bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pregnancy outcomes after weekly oral administration of ethanol during gestation in the pig‐tailed Macaque: Comparing early gestational exposure to full gestational exposure
Authors: Clarren Sterling K. , Astley Susan J. 
Published: June 2005

AbstractAn oral dose of 1.8 g/kg ethanol given once per week throughout gestation to gravid pig‐tailed macaques (Macaca nemestrina) has been established previously as teratogenic. This study was designed to use this nonhuman primate model to mimic a common problematic human circumstance in which women intermittently abuse alcohol into early pregnancy, realize that they are in fact pregnant, and then want to know the chance that the conceptus is harmed. In order to evaluate this situation, gravid macaques were assigned to one of four dosing cohorts. Animals were given the 1.8 gm/kg dose of ethanol once per week for the first 3, 6, or 24 weeks (full gestation) of pregnancy. Control animals received an isocaloric, isovolemic sucrose solution once per week for 24 weeks. The pregnancies were carefully monitored and the infants were comprehensively evaluated for the first 24 months of life. This paper describes the pregnancies while subsequent papers will describe the infants.Peak plasma ethanol levels ranged from 175 to 250 mg/dl. Weekly maternal exposure to this intoxicating dose of ethanol, starting early in pregnancy, did not influence risk of pregnancy failure during the first 30 days of gestation but appeared to be associated with an increased risk of abortion occurring between gestational days 30 and 160. Of the pregnancies that were successfully carried to full term, the potentially teratogenic dose of ethanol did not alter pregnancy outcome in any clinically significant way.
In vitro embryotoxicity of a series of para‐substituted phenols: Structure, activity, and correlation with in vivo data
Authors: Oglesby Linda A. , Ebron‐McCoy Marian T. , Logsdon Tina R. , Copeland Frank , Beyer Patricia E. , Kavlock Robert J. 
Published: June 2005

AbstractThe embryotoxicity of phenol and twelve para‐substituted congeners on mid‐gestation rat embryos was evaluated in vitro. Through application of correlative procedures and stepwise regression, equations describing the relationship between physical‐chemical properties and various measures of activity were developed. Embryotoxicity was quantified by the log of the reciprocal of the potency estimates for reduction in selected growth parameters and induction of four morphological defects. In general, co‐cultured hepatocytes ameliorated embryotoxicity; only phenol‐induced embryotoxicity was enhanced by the presence of hepatocytes. In the absence of hepatocytes, measures of growth retardation were positively correlated with molar refractivity of the phenols. With hepatocytes, lipophilicity became important for describing the potential to induce growth deficits. The structural defects had varying correlation patterns in both culture systems. Potencies of these congeners in vitro were also compared to maternal and developmental potencies observed in vivo (Kavlock, Teratology, 41:43–59, '90). Two of the congeners were very toxic in both systems. For the remaining congeners, one maternal toxicity measure was found to be positively correlated with embryotoxicity for growth and development in vitro without hepatocytes. With hepatocytes, a broad spectrum of correlations, both positive and negative, were observed between in vivo developmental toxicity endpoints and in vitro embryotoxicity. Data from preliminary dosimetry studies suggest that phenol congeners may accumulate in embryos exposed in vitro more readily than with in vivo exposure. Potency calculations based on dosimetry information may demonstrate better correlations between data and allow additional relationships between chemical structure and activity to be developed.
A quantitative and morphological study of ectodermal microvilli in ten areas in the control and experimental prenatal rat
Authors: Tulsi Ram S. , Harding Anthony J. , Joschko Marion A. , Dreosti Ivor E. 
Published: June 2005

AbstractThis study provides a baseline of mainly quantitative morphologic information in relation to the ectodermal microvilli in ten areas in the control and experimental prenatal rat with special reference to the period of neural tube closure. Embryos from six litters were used and ten areas were examined mainly with the scanning electron microscope. Statistical analysis showed no significant difference between litters nor between the ten areas examined. In the 376 hr (day 15.6) fetus only the ectodermal cells of the nostril region demonstrated a rich population of microvilli, a fact possibly associated with late maturation of that region. Some evidence is provided to show that there is an increase in the population of microvilli in the 276 hr (day 11.5) embryo following experimentally induced zinc deficiency and introduction of nicotine in the culture medium. The possible mechanisms underlying the increase in ectodermal microvilli are i) an attempt by ectodermal cells to absorb nutrients, ii) a reflection of cells under stress, iii) failure of early embryonic ectodermal cells to shed microvilli normally associated with developmental changes, and iv) a generalized developmental delay rather than some cellular response to a trace element nutritional deficiency and a teratogen.
Effects of (R)‐deoxycoformycin (pentostatin) on intrauterine nucleoside catabolism and embryo viability in the pregnant mouse
Authors: Knudsen T. B. , Winters R. S. , Otey S. K. , Blackburn M. R. , Airhart M. J. , Church J. K. , Skalko R. G. 
Published: June 2005

