bluuebunny/crossref_metadata_2025 huggingface dataset:
Lectin teratogenesis: Defects produced by Concanavalin a in fetal rabbits
Authors: Desesso John M.
Published: June 2005

Concanavalin A (con A) is teratogenic to rabbit embryos during gestational days 12–15. Intracoelomic injections of 40 μl con A solution (4 μg/μl) were performed on rabbit embryos during gestational days 10–15. Control embryos received either 40 μl of saline, sham injection or no treatment. Con A caused increased fetal resorptions on days 10 and 11, but malformation levels did not differ from controls. On days 12–15, con A produced craniofacial, trunk and limb anomalies. The highest percentage of malformations occurred on day 14. The defects were classified into four groups: (1) malformations of limbs including paw and digital dysplasias as well as fusions of the limbs to the head or body wall; (2) “closure” defects such as umbilical hernia, encephalocoele, exencephaly or ectopia cordis; (3) “contracture” defects such as club paws, extended knees, or clenched digits, which exhibited normal osseous and cartilaginous skeletons; and (4) miscellaneous, non‐specific anomalies including fused or dysplastic sternebrae or ribs. Histologic analysis of selected 12‐day embryos 4 to 18 hours post‐injection was performed to ascertain potential sites of teratogenic action. At 12 hours ectodermal necrosis was observed in the limb buds adjacent to the apical ectodermal ridge. By 18 hours, the ectoderm had eroded, exposing the basal lamina to the amniotic fluid. Focal areas of mesenchymal necrosis were observed in association with the ectodermal erosion. The potential roles of amniocentesis and limb bud repair in the genesis of the malformations are discussed.
Comparative distribution and embryotoxicity of methotrexate in pregnant rats and rhesus monkeys
Authors: Wilson James G. , Scott William J. , Ritter Edmond J. , Fradkin Rochelle
Published: June 2005

Dosages of methotrexate of roughly comparable embryotoxicity were determined to be 0.3 mg/kg on gestation day 10 in rats and 3.0 mg/kg/d on days 29 through 32 of gestation in rhesus monkeys. These times represented similar periods in development. This regimen in rats was moderately embryolethal, slightly teratogenic, and caused some intrauterine growth retardation; in monkeys it was mildly embryolethal, not teratogenic, and caused only transitory growth retardation.

Methotrexate was largely cleared from maternal plasma of both species within 8 hours, and in spite of a higher administered dose and initial concentration in monkey, the rate of fall was faster than in rat. The fraction of total drug concentration remaining unbound in plasma was approximately 30‐40% during the first 4 hours after treatment in both species. Embryo concentrations, however, were strikingly different during the first 8 hours, ranging between 108 and 209 ng/g in monkey but between 3.4 and 7.7 ng/g in rat. A slow rate of fall in embryo concentrations in both species was estimated to be inversely proportioned to the rate of growth of embryos, which was in accord with the fact that the absolute amount per embryo was little changed in 24 hours.

Thus, the degree and type of embryotoxicity was not closely correlated with the level or duration of concentration in the embryos: a small maternal dosage in rat produced moderate embryotoxicity and very low embryo concentrations; a large maternal dosage in monkey produced slight embryotoxicity despite high embryo concentrations.
The effect of the time of administration of chromium trioxide on the embryotoxic response in hamsters
Authors: Gale Thomas F. , Bunch John D.
Published: June 2005

Prior work has demonstrated that chromium trioxide is embryotoxic in hamsters if administered to pregnant animals early on the eighth gestation day. The major manifestations are cleft palate and an increased frequency of resorptions. In the present study a single iv dose (8 mg/kg) of chromium trioxide was injected into pregnant hamsters at 8 A.M. on either day 7, 8, 9, 10 or 11 of gestation in order to determine the effect of altering the time of treatment on embryotoxicity. Fetuses from females treated with chromium or demineralized‐distilled water were collected on day 15 of gestation and were examined for the types and frequency of external and internal malformations. The number of resorption sites was recorded. Cleft palate, the major malformation detected, was produced only when chromium was administered on days 7, 8 or 9 of gestation. Since the frequency of resorptions and the incidence of cleft palate varied with the time of treatment it is concluded that the time at which chromium trioxide is injected into the pregnant hamster does influence embryotoxicity. The results suggest that an interference with embryonic growth may be an important factor in chromium‐induced cleft palate in hamsters.
Newborn and adult face shapes related to mouse cleft lip predisposition
Authors: Trasler Daphne G. , Machado Marie
Published: June 2005

