bluuebunny/crossref_metadata_2025_split huggingface dataset:
Embryotoxicity of the intercalating agents m‐AMSA and o‐AMSA and the epipodophyllotoxin VP‐16 in postimplantation rat embryos in vitro
Authors: Mirkes Philip E. , Zwelling Leonard A. 
Published: June 2005

AbstractThe intercalating agent, m‐AMSA, and the epipodophyllotoxin, VP‐16, both topoisomerase II—reactive anticancer agents, are also embryotoxic agents in rat embryos cultured in vitro. Quantifying the embryotoxic effects of these drugs revealed that the no observed adverse effect level (NOAEL) for m‐AMSA is 10 nM, the embryotoxic concentration range is 50–500 nM, and complete lethality is observed at 1 μM. In contrast, the NOAEL for o‐AMSA, an inactive isomer of m‐AMSA, is 1.0 μM, the embryotoxic concentration range is 10–100 μM, and complete lethality occurs at 200 μM. Based upon the concentrations of drugs required to produce 50% embryotoxicity or 50% malformed embryos, m‐AMSA exhibits a 200–500‐fold‐higher embryotoxicity compared to o‐AMSA. VP‐16 exhibits a NOAEL of 1.0 μM, an embryotoxic concentration range of 2–5 μM, and complete lethality at 10 μM. Compared to m‐AMSA, VP‐16 is approximately 10‐fold less embryotoxic. At appropriate concentrations, all three drugs were dysmorphogenic resulting in embryos that were characterized by hypoplasia of the prosencephalon with associated microopthalmia and dilation of the rhombencephalon.As a prelude to future studies focusing on the mechanism of drug‐induced embryotoxicity, we have used established biochemical and immunologic methods to identify and quantify topoisomerase II in rat embryos. In addition, we have demonstrated that the embryo topoisomerase II can be inhibited by both m‐AMSA and VP‐16. Finally, we have used a human cDNA probe to detect topoisomerase II mRNA in the rat embryo. Thus, the combination of the in vitro whole embryo culture and these biochemical/molecular assays should allow us to explore the role of a specific nuclear target, i.e., topoisomerase II, in the teratogenic effects of some commonly employed chemotherapeutic agents.
Marked accumulation of valproic acid in embryonic neuroepithelium of the mouse during early organogenesis
Authors: Dencker Lennart , Nau Heinz , D'argy Roland 
Published: June 2005

AbstractValproic acid, an antiepileptic drug, causes neural tube defects in mice and man. 14C‐labeled valproic acid (sodium‐salt) was administered to pregnant mice on days 8 and 9 of gestation (period of high sensitivity in regard to formation of neural tube defects in this species). Two dose levels of valproic acid (1 and 400 mg/kg) were used; in each case the total radioactivity administered was the same: 400 μCi/kg or 14.7 MBq/kg. Autoradiography combined with computerized densitometry revealed that in low‐dose animals most of the radioactivity was confined to maternal liver and kidney, while at high doses more activity was observed in soft tissues and fluids, including amniotic fluid. In the embryo, the neuroepithelium showed the highest concentration, irrespective of dose and survival interval (30 min, 3 h, and 6 h). Upon administration of the high dose, up to five times more radioactivity (approximately 2,000 times more valproic acid) was recovered in embryonic tissues than after the low dose. It is concluded that high doses of VPA saturate the capacities of metabolism, excretion, and protein binding in the maternal organism, resulting in a higher proportion of the dose reaching the embryo, allowing more of the drug to be accumulated by the target organ, the neuroepithelium.
Effects of thyroid antagonists on rat embryos cultured in vitro
Authors: Stanisstreet M. , Herbert L. C. , Pharoah P. O. D. 
Published: June 2005

AbstractA literature review of individual pregnancies and recent surveys involving large cohorts reveal an association between congenital malformation and maternal hyperthyroidism, suggesting that some aspect of hyperthyroidism or its treatment might compromise the development of the fetus. Experiments have shown that the thyroid antagonist, ethylenethiourea (ETU), causes fetal malformations when administered to pregnant rats, but it is not known whether it is ETU or the imbalance in maternal thyroid hormone which it causes which is the teratogenic agent. Here we employ in vitro culture to determine the possible direct effects on rat embryos of two thyroid antagonists, ETU and methimazole (MMI), the latter being one which is used for treatment of thyrotoxicosis in humans. It was found that ETU can compromise the development of rat embryos in vitro, confirming that ETU has a direct effect on the rat embryo. It was also found that MMI can cause abnormal development of rat embryos in vitro, although the concentration at which MMI disturbs rat embryogenesis is higher than that which is reached in hyperthyroid patients treated with clinical doses of MMI or carbimazole.
Direct embryotoxicity of cocaine in rats: Effects on mitochondrial activity, cardiac function, and growth and development in vitro
Authors: Fantel A. G. , Person R. E. , Burroughs‐Gleim C. J. , Mackler B. 
Published: June 2005