AbstractThe viability of early mouse embryos is acutely sensitive to (R)‐deoxycoformycin (pentostatin), a tight‐binding inhibitor of adenosine deaminase (ADA). Previous studies have shown that a single 5‐mg/kg dose on day 7 (plug = day 0) of gestation fully inhibits uteroplacental ADA activity within 0.5 h; causes massive cell death in the neural plate and primary mesenchyme by 6 h, major craniofacial anomalies by day 10, and resorption by day 12 [Knudsen] et al., '89; Airhart et al., '91). The present study has examined further the developmental toxicity and early effects of this inhibitor on ADA metabolism. (R)‐Deoxycoformycin was administered to pregnant CD‐1 (ICR) mice as a single intraperitoneal dose of 0.5‐10 mg/kg total body weight on days 6–11 of gestation. The major adverse effect, early resorption, was dose dependent and specific to day 7–8 exposure. Treatment with 5 mg/kg on day 7 resulted in 85% resorptions, 15% malformations, and a 24% reduction in mean fetal weight, whereas the same dose of (S)‐deoxycoformycin had no effect. Levels of adenosine and 2 ′‐deoxyadenosine, which are the endogenous substrates of ADA, were monitored in the embryo/decidual unit (E/D) by reversed‐phase high‐performance liquid chromatography (RP‐HPLC). In response to the inhibitor, both nucleosides increased transiently in the antimesometrial compartment (antimesometrial decidua + embryo). Peak levels (Cmax) of adenosine and 2 ′‐deoxyadenosine were dose dependent over the range tested (0.05‐10 mg/kg). Exposure to 5 mg/kg on day 7 raised adenosine levels within 0.5 h to 42‐fold over the basal level of 0.06 nmol/mg protein. There was an even stronger effect on 2 ′‐doexyadenosine levels, which were elevated 674‐fold over the detection limit of 0.0005 nmol/mg protein. Direct exposure to the inhibitor in serum‐free E/D culture produced similar results: 50 μM (R)‐deoxycoformycin within 1 h raised adenosine levels 26‐fold and 2 ′‐deoxyadenosine levels 410‐fold. In vivo studies also showed a general correlation between embryolethality and the length of adenine nucleoside pool expansion, apparent for exposure on day 7, 8, or 9 but not on day 6, suggesting that the embryo becomes sensitive to adenosine or 2 ′‐deoxyadenosine once the neural plate has formed.
Distal phocomelia of the forearm in a thirteenth‐century skeleton from Poland
Authors: Mann Robert W. , Wiercinska Alina , Scheffrahn Wolfgang 
Published: June 2005

AbstractThe skeleton of a 35‐ to 40‐year‐old male (A.D. 1250 to 1300) with distal phocomelia (intercalary transverse) of the right forearm and severe (90‐1000) right‐sided scoliosis is examined. Congenital malformation of the right forearm resulted in absence of the radius and ulna, and attachment of the upper arm and hand to the trunk. Lesser abnormalities consist of a hypoplastic right scapula and misshapened ribs and sternum. This rare deformity reflects the variability and antiquity of congenital malformations of the upper limb.
Retinamides: Hydrolytic conversion of retinoylglycine to retinoic acid in pregnant mice contributes to teratogenicity
Authors: Kochhar D. M. , Shealy Y. F. , Penner John D. , Jiang Heng 
Published: June 2005