Embryonic face shape was postulated to be a factor in the multifactorial basis for susceptibility to cleft lip (CL) in A/J mice, since A/J differed from C57BL/6 (resistant embryos). To test this hypothesis new lines were created by selection and the embryos measured (Juriloff and Trasler, 1976). The L line with 9% CL had the predicted narrow internasal pit distance like A/J (12% CL) compared to the M line (0% CL) like the resistant C57BL/6 (0% CL). Newborns and adults of these four lines and CL/Fr (23% CL) were measured to find whether they, like embryos, have face shapes related to their CL predisposition. Measurements were made on newborn and 2 1/2 month old mouse skulls and on heads fixed for soft tissue. Premaxilla length (PL, distance from incisive foramen to anterior edge of anterior palatine foramen) was significantly shorter in newborns and adults in CL lines CL/Fr, A/J and L than non‐CL lines M and C57BL/6. Premaxilla width (PW) tended to be narrower in adults (except A/J) and gum (i.e. filtrum) length (GL) in newborns and adults tended to be shorter in CL lines. Discriminant analysis of adult skeletal data involving four variables PL, PW, Interorbital distance (ID) and length of nasal bones (LN) discriminated A/J and L from M and C57BL/6 lines. Discriminant analysis with ID omitted discriminated CL lines A/J, L and CL/Fr from non‐CL lines M and C57. For variables PL, LN and ID in newborn skulls discriminant analysis had less discriminating ability, but showed a strong tendency to separate A/J and L from C57 and M. Thus a particular facial complex associated with CL predisposition has been found.
Fetal and placental weight relationships in the albino rat near term
Authors: Norman Neroli A. , Bruce Neville W.
Published: June 2005

The relationship of fetal weight to placental weight was examined in 34 albino rats on day 22 of gestation. The influence of maternal weight, fetal position and the number of fetuses in the litter and each uterine horn were assessed also. There was no indication that rats with heavier placentas had heavier or lighter fetuses. However, within each litter, placental weight was weakly correlated (r = 0.297, p < 0.01) with fetal weight. Maternal weight at mating, although positively related to the number of corpora lutea, was not related to mean fetal or placental weight. The number of fetuses in the Jitter was negatively related to placental weight but there was no apparent relation to fetal weight. Fetuses and placentas at the ovarian end of the horn were significantly lighter than those at the vaginal end. The strength of the fetal weight:placental weight correlation in the rat is compared to those in other species.
Fetal and placental responses to artificially induced hyperthermia in rats
Authors: Arora K. L. , Cohen B. J. , Beaudoin A. R.
Published: June 2005

Pregnant rats were utilized to study the effect of maternal hyperthermia on fetal development. Eight groups of six to eight rats were exposed to ambient temperatures of 43‐44cC at various stages of pregnancy. All rats were killed on day 20 of gestation. Edema, microencephaly and microph‐thalmia followed heat treatment on day 4, 6, or 8 and skeletal defects occurred on day 10 of gestation. Apparently heat stress of dams after day 14 of gestation had little or no effect on embryos. Most placentas from day 6‐10 treatment groups were significantly heavier than control and exhibited extensive thickening and necrosis of decidua basalis. Our results suggest that the rat is a useful model for investigating maternal hyperthermia as a possible cause of human placentophathies and fetal retardation.
Gap junctional vesicles in the neural tube of the splotch (Sp) mutant mouse
Authors: Wilson Doris B. , Finta Laurel A.
Published: June 2005