AbstractDay 10 rat embryos were exposed to cocaine HCl (10–100 μM) in vitro in 20% (designated normoxic) and 10–12% (designated moderately hypoxic) oxygen and examined the following day. In normoxia, it caused prompt and significant decreases in heart rates and significant reductions in measures of growth and development and diameters of the vitelline arteries. In moderate hypoxia, cocaine exposure resulted in axially asymmetric defects reported previously only in embryos exposed to extreme hypoxia or to hypoxia generated by redox cyclers.Day 10 or 11 embryos or isolated hearts from the latter stage were incubated with cocaine under normoxic conditions. Acute and significant concentration‐dependent decreases in heart rates occurred on day 10. The rates in day 11 embryos and in isolated hearts from day 11 embryos were less sensitive than those on day 10. Cocaine also significantly inhibited the activity of the terminal electron transport system of the mitochondria of embryos.Maternal cocaine exposure has been associated with uterine vasoconstriction and decreases in fetal oxygenation. The latter has been shown to stimulate glucose uptake. We hypothesize that placental vasoconstriction limits the ability of embryos to meet the increased glucose demands induced by hypoxia. The developmental toxicity of nutrient and oxygen deprivation is further enhanced by significant decreases of mitochondrial activity. We propose therefore that compromised energy supplies form the basis of the developmental toxicity of cocaine.
Developmental effects and mineral interactions in rats fed textured vegetable protein
Authors: Welsh John J. , Rader Jeanne I. , Collins Thomas F. X. , Black Thomas N. , Rorie James I. , Kopral Christine A. 
Published: June 2005

AbstractThe teratogenic effects of feeding a diet based on textured vegetable protein to Long‐Evans rats were studied along with maternal and fetal mineral interactions and their relationship to diet composition. Pregnant rats were fed purified diets containing 18% protein as casein (CAS), textured vegetable protein (TVP, from defatted soy flour) with 18 mg Zn/kg, or TVP diet with 100 mg Zn/kg. A fourth group was fed diet NIH‐31. The animals received their diets throughout pregnancy and were sacrificed on day 20 of gestation. Fetuses were examined for developmental effects, and mineral levels were determined in maternal and fetal tissues by inductively coupled argon plasma–atomic emission spectrometry. Females fed the casein diet or diet NIH‐31 had normal weight gains throughout pregnancy and their progeny exhibited normal development. The animals on the TVP‐containing diet with 18 mg Zn/kg had decreased food consumption and body weights, and their fetuses exhibited developmental anomalies as well as reductions in size and weight. These developmental alterations may be the result of decreased zinc levels in the fetal tissues, caused by reduced bioavailability of the trace element in the maternal diet. Significant increases in tissue iron accompanied the low zinc levels. No developmental effects were found in animals receiving the high Zn‐TVP diet, and mineral data from these animals were not significantly different from the casein group.
Developmental toxicity of orally administered 2′,3′‐dideoxycytidine in mice
Authors: Lindström Pia , Harris Martha , Hoberman Alan M. , Dunnick June K. , Morrissey Richard E. 
Published: June 2005