AbstractRetinamides are prominent among synthetic vitamin A derivatives (retinoids) which can prevent or reduce the incidence of certain carcinogen‐induced neoplasms in animals. They also possess lower toxicity toward adult and developmental systems than natural retinoids, presumably because of the presence of an amide endgroup which resists ready hydrolysis. In this investigation, we compared the developmental toxicities in mice of N‐(4‐hydroxyphenyl) retinamide(4‐HPR), N‐ethylretinamide (ER) and two retinoylamino acids, N‐(all‐trans‐retinoyl)glycine (RG) and N‐(all‐trans‐retinoyl)‐DL‐leucine (RL), which are formed from retinoic acid and the α‐amino acids; RG and RL were shown in a previous study to differ from each other and from retinoic acid in certain toxicity bioassays. We found that while 4‐HPR, ER, and RL were only minimally embryotoxic, RG was uniquely active as a teratogen with potency equivalent to that of retinol, the precursor of retinoic acid. Since binding to cytoplasmic proteins and nuclear receptors is a function of the presence of an acidic endgroup in the retinoid molecule, we investigated if RG given to pregnant mice was converted to retinoic acid (RA) and if teratologically significant amounts were detectable in the embryo. A single 100 mg/kg dose of RG in oil vehicle was given orally to ICR mice on day 11 of gestation (plug day = day 0). Extraction and quantification by HPLC of the retinoids in the maternal plasma and in whole embryos were performed at hourly intervals for the first 10 h after dosing and at 26 h. RG was absorbed rapidly reaching peak levels in the maternal plasma at 1 h after the dose and maintained a level of 15 μg/mL for up to 4 h, before starting a decline. RG also transferred to the embryo reaching peak levels greater than 0.75 μg/g wet weight between 2 and 4 h after the dose. All‐trans RA was detected in the maternal plasma and the embryo at 1 h after the dose, reaching peak levels at 2 h in both compartments (0.43 μg/mL or g), before starting a decline. Small quantities of 13‐cis RG (a contaminant in the original solution comprising 2‐3% by weight) and 13‐cis RA were also detected in both compartments, but their amounts in the embryo were considered insufficient to contribute to teratogenicity. Based on previous experience with single dose pharmacodynamics in mice on day 11 of gestation, we conclude that quantitatively significant levels of RA were generated through hydrolysis of RG in pregnant mice which alone would be sufficient to induce teratogenesis.
Correlations of developmental end points observed after 2,4,5‐trichlorophenoxyacetic acid exposure in mice
Authors: Chen James J. , Gaylor David W. 
Published: June 2005

AbstractA large‐scale developmental toxicology study of 2,4,5‐trichlorophenoxyacetic acid was conducted in four inbred strains and one outbred strain of mice. The most significant developmental effects observed were reduced fetal weight and increased incidences of cleft palate (malformation) and prenatal death (deaths/resorptions). The correlation coefficients among the proportion of deaths/resorptions, proportion of malformations, average fetal weights, and number of viable fetuses were investigated, with each variable measured on a per‐litter basis. Generally, the correlation coefficients between average fetal weight and number of viable fetuses were negative for the control and low‐dose groups in the C57BL/6, C3H/He, and BALB/c strains. Overall, the correlation coefficients between proportion of malformations and number of viable fetuses were not significant. The correlation coefficients between proportion of malformations and average fetal weight were negative for all but one case. The correlations were weak in the control and low‐dose groups, in which the malformation rates were very low, and were strong in the high‐dose groups. The correlation coefficients between proportion of deaths/resorptions and proportion of malformations were generally positive at the high doses; some negative correlations were observed in control and low‐dose groups. The correlation coefficients between proportion of deaths/resorptions and average fetal weight were negative for the A/JAX and CD‐1 strains. In summary, the strongest relationship observed was the negative correlation between fetal weight and malformation.
Microinjections of cultured rat conceptuses: Studies with 4‐oxo‐all‐trans‐retinoic acid, 4‐oxo‐13‐cis‐retinoic acid and all‐trans‐retinoyl‐β‐glucuronide
Authors: Kraft Joan Creech , Bechter Rudolf , Lee Qwihee P. , Juchau Mont R. 
Published: June 2005