The lumbosacral region of the neural tube was studied by means of transmission electron microscopy in retrospectively confirmed normal ( + /+ Sp/ + ) and abnormal (Sp/Sp) embryos of the splotch mutant mouse early on the ninth day of gestation when the caudal neural groove is normally in the process of closing to form the neural tube. In abnormal embryos, a consistent feature is the presence of gap junctional vesicles, particularly in the region of the neural groove which subsequently fails to close, whereas these structures are rarely observed in similar areas of normal embryos. The possible significance of gap junctional vesicles is discussed in terms of cellular adhesion during early neurogenesis.
The teratogenic activity of a thalidomide analogus EM12 in rats on a low‐zinc diet
Authors: Jackson André J. , Schumacher Herbert J.
Published: June 2005

The relationship between the teratogenicity of EM12, 2‐(2,6‐dioxopiperiden‐3′‐yl) phthalimidine, a stable analogue of thalidomide, and zinc status in the maternal animal was investigated using pregnant rats on a low‐zinc diet (1 ppm zinc, days 0–14 gestation) as the experimental model.

Previous studies with this compound in rats fed a commercial diet at oral doses up to 250 mg/kg per day for three days and intravenous doses up to 10 mg/kg per day for three days failed to produce “typical” thalidomide malformations. However, when a dose of 150 mg/kg was given intraperitoneally to rats on a low‐zinc diet, typical thalidomide malformations occurred with an incidence of 57.5%.
Changes in chemical composition of chick embryos treated with a β‐xyloside and a lathyrogen
Authors: Gibson K. D. , Segen H. J. , Doller H. J.
Published: June 2005

Nine‐day chick embryos were treated with 4‐methylum‐belliferyl β‐D‐xyloside or β‐aminopropionitrile fumarate, and their gross chemical composition was examined one week later. Total DNA was 10–20% less in embryos treated with either drug than it was in control embryos. Xyloside‐treated embryos showed marked increases in percent wet weight and in sodium/DNA and chloride/DNA ratios, and small decreases in protein/DNA, hydroxyproline/DNA and sulfate/DNA. None of these parameters was affected in embryos treated with β‐aminopropionitrile. Approximately 85% of the uronic acid of control embryos was present as chondroitin sulfate, with a degree of sulfation of 80% and charge density of 1.8; all of this chondroitin sulfate was covalently linked to peptide and had a number‐average molecular weight of 29,300. In embryos treated with β‐xyloside, 90% of the uronic acid was present as chondroitin sulfate, with a degree of sulfation of 40% and charge density ranging from 1 to 2; 27% of this chondroitin sulfate, with an average molecular weight of 25,400, was peptide linked, while 73% was linked to 4‐methylum‐belliferone arid had an average molecular weight of 22,900. The chemical differences between embryos treated with the xyloside and embryos treated with the lathyrogen reinforce the conclusion on morphological grounds that these are distinct syndromes involving different aspects of the extracellular matrix.
Retrospective study of the relationship between agricultural use of 2,4,5‐T and cleft palate occurrence in Arkansas
Authors: Nelson C. J. , Holson J. F. , Green H. G. , Gaylor D. W.
Published: June 2005

The relationship between use of the herbicide 2,4,5‐T in Arkansas and the concurrent incidence of facial clefts in children was studied retrospectively. Pertinent animal studies of the toxicity of 2,4,5‐T, and related compounds were reviewed; embryotoxic and teratogenic effects, including cleft palate, have been noted in several mammalian species.

Although newspaper articles appeared linking defoliant use with increased birth anomalies in South Vietnam in 1969, human epidemiology studies have not established a causal relationship between use of 2,4,5‐T and birth defects. We felt that additional information concerning the human problem was needed to complement the experimental animal data, so we analyzed facial cleft rates and concurrent estimated use of 2,4,5‐T in Arkansas during 1948‐1974. Estimated level of exposure to 2,4,5‐T was determined by categorizing the 75 Arkansas counties into high‐, medium‐, or low‐exposure groups on the basis of their rice acreage during 6‐ or 7‐year intervals beginning in 1943. A total of 1,201 cases of cleft lip and/or cleft palate for these 32 years was detected by screening birth certificates and checking the records of the Crippled Children's Services. Facial cleft rates, presented by sex, race, time period, and exposure group, generally rose over time. No significant differences were found for any race or sex combination. We believe that the general increase seen in facial cleft incidence in the high and low‐exposure groups is attributable to better case finding rather than maternal exposure to 2,4,5‐T.
Early human pregnancy with the intrauterine contraceptive device in situ: Incidence of heteroploidy
Authors: Honoré Louis H.
Published: June 2005

