bluuebunny/crossref_metadata_2025 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

An 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

The 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

This 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

The 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

The 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

Retinamides 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

A 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

4‐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

Dihydrofolate 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

A 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

Studies 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

This 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

A 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

The 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.
Fetal dexamethasone exposure alters macromolecular characteristics of rat brain development: A critical period for regionally selective alterations?
Authors: Carlos R. Q. , Seidler F. J. , Slotkin T. A.
Published: June 2005

Fetal glucocorticoid exposure retards postnatal growth and evokes abnormalities of nervous system structure and function. To examine the underlying mechanisms, we administered 0.2 or 0.8 mg/kg of dexamethasone to pregnant rats on gestational days 17, 18, and 19 and assessed brain region cell development with indices of DNA content (total cell numbers), DNA concentration (cell packing density), and protein/DNA ratio (relative cell size). Dexamethasone evoked deficits of pup body and brain region weights, but the brain regions displayed growth‐sparing associated initially with preservation of cell numbers (normal or elevated DNA content and concentration), at the expense of relative cell size (decreased protein/DNA). Subsequently, brain cell acquisition lagged behind that of controls, with deficits in DNA and elevations of protein/DNA. In midbrain + brainstem and in cerebellum, cell markers returned to normal by weaning. However, the forebrain showed persistent elevations of DNA and reduced protein/DNA, indicative of replacement of neurons with glia. Because the treatment period coincided with the timing of neuronal cell replication in the forebrain, but not in the other regions, these results suggest that the critical period for lasting deficits of dexamethasone coincides with the peak of neuronal mitosis. © 1992 Wiley‐Liss, Inc.
In vitro exposure of preimplantation mouse embryos to cocaine and benzoylecgonine inhibits subsequent development
Authors: Kaufmann Robert A. , Armant D. Randall
Published: June 2005

Cocaine is used by over 20% of women of reproductive age. Although there have been numerous studies focusing on its effects on reproductive processes, none has evaluated its direct effect on preimplantation development. We have investigated the effect of cocaine and its major metabolite, benzoylecgonine, on in vitro preimplantation mouse embryogenesis. One‐cell embryos were exposed at the one‐, two‐, four‐, or eight‐cell stage for 24 hr to medium containing 0–400 μg/ml cocaine or benzoylecgonine and then cultured to the blastocyst stage. Cocaine had its strongest inhibitory effect at the earliest stages of development. At the one‐ and two‐cell stages, there was a significant inhibition of blastocyst formation following exposure to cocaine concentrations of 25–400 μg/ml, and at the four‐cell stage there was an inhibitory effect at 100 and 400 μg/ml cocaine. Benzoylecgonine inhibited the development of embryos to blastocyst only at the one‐ and two‐cell stages, at concentrations of 100–400 μg/ml. These findings suggest that cocaine is capable of blocking preimplantation embryogenesis, particularly following exposure at the earliest stages, and that this toxicity may abate as cocaine is biotransformed to benzoylecgonine. © 1992 Wiley‐Liss, Inc.
Spina bifida aperta induced by valproic acid and by all‐trans‐retinoic acid in the mouse: Distinct differences in morphology and periods of sensitivity
Authors: Ehlers Katharine , Stürje Helga , Merker Hans‐Joachim , Nau Heinz
Published: June 2005