Abstract4‐Oxo‐all‐trans‐retinoic acid, 4‐oxo‐13‐cis‐retinoic acid and all‐trans‐retinoyl‐β‐glucuronide were intraamniotically microinjected in rat embryos on day 10 of gestation and cultured until day 11.5. A comparison of the concentration‐effect relationships showed that the dysmorphogenic effects produced by these metabolites were qualitatively similar to those of parent all‐trans‐retinoic acid. Compared with all‐trans‐retinoic acid (300 ng/ml), the dysmorphogenic effects were elicited by a 2‐fold higher concentration of 4‐oxo‐all‐trans‐retinoic acid, an approximately 10‐fold higher concentration of 4‐oxo‐13‐cis‐retinoic acid and a 16‐fold higher concentration of all‐trans‐retinoyl‐β‐glucuronide. A surplus of uridine 5 ′‐diphospho‐glucuronic acid, microinjected together with 300 ng/ml all‐trans‐retinoic acid, decreased the observed embryotoxicity of all‐trans‐retinoic acid, suggesting the possibility of glucuronidation in tissues of the conceptus per se. The results of the study provide further support for the hypothesis that 4‐oxo‐all‐trans‐retinoic acid and all‐trans‐retinoic acid are, in contrast to the corresponding cis‐isomers and glucuronides, ultimate dysmorphogenic retinoids.
Methotrexate‐induced developmental toxicity in rabbits is ameliorated by 1‐(p‐tosyl)‐3,4,4‐trimethylimidazolidine, a functional analog for tetrahydrofolate‐mediated one‐carbon transfer
Authors: DeSesso John M. , Goeringer Gerald C. 
Published: June 2005

AbstractDihydrofolate reductase reduces folic acid to tetrahydrofolate as a prerequisite to one‐carbon metabolism, which is required for normal embryonic de novo DNA synthesis. The developmental toxicity of methotrexate (MTX) has been attributed to MTX's ability to inhibit the activity of dihydrofolate reductase and thereby indirectly suppress one‐carbon metabolism. The compound 1‐(p‐tosyl)‐3,4,4‐trimethylimidazolidine (TTI), which is structurally unrelated to folate, reestablishes one‐carbon metabolism by the biomimetic transfer of single carbon units. Whether the developmental toxicity of MTX is indeed caused via suppressed one‐carbon metabolism was tested in New Zealand white rabbits following concurrent maternal treatment with MTX and TTI. TTI reduced MTX developmental toxicity judged by increased mean fetal body weights, decreased percentage of malformed fetuses, and reduced incidences of major malformations. Two doses of TTI (90 mg/kg, each) at 1 hr prior to and 1 hr after MTX also reduced the developmental toxicity, but was no more effective than the single‐injection regimen. Treatment with TTI alone caused no developmental toxicity. Histologically, MTX caused enlarged intercellular spaces in limb bud mesenchyme that began at 6‐8 hr and increased in size until 16 hr. Mesenchymal nuclei appeared basophilic, with angular contours. Pretreatment with TTI delayed MTX‐induced histological changes until 20‐24 hr after MTX in 36‐50% of embryos and completely protected the remainder. The sequence of MTX‐induced changes was not altered among affected embryos, although the severity of the lesions did not appear as great. Saline‐only or TTI‐only treatments caused no alterations in limb buds. These data are consistent with the concept that impaired one‐carbon metabolism is indeed the fundamental process underlying MTX developmental toxicity.
Conjoined twins: Theoretical embryologic basis
Authors: Spencer Rowena 
Published: June 2005

AbstractA theoretical basis for the embyology of conjoined twins was formulated from clinical experience with ten cases and extensive review of pertinent embryologic and clinical literature, including over 500 cases. Regarding the age old question of fusion or fission, it is concluded that there is no known embryologic process by which conjoined twins can be formed by fission but firm evidence to support fusion in all cases. Whether the fusion occurs between embryos on one embryonic disc or on two is of no consequence since they are all monovular. Intact ectoderm will not fuse to intact ectoderm, and all seven types of conjoined twins are explained by seven possible sites of union in the early embryo. One new term is proposed: parapagus, from the Greek para, meaning “side,” combined with pagus, meaning “fixed”; this is the group formerly called dicephalus or diprosopos. These anterolaterally united parapagus twins must result from two nearly parallel notochords in close proximity; craniopagi and pygopagi from fusion at the cranial and caudal neuropores, respectively; cephalopagi and ischiopagi from union at the pharyngeal and cloacal membranes, respectively; thoracopagi from merging of the cardiac anlage; and omphalopagi from fusion of the umbilicus or of the edges of two embryonic discs in any area not including the above sites. Parasitic twins result from embryonic death of one twin, leaving various portions of the body vascularized by the surviving autosite.The rarity of cases (2) not easily explained by the above theories, and the nearly 6% of twins with two umbilical cords arising from the placenta would seem to support these conclusions.Should one wish to learn the methods of a conjurer, he might vainly watch the latter's customary repertoire, and, so long as everything went smoothly, might never obtain a clue to the mysterious performance, baffled by the precision of the manipulations and the complexity of the apparatus; if, however, a single error were made in any part or if a single deviation from the customary method should force the manipulator along an unaccustomed path, it would give the investigator an opportunity to obtain a part or the whole of the secret. Thus … it seems likely that through the study of the abnormal or unusual some insight may be obtained into that mystery of mysteries, the development of an organism … especially … where the abnormalities … are due to some modification in the germ itself, leading the organism to develop in accordance with laws as definite and natural, though not as usual, as those governing normal development (Wilder, '08). © 1992 Wiley ‐Liss, Inc.
Valproic acid‐induced placental and teratogenic effects in rats
Authors: Khera K. S. 
Published: June 2005