Abstract2′,3′‐Dideoxycytidine (DDC), a potent inhibitor of human immunodeficiency virus (HIV), is presently undergoing clinical trials as a promising anti‐AIDS drug. Since there are very limited published animal toxicity data available, and nucleoside analogues are being considered for treatment of HIV‐infected pregnant women, a study was conducted in mice to investigate the potential adverse developmental effects of this drug. DDC, suspended in 0.5% methyl cellulose, was administered via gavage twice per day during gestation days (gd) 6 through 15 to C57Bl/6N mice in a total dose of 0, 200, 400, 1,000, or 2,000 mg/kg/day. Maternal weight gain during the gestation and treatment period, as well as gravid uterine weight, decreased significantly in the 2,000 mg group, but weight gain, corrected for gravid uterine weight, was not affected by DDC. The percent resorptions per litter increased significantly in the highest dose group, and there were fewer live litters because of complete litter resorption in six dams. Among litters with live fetuses, the mean litter size was significantly reduced in the 2,000 mg group. Average fetal body weight per litter decreased significantly in the 1,000 and 2,000 mg groups. The number of fetuses with any malformation, the number of litters with one or more malformed fetuses and the percent of malformed fetuses per litter increased significantly in the 1,000 and 2,000 mg groups. There was an increase in malformations at 400 mg/kg/day; however, it was not statistically significant. In conclusion, DDC produced developmental toxicity (malformations, reduced fetal body weight, and resorptions) in the absence of overt maternal toxicity except for body weight changes due to resorptions and reduced fetal weights.
Delayed neural crest cell emigration from Sp and Spd mouse neural tube explants
Authors: Moase Connie E. , Trasler Daphne G. 
Published: June 2005

AbstractSplotch (Sp) and splotch‐delayed (Spd) are allelic mutations on chromosome 1 of the mouse. Embryos homozygous for either allele have neural tube defects (NTDs) and deficiencies in neural crest cell (NCC) derived structures. The fact that Spd mouse mutants sometimes have deficiencies in NCC derivatives in the absence of an NTD led to the hypothesis that neurulation and the release of NCCs may depend on a regulatory event that is common to both processes. Therefore, it may be possible to understand the cause of NTDs in these mutants by examining the basis of aberrant NCC derivatives. Caudal neural tubes were excised from day 9 Sp and Spd embryos and placed into gelatin‐coated tissue culture dishes, or 3‐dimensional basement membrane matrigel, and cultured for 72 hours. A cytogenetic marker was used to genotype the embryos. In planar cultures, no morphological differences were observed between NCCs from neural tube explants of Spd mutants compared to those from heterozygous or wild‐type embryos. However, there appeared to be a delay in the release of NCCs from the neural tube in both Sp and Spd mutants, which was particularly evident in Sp. After 24 hours in culture, the extent of NCC outgrowth, as well as the number of NCCs emigrating from explanted neural tubes, was significantly lower in Sp and Spd mutant cultures than in controls. No differences were observed in the mitotic indices among cells which had emigrated. By 72 hours, mutant cultures and their non‐mutant counterparts were similar in terms of outgrowth, cell number, and migratory capability. After 24 hours in 3‐dimensional basement membrane matrigel, cell outgrowth from Sp explants was also significantly less than controls. The pattern of NCC outgrowth in both types of culture conditions indicates a 24 hour delay in mutant cultures compared to controls. This stems from a delay in the release of NCCs from the neural tube, suggesting that the defect lies within the neuroeptihelium with respect to the release of NCCs.
Effect of sample size on reproducibility of behavioral teratological study results: A computer simulation experiment using data from the collaborative behavioral teratology study of the national center for toxicological research
Authors: Tachibana Toshiaki 
Published: June 2005

AbstractA computer simulation experiment which attempted to examine the effect of sample size on reproducibility of the effect of treatment was performed on the basis of actual data obtained from the Collaborative Behavioral Teratology Study of the National Center for Toxicological Research. The degree of the treatment effect was assessed in terms of the strength of the association (eta square). The results indicate that sample size has a large effect on the reproducibility of results which are assessed with the magnitude of SD for eta squares obtained from replication experiments. Suitable sample sizes to obtain relatively consistent results across studies were discussed, pointing out that not enough attention has been paid to the effect of sample size in the issue of reproducibility of results in some behavioral teratology studies.
Dithiocarbamates and prevention of cadmium teratogenesis in the hamster
Authors: Hatori Akiko , Willhite Calvin C. , Jones Mark M. , Sharma Raghubir P. 
Published: June 2005