The antiepileptic drug valproic acid (VPA) has been implicated as a human teratogen causing spina bifida aperta. Recently, we developed a mouse model inducing spina bifida aperta with VPA. To elucidate the pathogenesis of VPA‐induced spina bifida aperta we now investigated the anatomy and histology of this defect in the mouse. The morphology of spina bifida aperta induced by all‐trans‐retinoic acid (RA) was used for comparison. Various doses of VPA and RA were administered at different times to determine the periods of sensitivity for inducing spina bifida aperta with these drugs. Each administration regimen consisted of three doses applied at intervals of 6 hr. RA induced spina bifida aperta during an earlier developmental period (day 8 of gestation) than VPA (day 9 of gestation). The most effective regimens for induction of spina bifida aperta in mice were injections of 3 × 500 mg VPA‐Na/kg body weight (b.w.) intraperitoneally on day 9 of gestation at 0,6, and 12 hr; RA (12.5 mg/kg b.w.) was given orally on day 8 of gestation at 12 and 18 hr, day 9 at 0 hr. VPA did not induce spina bifida aperta on day 8 of gestation and RA did not induce this effect on day 9 of gestation. Histological studies of day 18 fetuses carrying spina bifida aperta were performed. The spina bifida aperta induced by VPA shows a disorganized and necrotic spinal cord. In the vertebral canal were observed cell debris, blood cells, capillaries, macrophages, and rests of meninges. These results indicate that the spinal cord is almost destroyed at the affected section. In contrast, the spina bifida aperta induced by RA demonstrates a spinal cord organized in the gray and white matter, the dorsal and ventral horn. But the neural canal does not exist, only a layer of ependymal cells lies on the surface of the spinal cord. Our results indicate that the morphology of spina bifida aperta induced by VPA differed distinctly from that induced by RA in the mouse fetus. Moreover VPA produced a spina bifida aperta with a specific morphology. Also the period of sensitivity for induction of this lesion differed and occurred earlier for RA than for VPA. VPA and RA may possibly induce spina bifida aperta via different mechanisms in the mouse. © 1992 Wiley‐Liss, Inc.
Comparison of staging systems for the gastrulation and early neurulation period in rodents: A proposed new system
Authors: Fujinaga Masahiko , Brown Nigel A. , Baden Jeffrey M.
Published: June 2005

Because there is no standard developmental staging system for the early postimplantation period of rodent embryos, investigators must now choose between a variety of systems that differ significantly. We have reviewed many of these staging systems and have summarized the ambiguities within them and the inconsistencies among them. In order to compare systems, we first obtained a consensus of the order of developmental events from the literature, and then attempted to fit existing systems into this order taking into account inconsistencies in terminology and blurred borderlines between stages. We were able to do this for most systems but not all because some were too divergent. We found that inconsistencies in definition of some terms, such as “primitive streak stage” and those used to describe the early neurulation process (neural plate, neural groove, neural folds, and head fold) cause much confusion. In order to develop an unambiguous system which can be used by all investigators, we propose to modify Theiler's system, which is one of the most commonly used systems but is not defined precisely during the early postimplantation period. We suggest making subdivisions of the original stages as follows: 1) stage 8 into 8a and 8b, by the degree of extension of the proamniotic cavity into the extraembryonic region; 2) stage 10 into 10a and 10b, by the completion of amnion formation; 3) stage 11 into 11a, 11b, and 11c, by the appearance of neural folds and foregut pocket. After Stage 12, the number of somite paris can be used to precisely stage embryos. These modifications to Theiler's system allow much more precise staging of early postimplantation embryos, allow it to be used as a standard by all investigators. © 1992 Wiley‐Liss, Inc.
A comparison of sodium arsenite‐ and hyperthermia‐induced stress responses and abnormal development in cultured postimplantation rat embryos
Authors: Mirkes Philip E. , Cornel Leanne
Published: June 2005

Acute exposures to sodium arsenite (50 μM) were embryotoxic in day 10 rat embryos exposed in vitro. Sodium arsenite–induced embryotoxicity was characterized by decreased growth (crown‐rump length, somite number, and embryo protein content) and abnormal development (hypoplastic prosencephalon, abnormal somites, and abnormal flexion of the tail). At embryotoxic exposures, sodium arsenite also induced the synthesis of three heat shock proteins (hsps), one of which is recognized by a monoclonal antibody specific for the heat‐inducible hsp 72. In addition, sodium arsenite induced the accumulation of heat‐inducible hsp 70 mRNA. Although the abnormal morphologies induced by sodium arsenite and hyperthermia appear to be different, the stress response as measured by the synthesis of hsps, the accumulation of hsp 72 protein, and the accumulation of hsp 70 mRNA is similar in embryos exposed to these two embryotoxic agents. Thus, sodium arsenite and hyperthermia both induce a stress response; however, the relationship between the induction of a stress response and the subsequent abnormal development that ensues is unclear. © 1992 Wiley‐Liss, Inc.
Cardiovascular birth defects and prenatal exposure to female sex hormones: A reevaluation of data reanalysis from a large prospective study
Authors: Hook Ernest B.
Published: June 2005