An indirect method, based on placental morphology, was used to establish the incidence of heteroploidy in early human pregnancy and to determine the possible effect of the IUD on its occurrence. The non‐IUD‐wearing control population, comprised of 5,779 healthy fertile women undergoing therapeutic abortion for socioeconomic reasons, yielded an incidence of heteroploidy of 0.83% as compared with an overall incidence of 46.7% in our group of spontaneous aborters. In contrast heteroploidy was never detected pathologically in IUD‐associated spontaneous and therapeutic abortions. It was concluded that the IUD significantly prevented the development of heteroploid conceptuses. The biological and clinical significance of these findings was discussed.
Biochemical and electrophoretic studies of cholinesterases in the muscular dysgenesis (mdg) mutant mouse
Authors: Nawrot Peter S. , Howell William E. , Wenger Byron S.
Published: June 2005

Acetyl‐ and butyrylcholinesterase activities were investigated in muscle, brain, blood plasma and erythrocyte membranes obtained from adult and fetal mice of different genotypes ( + / +, +/mdg, +/?, and mdg/mdg) with respect to the muscular dysgenesis (mdg) mutant gene. The study revealed that both AChE and BChE are present in muscle, brain and plasma, whereas erythrocyte membranes exhibit only AChE activity. Significantly lower (P < 0.05) AChE activity was observed in thigh muscle of 20‐day‐old fetuses homozygous for the mutant gene, compared with muscles of wild ( + / + ) and unknown genotypes ( + /?). The mutant (mdg/mdg) fetuses had a slightly significantly (P < 0.05) depressed level of AChE activity in brain tissue, as compared to fetuses of unknown genotype ( + /?). AChE activity was higher (P < 0.05) in the plasma of (mdg/mdg) fetuses than in that of fetuses of unknown genotype ( + /?) but did not differ significantly from those of wild type ( + / + ) fetuses. Samples of the same tissues were subjected to zone electrophoresis, for investigating patterns of cholinesterase isozymes, non‐specific esterases and total protein. Two distinct bands and a faster moving series of poorly resolved bands of acetylcholinesterase were found in muscle and brain of phenotypically normal fetuses. One of the main bands and the diffuse bands were absent in muscle and the diffuse bands were reduced in brain of homozygous (mdg/mdg) mutant fetuses. Except for increased Coomassie blue staining of a few bands in muscle, gels stained for AChE in other tissues, for BuChE, for alpha naphthyl esterase and for total protein showed no differences between mutant and control fetuses. No differences in any electrophoretic patterns were detected between heterozygous ( + /mdg) and homozygous wild type adults.
Development and standardization of screening methods for behavioral teratology
Authors: Buelke‐Sam Judy , Kimmel Carole A.
Published: June 2005

Behavioral alterations have been reported following perinatal exposures to a variety of agents. If subtle effects of this type are to be detected and prevented, sensitive and appropriate measures are needed for prospective screening of new compounds. However, studies reported in the literature have used differing exposure regimens, postnatal environmental conditions and behavioral testing procedures thus making it difficult to determine which existing techniques have particular relevance to screening new drugs and chemicals. It is imperative that such techniques be identified or new ones be developed for screening purposes, as the incorporation of behavioral evaluation into regulatory guidelines and protocols is being considered seriously. Before behavioral assessment can become a meaningful aspect of a routine screening system, considerable research and development must occur. The objectives of such a behavioral screen must be defined. Procedural standardization must be included in efforts to identify those methods which: (1) yield reproducible results within and across laboratories; (2) are sensitive to alterations produced by a range of agents; (3) are predictive of effects in man; (4) are cost‐efficient. Identification of positive control agents, critical periods for testing and early indicators of behavioral dysfunction is urgently needed. The utility of pharmacologic/environmental challenges in unmasking functional abnormalities, and the possibility of multitesting interactions should be investigated. As the resources necessary to accomplish such a task are enormous, it is imperative that behavioral teratologists from academia, industry and government work together during all phases of such development. Interlaboratory cooperation in standardization, validation and interpretation of test methods and results is especially encouraged.
The evolution of teratological testing
Authors: Wilson James G.
Published: June 2005

The beginnings of mammalian experimental teratology in this century are briefly reviewed and it is noted that prior to 1960 a degree of sophistication in concept and technology had already been achieved. Thus, contrary to claims that teratology had its beginning with the thalidomide catastrophe, a modest but expanding activity and body of knowledge already existed before this unfortunate event.