AbstractCertain dithiocarbamates (DTC) have been reported to protect against cadmium (Cd)‐induced lethality and to decrease Cd body burden. The present study evaluated the influence of sodium N‐benzyl‐D‐glucamine dithiocarbamate, sodium N‐di(hydroxyethyl)amine dithiocarbamate, sodium 4‐carboxyamidopiperidine‐N‐dithiocarbamate, and sodium N‐methyl‐D‐glucamine dithiocarbamate on Cd‐induced teratogenesis in the hamster. When given as a single ip injection at 2.2 mmol/kg 15 min prior to iv CdCl2 (2 mg/kg), all of the DTC afforded significant protection against Cd‐induced developmental toxicity and reduced kidney [Cd] in the dam. Maternal liver [Cd] was reduced with the glucamine and dihydroxyethyl amine analogs, but treatment with the piperidine failed to influence hepatic [Cd]. Pretreatment of the dams with DTC 24 hr prior to Cd challenge failed to protect against Cd‐induced embryotoxicity, and provided minimal, if any, reduction in renal or hepatic [Cd]. Pretreatment with the N‐methyl‐D‐glucamine congener 24 hr prior to Cd exposure increased embryolethality. The dose‐time relationships found here suggest that pharmacologically effective levels of these DTC decline within 24 hr of treatment and that induction of metallothionein does not play a major role in DTC antagonism of Cd poisoning.
Triploidy syndrome in a liveborn female
Authors: Schwaibold H. , Dulisch I. , Wittekind Ch. , Voikulescu I. , Kiefer G. , Böhm N. 
Published: June 2005

AbstractWe present the autopsy report of a liveborn triploid female, born after 36 weeks of gestation, who died at the age of 20 hours. External features were diagnostic: fetal hypoplasia, hypertelorism, microstomia, micro and retrognathia, preauricular skin tag, low‐set ears, and 3–4 syndactylia. All internal organs were hypoplastic. There were atrial and ventricular septal defects. Adrenals and kidneys were fused, the gallbladder was absent, and ovarian hilum cell were found to be hyperplastic. Triplolidy, 69xxx, was confirmed cytogenetically. The placenta was hypoplastic and, microscopically, revealed a peculiar type of immaturity, so‐called hydatidiform villous hypoplasia, findings which have not been previously reported. We suggest that the generalized fetal and placental hypoplasia and the severe hypoplasia of all internal organs are caused by a proliferative deficiency of the triploid cells. In addition, the nuclear DNA content was determined cytophotometrically from placental stromal cells and was found to be about 50% above the normal diploid DNA value; i.e., a triploid DNA value was confirmed.
Fallacies of international and national comparisons of disease occurrence in the epidemiology of neural tube defects
Authors: Borman Barry , Cryer Colin 
Published: June 2005

AbstractDespite extensive research, little progress has been made in elucidating the etiologies of anencephalus and spina bifida. International and national distributions of disease occurrence have often been used as a basis for generating etiological hypotheses (e.g., potato blight, tea consumption, and zinc deficiency hypotheses). However, few of the epidemiological studies of neural tube defects (NTDs) have been conducted with scientific rigor in design, and most are of dubious validity, often with low precision in the estimates. This paper shows that the accepted geographic patterns of NTDs may be attributable to variations in the validity of studies used to describe these patterns. The nonuniformity in the duration and diligence of case ascertainment, the lack of a standardized nomenclature and classification, and the definition of the denominator remain principal problems in evaluating the epidemiology of NTDs. For example, the distinction between incidence and prevalence is not always made, and there is no consistency in the placement of the gestational boundary between late fetal deaths and spontaneous abortions. Findings are compared from studies conducted at different times, without due regard to the effect of secular trends, and using studies that have varying levels of case ascertainment. In etiological research, it is important to perform studies that are accurate and precise, but the literature used to define the spatial distribution of NTDs has often been accepted without due regard to the effect of these factors.
Influence of some methodological factors on the radiosensitivity of the mouse zygote
Authors: Jacquet P. , Grinfeld S. 
Published: June 2005

AbstractThe experiments reported here were undertaken to investigate the influence of some methodological factors on the radiosensitivity of the mouse zygote. The following factors were studied: (1) the use of natural or hormone‐stimulated ovulation; (2) the procedure followed for fertilization:mating overnight, or only during a short period in the morning after all oocytes have been ovulated, in vitro fertilization; (3) the type of irradiation, i.e., in vivo or in vitro irradiation. The radiosensitivity of the zygotes was estimated under the different experimental conditions by measuring the ability of the irradiated embryos to cleave and to develop further to the blastocyst stage. Our results suggest that the protocols used for mating and fertilization probably have a greater influence on embryonic survival following irradiation than the use of gonadotropins to stimulate ovulation. The highest degree of synchrony in the development of the embryos is achieved by restricting mating to a short period or by using in vitro fertilization. The very low LD50s obtained under such synchronous conditions confirm the high radiosensitivity of the mouse zygote at the early pronuclear stage. Comparison between the effects of in vivo and in vitro irradiation does not indicate a greater radiosensitivity of the embryo irradiated in vitro in comparison to the embryo irradiated in vivo.
Critical review of articles regarding pregnancy exposures in popular magazines
Authors: Gunderson‐Warner Sandi , Martinez Lynn P. , Martinez Israel P. , Carey John C. , Kochenour Neil K. , Emery Maury G. 
Published: June 2005