AbstractStudies on teratogenicity and pathology of the cenceptus were conducted in Sprague‐Dawley rats treated with 600, 800, and 1,000 mg/kg valproic acid po on day 13 of pregnancy. Each of the three doses was maternotoxic and caused (1) resorptions and/or abortions, reduction in the number of live fetuses per litter and mean fetal weight, and defects of the tail, rib and phalanx; and (2) degenerative changes in the labyrinth (thrombosis, angiectasis in the maternal lacunar network, necrosis of cytotrophoblasts and suppressed proliferation of fetal capillaries), reduced diameter nearing obliteration of umbilical vessels, with or without karyorrhexis of embryonic tissues. The lesions in the placental labyrinth were specific but, in the embryonic tissues, they were generalized. It was postulated that the vascular lesions in the labyrinth and umbilicus may have influenced embryonic development by reducing maternoembryonic gaseous and nutritional exchange. © 1992 Wiley‐Liss, Inc.
In vitro approaches to the elucidation of mechanisms of chemical teratogenesis
Authors: Welsch Frank 
Published: June 2005

AbstractThis article describes some of the contributions that in vitro methods have made to our progress, albeit slow, toward understanding mechanisms of chemical teratogenesis. Emphasis is given to the painstaking and time consuming nature of approaches required to elucidate mechanisms. The examples considered are cyclophosphamide, 2‐methoxyethanol, and retinoids. Some of the newer methods that take advantage of the recent advances in molecular biology and analytical chemistry have already been applied to studies on teratogenic mechanisms. Prospects for the 1990s are excellent and promise more rapid progress than during the past decade toward unraveling the mysteries of normal developmental biology. That knowledge in turn should be immediately applicable for investigations on developmental toxicant‐induced abnormal development. © 1992 Wiley‐Liss, Inc.
Maternal factors affecting teratogenic response: A need for assessment
Authors: Keen Carl L. 
Published: June 2005

AbstractA review of current literature suggests that maternal nutritional status can be an important modulator of the developmental toxicity of a number of agents in the environment. While the provision of multivitamin/multimineral supplements during the periconceptional period is often associated with improved pregnancy outcome, it has been difficult to identify specific nutrient deficiencies as causative factors of abnormal development in humans. One explanation for this is that nutrient deficiencies can arise through a number of means in addition to a simple dietary deficit of the nutrient. The hypothesis is proposed that one mechanism contributing to the embryotoxicity of a diverse group of insults is an alteration in the metabolism of select nutrients. Evidence is presented that zinc is one nutrient whose metabolism can be markedly influenced by a variety of insults. One consequence of this alteration can be a reduction in embryonic zinc uptake, the development of embryonic zinc deficiency and abnormal development. © 1992 Wiley‐Liss, Inc.
Teratogenic Agent Information Centre: Fifteen years of counseling and pregnancy follow‐up
Authors: Eléfant E. , Boyer M. , Boyer P. , Galliot B. , Roux C. 
Published: June 2005

AbstractThe Teratogenic Agent Information Centre was set up 15 years ago in response to a growing demand from a medical profession struggling to cope with the problem of teratogenic risk. Our goal was to provide information on the real nature of the risk and to monitor all at‐risk pregnancies so as to obtain data in a field where there are still, unfortunately, many gaps in our knowledge. The results of these 15 years have been most encouraging, in that physicians have been provided with specialized information and the follow‐up of gestations had provided considerable clinical data, which has contributed to advancing our understanding in this domain. © 1992 Wiley‐Liss, Inc.