In data of the U.S. Collaborative Preinatal Study (CPS), the Drug Epidemiology Unit (DEU) reported a relative risk of about 2.3 between maternal female sex hormone exposure during months 1 to 4 of pregnancy and cardiovascular malformation in infants (Heinonen et al., '77a N. Engl. J. Med., 296:67–70). Wiseman and Dodds‐Smith ('84) reexamined the original CPS data and found the DEU had made errors in classification of exposure and disease of some cases. Also they challenged the classification of cases as “exposed” in those born to mothers who received the compounds outside the day 19 to 50 window of cardiovascular embryogenesis. Wiseman and Dodds‐Smith stated that their reanalysis “clearly showed that there was [in the data used by the DEU] no statistically significant association between exposure in the critical organogenic period of pregnancy and cardiac malformation in offspring.” They did not undertake any statistical analysis, but their reanalysis resulted in a widespread nonacceptance of the association reported by the DEU. The study reported here reclassified the cases of the original DEU study in accord with the implications of the Wiseman and Dodds‐Smith reanalysis of exposure and disease. After this reclassification, an effect magnitude measure of association, the relative risk rose from 2.33 to 2.48 and remained nominally significant statistically at the .05 level. Thus, if anything, the quantitative consequences of the Wiseman and Dodds‐Smith review of the data, when applied in an unbiased manner, result in an increase in the measure of effect. The increase is consistent with the theoretical epidemiological expectation that correction of random errors in a database and of other non‐differential misclassification, will tend to raise the estimate of an underlying association in the population studied. While these results reestablish the reported association, they do not, of course, prove that the positive association represents causal induction of defects in conceptuses by female sex hormones. © 1992 Wiley‐Liss, Inc.
Studies of the role of ischemia/reperfusion and superoxide anion radical production in the teratogenicity of cocaine
Authors: Fantel Alan G. , Barber Charles V. , Carda Mary B. , Tumbic Ruslan W. , Mackler B.
Published: June 2005

The administration of multiple doses of cocaine on a single day during late gestation is teratogenic in rats in which hind limb ectrodactyly is a major finding (Webster and Brown‐Woodman, '90). We have previously hypothesized that these limb malformations result from the generation of reactive oxygen species during the process of ischemia/reperfusion in vivo. In order to study the direct effects of cocaine versus the aberrant oxygenation it may induce, we have developed a system for culturing rat embryos between days 14 and 15 of gestation. Growth and development of cultured embryos are comparable to that of in vivo controls. Exposure to normoxia (95% O2) with or without cocaine failed to induce limb malformations and exposure to a single long period of hypoxia (20% O2) only reduced limb growth in the anterior‐posterior axis. By contrast, embryos receiving multiple brief exposures to hypoxia developed a significant incidence of hind limb ectrodactyly that appeared indistinguishable from that induced by cocaine in vivo. By incubating day 14 embryos in a nitroblue tetrazolium derivative, 1‐[4,5‐dimethylthiazol‐2‐yl]‐2,5‐diphenyltetrazolium bromide (MTT), it was shown that superoxide anion radical appears in the digital rays following two episodes of reperfusion. Little reaction product was seen under the other conditions. Finally, mitochondrial electron transport particles prepared from teratogenically sensitive limb buds spontaneously “leak” electrons to form superoxide anion radical whereas those from insensitive heart fail to do so. We propose that cocaine and other exposures that can transiently reduce conceptal oxygenation during late gestation are teratogenic by virtue of their capacity to induce ischemia/reperfusion. This process generates toxic oxygen radicals that can overwhelm the immature antioxidant defenses. © 1992 Wiley‐Liss, Inc.
Congenital heart disease in the offspring and maternal habits and home exposures during pregnancy
Authors: Tikkanen Jorma , Heinonen Olli P.
Published: June 2005

To test the effect of maternal habits and home exposures during early pregnancy on the occurrence of congenital heart disease in the offspring, 406 cases and 756 controls were studied. The cases included all cardiovascular malformations detected in Finland during 1982–1983, while the healthy controls were randomly selected from all babies born during the same period. Case and control mothers were interviewed after delivery using a structured and pre‐tested questionnaire.

Maternal overall drug consumption during the first trimester was as prevalent among case mothers (13.3%) as controls (14.6%). Neither was the risk of congenital heart disease associated with maternal use of contraceptive pills, salicylates, diazepam, or sweetening agents separately. Maternal exposures to disinfectants, dyes, lacquers, paints, pesticides, or glues at home were equally prevalent in case and control groups.

