equivalent to the parent compound in terms of anticonvulsant activity, it is considerably less teratogenic in studies which have examined prenatally exposed fetuses for morphological defects. This has made t‐2‐ene‐VPA an attractive potential antiepileptic agent. However, while neurobehavioral alterations have also been observed in rats prenatally exposed to VPA, even at doses below those which produce malformations, the developmental neurotoxicity of t‐2‐ene‐VPA had not previously been examined. The current study evaluated the long‐term behavioral effects of prenatal exposure to t‐2‐ene‐VPA. Pregnant CD rats were treated with 300 or 400 mg/kg t‐2‐ene‐VPA by gavage on days 7–18 of gestation, doses previously shown to produce no teratogenicity. A VPA group was administered 300 mg/kg for comparison. The pharmacokinetic profiles of the two compounds were similar. Behavioral findings in offspring prenatally exposed to VPA were consistent with previous findings, i.e., VPA offspring exhibited decreased locomotor activity, increased swimming maze errors, and reduced tactile startle responding compared to controls. In the 400 mg/kg t‐2‐ene‐VPA group, Cincinnati maze errors and auditory startle reactivity were increased, while no significant behavioral effects were detected in the 300 mg/kg t‐2‐ene group. These results indicate that the developmental neurotoxicity of t‐2‐ene‐VPA is lower than that of VPA but is still significant. © 1994 Wiley‐Liss, Inc.
Bendectin and birth defects: I. A meta‐analysis of the epidemiologic studies
Authors: McKeigue Paul M. , Lamm Steven H. , Linn Shai , Kutcher Jeffrey S. 
Published: June 2005

Abstract“Bendectin”Bendectin is the US trademark for a combination of doxylamine and dicyclomine used for the treatment of nausea and vomiting of pregnancy. Prior to 1977, it also contained pyridoxine. Analogous products were distributed in the United Kingdom under the trademark “Debendox” and in Germany under the trademark “Lenotan.”
(Doxylamine/Dicyclomine/Pyridoxine) was widely used for the treatment of nausea and vomiting of pregnancy until 1983, when production was discontinued in the face of lawsuits alleging that the drug caused congenital malformations. We have conducted a meta‐analysis of the 16 cohort and 11 case‐control studies that report birth defects from Bendectin‐exposed pregnancies. This meta‐analysis provides an estimate of the relative risk of malformation at birth in association with Bendectin exposure. The pooled estimate of the relative risk of any malformation at birth in association with exposure to Bendectin in the first trimester was 0. 95 (95% Cl 0. 88 to 1. 04). Separate analyses were undertaken for cardiac defects, central nervous system defects, neural tube defects, limb reductions, oral clefts, and genital tract malformations. In these categories, the pooled estimates of relative risk ranged from 0. 81 for oral clefts to 1. 11 for limb reductions, with all 95% confidence intervals enclosing unity. With the exception of studies for oral clefts and for pyloristenosis, tests for heterogeneity of association indicated for each table that all studies were estimating the same odds ratio. These studies, as a group, showed no difference in the risk of birth defects between those infants whose mothers had taken Bendectin during the first trimester of pregnancy and those infants whose mothers had not. It is unlikely that Bendectin exposure contributed to the prevalence of congenital malformations in the population.© 1994 Wiley‐Liss, Inc.
Paternal age and the risk of congenital heart defects
Authors: Olshan Andrew F. , Schnitzer Patricia G. , Baird Patricia A. 
Published: June 2005

AbstractThe effect of paternal age on the risk of birth defects among affspring is less well studied than the effect of maternal age, with few comprehensive epidemiologic studies having been conducted. Advanced paternal age has been shown to be associated with an increase in new dominant mutations that result in particular congenital anomalies. The relationship between paternal age more common birth defects, for example, cardiac defects, has not been as extensively evaluated. Therefore, a total of 4, 110 cases of congenital heart defects was identified from the British Columbia Health Surveillance Registry. Matched controls were obtained from the birth files of British Columbia for the years 1952–1973. Prevalence odds ratios for paternal age, adjusted for maternal age and other factors, were estimated for 8 cardiac defect groups.A suggestive general pattern of increasing risk with increasing age among cases (excluding chromosomal anomalies) relative to controls was found for ventricular septal defects (VSD), atrial septal defects (ASD), and patent ductus arteriosus (PDA). In addition, an increased risk among men younger than 20 yr was found for VSD and ASD. These findings are consistent with the results of some previous epidemiologic studies. Based on the results of the study it is estimated that for cardiac defects such as VSD, approximately 5% of cases may be due to advanced paternal age (>35yr), Possibly through dominant mutations. © 1994 Wiley‐Liss, Inc.