This activity and this knowledge, however, were largely confined to academic and research institute laboratories and made little impact on the agencies in medicine, government and industry which oversaw public health and safety and set policies intended to preserve them. No individual, group, or agency can rightly be blamed for not having sooner brought together the concepts and methodology needed for meaningful animal testing and the regulatory insight and experience needed intelligently to apply test data to human safety evaluation. To accomplish this liaison seems to have required the largest toxicological catastrophe yet recorded in human history.

The major events leading to formulation of the first standardized guidelines are reviewed, but it is emphasized that even today the best animal testing can only provide a limited statement of probability regarding human risk vis‐à‐vis safety.
Morphological alterations in the developing fetal rat limb due to maternal injection of chlorambucil
Authors: Brummett Elaine S. , Johnson E. Marshall
Published: June 2005

On day 14 of pregnancy, rats were injected i.p. with 9.5 mg/kg of chlorambucil. At term, all the fetuses were stunted and had obvious skeletal malformations. From days 15‐‐20 of gestation there was a steady progression of cell death and histologic derangement in long bone formation. This began on day 15, the day following exposure to chlorambucil, with extensive cell death of chondroblasts in the long bone primordia. By day 16, dead or dying cells were located in the cartilage model and became associated with a higher than normal matrix to cell ratio. In day 17 limbs, many cells of the cartilage model were irregular in size and shape so that the normally precise cellular arrangement was lacking. On day 18, periosteal and enchondrial calcification was delayed and scanty. The fibular hemimelia observed in all drug‐treated term fetuses stained with alizarin appeared to result from lack of development of the proximal half of the cartilage model. The observed alterations, particularly bowing of the ulna, in the teratogen‐treated fetuses appeared to result primarily from specific cell death and formation of aberrant cell types but abnormal cell products may also play a role.
Prevention by Tiopronin (2‐mercaptopropionyl glycine) of methylmercuric chloride‐induced teratogenic and fetotoxic effects in mice
Authors: Fujimoto Toyoaki , Fuyuta Masatoshi , Kiyofuji Eiiti , Hirata Shuichi
Published: June 2005

Previous investigations (Fuyuta et al., 76, '79) have shown that a single oral administration of 25 mg/kg methylmercuric chloride (MMC) to pregnant ICR mice on day 10 of pregnancy induced cleft palate in a remarkably high incidence in fetuses. Based on these findings, the present study dealing with the prevention of cleft palate by Tiopronin, (2‐mercaptopropionyl glycine, Tp), was initiated. Twenty females in the positive control group were given 25 mg/kg MMC orally on day 10 of pregnancy and then given physiological saline intraperitoneally. Twenty females in the negative control group were given distilled water orally and then given saline intraperitoneally. Cleft palate was found in 98.1% of fetuses in the positive control group and none of them in the negative control group. Twenty females were pretreated with a single oral dose of 25 mg/kg MMC on day 10 of pregnancy and were posttreated with Tp intraperitoneally, immediately and at every 24, 48, and 72 hours after the MMC treatment. The doses of Tp were 320, 160 and 80 mg/kg/day. The incidences of cleft palate in fetuses were reduced to 1.49, 31.3 and 47.8% in the Tp‐treated groups with the doses of 320, 160 and 80 mg/kg/day, respectively. Tiopronin could effectively prevent the expected incidence of cleft palate. Other types of abnormalities as well as fetotoxicity represented by reduced fetal body weight were also effectively prevented with the Tp‐Treatment.
Threatened abortion, hormone therapy and malformed embryos
Authors: Matsunaga Ei , Shiota Kohei
Published: June 2005