Several earlier miscarriages was a predictor of an infant born with congenital heart disease (OR = 2.7, CI95 = 1.4–5.3). Maternal ultrasound examination was performed during the first 16 weeks of pregnancy more often among the case group (28.3%) than among the control group (22.0%). However, the association between ultrasound examination and the risk of congenital heart disease in the offspring was not statistically significant (OR = 1.2, 95% confidence interval 0.9–1.7) when adjusted for confounding factors such as the threat of miscarriage in logistic regression analysis.

It is concluded that maternal ultrasound examination, intake of some common drugs, and exposure to a number of environmental factors at home during early pregnancy are probably not harmful for the developing fetal heart. © 1992 Wiley‐Liss, Inc.
Methionine decreases the embryotoxicity of sodium valproate in the rat: In vivo and in vitro observations
Authors: Nosel Philip G. , Klein Norman W.
Published: June 2005

Methionine provided in the drinking water of pregnant rats injected with sodium valproate reduced the frequency of resorptions but did not improve embryo growth. Rats drinking methionine supplemented water had approximately twice the level of serum‐free methionine and consumed only one‐half the volume of water of controls. Using whole rat embryo cultures, the simultaneous addition of methionine and sodium valproate to the medium provided no protection from neural tube defects, nor did the addition of methionine to a medium of serum obtained from rats previously dosed with sodium valproate. However, protection from the teratogenic effects of sodium valproate was afforded by methionine when the culture medium was sera from rats consuming methionine and was particularly striking when embryos for culture were taken from pregnant rats that had been consuming methionine. These observations along with those of others indicated the importance of dietary and culture media methionine levels in evaluating experimental and regulatory teratology studies and suggested the possibility that methionine may play an important role in human teratology where multifactorial causes have been implicated in problems such as neural tube closure defects. © 1992 Wiley‐Liss, Inc.
Abnormalities in ureter and kidney development in mice given acetazolamide‐amiloride or dimethadione (DMO) during embryogenesis
Authors: Miller Thomas A. , Scott William J.
Published: June 2005

These experiments more accurately define the effects of the combination acetazolamide‐amiloride or a single dose of dimethadione (DMO), the active metabolite of trimethadione, on the development of the ureter. When acetazolamide‐amiloride was administered in C57BL/6NCrlBR mice on day 9, 9.5, or 10 of gestation (plug = day 0) a second ureter was formed, anterior to the original ureter, inducing a second kidney. The second ureter then fails to make a connection with the developing bladder and remains attached to the mesonephric duct. The mesonephric duct becomes the vas deferens in the male and deteriorates completely in the female leading to either a resticted ureter or a blocked ureter depending on the sex of the fetus. Administration of a single dose of DMO between gestational day 9 and 10.3 produced both renal agenesis and ureters of varying lengths. Some ureters were of normal length with a tuft of one or two nephrons at their tip, while others were one half or one quarter of their normal length. In some instances the ureter was completely absent. The reason for this strong effect on the ureter is unknown. © 1992 Wiley‐Liss, Inc.
A population‐based study of congenital diaphragmatic hernia
Authors: Torfs Claudine P. , Curry Cynthia J. R. , Bateson Thomas F. , Honoré Louis H.
Published: June 2005

From 1983 through 1987, in a California population of 718,208 births, 237 infants were born with a congenital diaphragmatic hernia (CDH), a birth prevalence of 3.30 per 10,000 total births (live births and stillbirths). We proposed that the various types of this defect, characterized by their different pathogeneses, would be reflected in differences in their descriptive epidemiologies. We evaluated various demographic, maternal, and infant characteristics for three major types of defects, the Morgagni hernia, the pars sternalis hernia, and the posterolateral hernia, categorizing the latter type into isolated defect (N = 129), multiple congenital anomalies including nonchromosomal syndromes (N = 86), trisomies (N = 10), and chromosomal anomalies other than trisomies (N = 2). For the posterolateral hernia, we present the distribution of associated anomalies (43%) and specifically of midline defects (19%). Although the number of cases for the Morgagni hernia (N = 5) and the pars sternalis hernia (N = 5) were small, comparisons with the posterolateral hernia suggested lower sex ratios, of borderline significance for the pars sternalis hernia (P < 0.09), and higher mean maternal ages for both groups. Within the posterolateral type, we found a significantly higher male to female ratio (M/F = 1.58) only for the isolated subgroup compared to the population (P < 0.03), and a borderline significant rural/urban difference in prevalences (2.12 vs. 1.45 per 10,000) (P < 0.06). Additionally, the distribution of monthly prevalence rates adjusted for gestational age suggested opposite seasonal trends between the isolated and the other posterolateral hernias; within this latter subgroup the difference between the highest monthly rate (1.68) and the lowest (0.96) was of borderline significance (P < 0.09). Our results suggest the need to consider the respective types and subgroups of CDH separately in epidemiologic studies. © 1992 Wiley‐Liss, Inc.
Lens and mesenchyme ultrastructure in gestational day 11 trisomy 1 mice
Authors: Smith Barbara S. , Walker Nola J.
Published: June 2005