AbstractTo determine the scope of teratogen information available to the public through the media, a survey of 15 popular magazines was conducted. All 1985 issues of the selected magazines were reviewed for articles addressing pregnancy exposure concerns, yielding 56 articles from 10 magazines. The remaining 5 publications provided no pertinent articles. Two health professionals, both experienced teratology counselors, independently rated each article for accuracy of content and quality of presentation based on standardized evaluation criteria. The findings were compared and agreement for all criteria in each article was reached by the 2 reviewers. Regarding the quality of the information in the 56 articles, 31 (55.4%) were scored as misleading or inaccurate. On examination of overall presentation, 26 (46.4%) were rated as alarming and 8 (14.3%) presented a false sense of security; 22 (39.3%) provided a balanced presentation. A review of the types of articles rated revealed 19 (33.9%) general overviews of pregnancy issues, 18 (32.1%) news stories, 17 (30.4%) question‐and‐answer columns, and 2 (3.6%) feature stories. Of the reviewed papers, 7 (12.5%) included a citation from which the primary data could be obtained and only 14 of the articles (25%) suggested that the reader contact her/his healthcare provider regarding the issues. We conclude that the information available in popular magazines regarding exposures in pregnancy is frequently misleading, alarming, and unsupported by the scientific literature.
Interlitter variability and developmental stage of day 11 rat embryos produced by overnight and morning short‐period breeding regimens
Authors: Fujinaga Masahiko , Jackson Ethan C. , Baden Jeffrey M. 
Published: June 2005

AbstractDay 11 rat embryos produced by overnight and morning short‐period breeding regimens were compared for differences in interlitter variability and stage of development. Female Sprague‐Dawley rats were mated either overnight (5 PM‐9 AM, n = 22) or for 2 hr in the morning (8–10 AM, n = 20), and the presence of a vaginal plug was determined (day 0). At 11 AM on day 11 of gestation, rats were killed and embryos were examined for crown‐rump length, somite number, and general morphology; protein content was determined later. There were no differences in mean number of implantations, live embryos, and abnormalities between the two regimens. There were significant differences in mean crown‐rump length, somite number, and protein content but not in the magnitude of their variances. The difference in mean somite number was 1.2 (23.7 vs. 24.9), which corresponds to a time difference in development of approximately 2 hr. The range of mean somite number in morning short‐period breeding group was 3.2 (22.2–25.4), corresponding to approximately 5.3 hr. These results are inconsistent with the popularly held hypothesis that the timing of fertilization is the major cause of interlitter variability.
Effects of sustained dietary ethanol on the ultrastructure of the visceral yolk‐sac placenta of the rat
Authors: Jollie William P. 
Published: June 2005

AbstractThe present investigation reports ultrastructural alterations in endodermal epithelial cells of the rat visceral yolk‐sac placenta that accompany alcohol‐induced changes in intracellular trafficking of endocytosed maternal serum proteins. Fine structural changes include restructuring of mitochondrial cristae (foliate to vesicular and tubular forms), beading of cisterns of granular endoplasmic reticulum, hypertrophy and hyperplasia of Golgi elements, differentiation of the Golgi membranes to a GERL configuration, and a notable increase in numbers of primary lysosomes. Such changes in ultrastructure suggest that exposure of this developing maternofetal exchange system to high levels of ethanol in maternal blood increases the production of primary lysosomes near term for proteolysis of maternal serum proteins within the visceral yolk‐sac epithelium. Near term, targeting of endocytosed protein to secondary lysosomes for proteolysis appears to be augmented; transcellular routing of maternal protein (e.g., IgG) for placental transport may be impeded. Thus significance of the observed changes in the fine structure of this placenta may relate to the mechanism(s) of action of maternal alcohol consumption on the acquisition of neonatal immunity, intrauterine growth retardation, and the production of congenital malformations.