Causal relations between maternal genital bleeding, supportive hormone therapy and external malformations of the embryos were investigated with special reference to the critical period of organogenesis. This was done using morphological and obstetrical data obtained by Nishimura and his associates from 667 undamaged embryos derived from induced abortions whose mothers had genital bleeding in early pregnancy. In addition, data from 90 embryos with polydactyly and 38 with limb reductions in the Nishimura collection were used for case history studies. Evidence was presented to demonstrate that, for major malformations such as CNS anomalies, cleft lip, polydactyly and limb reductions, maternal genital bleeding was not a cause but a consequence of the conception of an abnormal embryo. No indication was revealed that exogenous female hormones currently used in Japan for preventing miscarriages could produce major malformations recognizable at the embryonic stage, including limb reductions, nor salvage the severely malformed embryos. This does not however mean to exclude the possible relationship of progestogens/estrogens intake during early pregnancy with an increased incidence at birth of certain internal and/or external malformations. It was suggested that most, if not all, of the minor anomalies observed at certain embryonic stages are kinds of normal variants without any functional impairment of embryonic development.
Down syndrome, water fluoridation, and maternal age
Authors: Erickson J. David
Published: June 2005

It has been claimed that there is a positive association between the frequency of Down syndrome and the fluoridation of drinking water. It has also been suggested that this association is most pronounced in young women. Recent congenital malformations data obtained from birth certificates from large U.S. cities have been analyzed. Some cities had fluoridated water supplies, while others had supplies deficient in fluoride. The rates of Down syndrome in the cities with fluoridated and in those with non‐fluoridated water supplies were comparable. In addition, there was no indication of any maternal age‐specific association.
The susceptibility of inbred strains of hamsters to cadmium‐induced embryotoxicity
Authors: Gale Thomas F. , Layton William M.
Published: June 2005

Prior research has involved several aspects of cadmium‐induced embryotoxicity in non‐inbred hamsters, mice, and rats. This study compares the embryotoxic profile of cadmium in one non‐inbred (LVG) and five inbred (CB, LHC, LSH, MHA, PD4) strains of hamsters. A single IV dose (2 mg/kg) of cadmium sulfate was injected into pregnant hamsters early on the 8th gestation day. Fifteenth gestation day fetuses from treated, and control animals were studied for the kinds and incidence of external, internal, and skeletal malformations, as well as the frequency of resorptions. All six hamster strains developed significant resorption rates and external, internal, and skeletal abnormalities, e.g., exencephaly, microphthalmia, cleft lip, cleft palate, renal agenesis, rib fusions, etc. Significant interstrain differences were detected in only three categories of embryonic damage, i.e., resorptions, microphthalmia, and renal agenesis. The data of this study was compared with that of another study in which the same hamster strains were exposed to the metallic teratogen, lead. While the manner by which cadmium damages the mammalian embryo is unknown at this time, several possibilities are presented.
Abnormally elevated blood pressure in the trypan blue‐treated chick embryo during early morphogenesis
Authors: Rajala G. M. , Kaplan S.
Published: June 2005

Treating chick embryos with trypan blue at 48 hours of incubation was previously shown to lead to: (1) distension of the caudal dorsal aortae to twice the normal cross‐sectional area by 12 hours posttreatment; (2) rupture of one or both of the dorsal aortae, with hemorrhage into the surrounding tissue spaces by 16 hours posttreatment; and (3) structural damage due to expanding caudal hematomas by 24 hours posttreatment. An increase in blood pressure, heart rate, cardiac output, or circulating fluids, or a selective weakening of the caudal tissues were proposed as possible causes of vessel rupture and hematoma formation. Our present experiments were designed to measure mean ventricular blood pressure (MVBP) and heart rate in treated and control embryos to determine what role these factors may have in the induction of caudal hematomas. Our major findings were: (1) Treated embryos had a significantly elevated MVBP, but no significant change in heart rate when compared to saline‐treated and unopened controls at 12–16 hours after treatment. (2) Treated embryos without hematomas had a slightly elevated MVBP and a significantly lower heart rate when compared to both control groups at 24 hours after treatment. (3) Treated embryos with hematomas had a significantly lower MVBP and heart rate when compared to the treated embryos without hematomas and both control groups at 24 hours after treatment. We conclude that the rupture of the dorsal aortae in trypan blue‐treated embryos is due, at least in part, to increased blood pressure.
Role of decreased cardiac output in isoproterenol‐induced cardiovascular teratogenesis in chick embryos
Authors: Gilbert Enid F. , Bruyere Harold J. , Ishikawa Shizen , Foulke Laura M. , Heimann Sandra R.
Published: June 2005