The lenses and head mesenchyme of two 11‐gestational day trisomy 1 mouse embryos and a normal littermate were examined using transmission electron microscopy (TEM). One trisomic embryo had a small lens with a lens stalk; the other was aphakic. The resolution available with TEM allowed detailed evaluation of cell organelles, spatial relationships and the intra‐ and extracellular structural environment of the lens and head mesenchyme in normal and aneuploid embryos. Differences in fine structure between normal and trisomic lenses included (1) type of epithelium, (2) size of intercellular lacunae, and (3) activity of Golgi complexes. Differences in mesenchyme included (1) the number and size of cytoplasmic extensions, (2) shape of the cells, and (3) reduced endotheliomesenchymal interactions. © 1992 Wiley‐Liss, Inc.
Intermittent pattern of neural tube closure in two strains of mice
Authors: Golden Jeffrey A. , Chernoff Gerald F.
Published: June 2005

Development of the neural tube is often described as a continuous process that begins in the cervical region of the embryo and proceeds both rostrally and caudally. Examination of neural tube closure in the cranial region of LM/Bc and SWV/Bc mice revealed an intermittent pattern with four distinct areas of closure. Closure I begins at the level of somites 1–3 and proceeds bidirectionally. Closure II is initiated at the prosencephalic‐mesencephalic border and also proceeds bidirectionally. Closure III is unidirectional, beginning adjacent to the stomodeum and proceeding caudally to meet closure II. Finally, closure IV takes place over the rhombencephalon where it meets closure II to complete rostral neural tube closure. In these two strains of mice anterior neural tube closure progressed as somite number increased. However, the SWV strain required a longer gestational time to develop equal numbers of somites and therefore to complete closure. In light of the intermittent pattern of closure observed in mice, the development of the rostral nervous system in other mammals, including humans, should be reconsidered. © 1993 Wiley‐Liss, Inc.
Morphology of the cardiovascular system in conjoined twins: Spatial and sequential segmental arrangements in 36 cases
Authors: Gerlis Leon M. , Seo Jeong‐Wook , Ho Siew Yen , Chi Je G.
Published: June 2005

Thirty‐six pairs of conjoined twins are reviewed from the joint experience of the authors. The external forms of conjunctions were 18 thoracopagus (joined at chest), eight cephalothoracopagus (joined at head and chest), eight dicephalus (single trunk and two heads), one craniopagus (joined at head), and one omphalopagus (joined at abdomen). There was one case with a single conventional heart in association with isomerism of the left lungs and absence of the heart in the left‐side twin. Six cases had two conventional hearts. All of them had associated lesions, which were more severe in three cases (50%) with abnormal laterality. All of the cephlothoracopagus (eight cases) had two shared hearts. Cardiac lesions were commonly seen in the posterior heart, but the arrangement of atrial appendages were normal in every heart. Twenty‐one cases of either dicephalus or thoracopagus had a compound heart. Three cases (14%) had fusion only at the level of venous sinus; three others (14%) were fused at the atrial level only, but 15 cases (71%) had fusion at both atrial and ventricular levels. Abnormal laterality was an associated lesion in ten cases (48%) with a compound heart. The fusion at the atrial level always occurred between right atriums, but ventricular fusion was more commonly between two left ventricles. Four atrial or ventricular chambers, if fused, were arranged in a cruciate arrangement. Mode of conjunction was as important, in the formation of the cardiovascular system, as was the degree of fusion. Abnormal laterality, which is commonly associated in lateral or mixed lateral/facing conjunction, was the most important factor affecting the general morphology of the cardiovascular system. © 1993 Wiley‐Liss, Inc.