Studies employing microcinematography, time‐lapse microphotography, electrocardiography, and bioelectrical impedance cardiography indicate that a decrease in cardiac output may be important in isoproterenol‐induced cardiovascular teratogenesis in the chick embryo and merits further investigation. It has been demonstrated by microcinematography that the rate of flow through embryonic chick hearts (Hamburger‐Hamilton developmental stages 24–26) treated with 7.5 × 10−4 M isoproterenol is less than that observed before or without drug administration. Bioelectrical impedance cardiograms have confirmed the above observations. Furthermore, isoproterenol induced momentary asystoles and depressed heart rates for as long as 1–2 hours. Pretreatment of embryos with practolol, a β‐1 adrenergic receptor antagonist, induced more normal cardiac performance after isoproterenol administration. Time‐lapse microphotographs demonstrated morphological alterations, indicating possible venous pressure changes in the vitelline system. Those findings are consistent with a hypothesis that practolol prevents isoproterenol‐induced acute heart failure in the embryonic chick.
Reproductive tract anomalies in mice after prenatal exposure to DES
Authors: Walker Bruce E.
Published: June 2005

Mice were injected prenatally with diethylstilbestrol (DES), using various treatment schedules to see if anomalies could be induced comparable to those seen in DES‐exposed women. Among 96 female offspring, the only tumors of the reproductive tract observed within 14 months of age were two benign tumors of the ovary. However, three other types of anomalies were identified among 20 mice in which the reproductive tract was sectioned. Adenosis occurred with a frequency of 40% in the upper half of the vagina, especially in the fornices. Large, transverse ridges of the vaginal mucosa were present in five mice. Metaplasia of the cervical squamo‐columnar junction was seen in 80% of the sectioned reproductive tracts. These anomalies are similar in morphology and frequency to those seen in women exposed prenatally to DES. Thus, an animal model has been discovered in which the developmental origin and eventual fate of these anomalies can be studied.
Effects of maternal diabetes on early embryogenesis: I. The teratogenic potential of diabetic serum
Authors: Sadler T. W.
Published: June 2005

Effects of maternal diabetes on initial stages of organogenesis was examined by culturing early somite stage mouse embryos in the presence of diabetic serum. Serum for the cultures was prepared from rats which had been made mildly or severely diabetic by the intraperitoneal administration of 50 mg/kg or 75 mg/kg streptozotocin, respectively. Effects of this diabetic serum were age‐and dose‐related, with a higher incidence of malformations occurring among younger (2–3 vs 4–6 somite) embryos and among embryos exposed to serum from severely diabetic animals. The most commonly occuring anomaly was inhibition of neural tube closure which involved cranial (exencephaly) regions only, and was accompanied by growth inhibition in embryos exposed to severely diabetic serum. Histologically, embryos cultured in diabetic serum exhibited a wave of cell necrosis which occurred during the first 4–8 h of culture and was primarily restricted to neuroepithelial and prospective neural crest cells. However, by 24 h the neurotic debris had disappeared, even in severely malformed embryos. These abnormalities are similar to central nervous system defects described for offspring from diabetic mothers. Furthermore, the severity of diabetes produced by streptozotocin treatment promoted glucose and insulin levels comparable to those observed in diabetic patients.
A turner‐like phenotype in the aborted fetus
Authors: Poland Betty J. , Dill Fred , Paradice Barbara
Published: June 2005

Twenty‐two fetuses with bilateral hygromata, lymphedema, and other associated anomalies are described. Two fetuses had a 45,X karyotype, five were sex chromatin‐negative. The association of specific external and internal anomalies is suggestive of the phenotype of Turner syndrome and a 45,X karyotype.
A compendium of the genetically induced congenital Malformations of the mouse
Authors: Kalter H.
Published: June 2005

Over one‐quarter of the more than 870 known alleles in the house mouse cause congenital malformations, forming a valuable but hardly used experimental resource for the study of numerous aspects fo prenatal maldevelopment. These “teratogenes” are here extensively tabulated according to the types of malformations produced, and their various effects are listed, Introducing the tables are some general remarks including comments on variability of gene action and a breakdown of the number of the genes that are recessive and dominant.
Teratological and radiocephalometric analysis of craniofacial malformations induced with retinoic acid in rhesus monkeys (Macaca mulatta)
Authors: Hendrickx A. G. , Silverman S. , Pellegrini M. , Steffek A. J.
Published: June 2005

Fifteen pregnant Macaca mulatta were treated with doses of 20 or 40 mg of retinoic acid between 19–45 or 17–45 days of gestation, respectively, for 4–8 consecutive days. Based on gross examination, ten malformed infants, including one stillbirth and one abortus, four normal infants, and one resorption were produced. The most critical sensitive period was between days 24–35 of gestation, and the malformations primarily involved the craniofacial skeleton. Ten treated infants and eight age‐matched controls were cephalometrically analyzed using craniometric points as closely correlated as possible with those in humans in order to define the craniofacial malformations induced prenatally by retinoic acid. Although all ten animals had detectable linear and angular deviations from the controls, four had cephalometric patterns which appeared to be of similar developmental origin.
Teratogenic effects of retinoic acid in pigtail monkeys (Macaca nemestrina) II. Craniofacial features
Authors: Newell‐Morris Laura , Sirianni Joyce E. , Shepard Thomas H. , Fantel Alan G. , Moffett Benjamin C.
Published: June 2005

The teratogenic effects of retinoic acid, the alcohol‐soluble acid form of vitamin A, on the craniofacial complex of 11 macaque (Macaca nemestrina) whose mothers had received the compound from days 20 to 44 are described. The fetuses ranged in gestational age from 81 to 185 days and exhibited features of the so‐called retinoic acid syndrome (RAS). The syndrome includes both craniofacial defects and postcranial anomalies of the musculoskeletal and urogenital systems. The craniofacial anomalies were described with reference to gross external appearance and radiographic observations. The most frequent findings were cleft palate, malformed ears, hypertelorism, exophthalmos, hypoplasia of the bone of the mid‐face and mandible, a curvature of the inferior border of the mandible, retrognathia, and distortion of the cranium. Lateral cephalograms on nine animals of the RAS sample were measured using six linear dimensions which define the cranial base, face height, palatal length, and mandibular length. The measurements were plotted relative to normal curves which describe growth of the dimensions through the macaque fetal period. For their age, the abnormal animals were small in the craniofacial region. The same measurements were then plotted relative to the size of the fetus, to investigate the possibility of a differential response of the various craniofacial areas to the teratogen. Mandibular length and anterior cranial base were the most reduced dimensions, followed by anterior and posterior face height, with palatal length the least affected. Comparison of the features of the RAS syndrome in the macaque fetus with those reported for various human mandibulofacial dysostosis syndromes yields similarities, but there are enough differences to indicate that the syndromes are not identical in the two species. The utility of the approach used, wherein several craniofacial dimensions of the abnormal are assessed relative to normal growth curves and relative to body size, is emphasized.
Gene‐teratogen interaction in insulin‐induced mouse exencephaly
Authors: Cole Wendy A. , Trasler Daphne G.
Published: June 2005

Heterozygotes for the mutant genes crooked (Cd) or rib fusion (Rf), crossed to either strain A/J or SWV produce mutant F1 offspring with minor skeletal defects. If the mothers are also treated with teratogenic doses of insulin, the mutant Fl heterozygotes develop exencephaly significantly more often than nonmutants. That the heterozygous mutant gene increased the embryo's sensitivity to insulin‐induced exencephaly was also demonstrated by dose‐response curves. For A/J and SWV crosses, probit regression lines for the mutant crosses were fitted to common slopes that were significantly different from those of probit regression lines for the nonmutant crosses. The nonparallelism of the mutant versus the nonmutant groups of lines indicated the presence of a gene‐teratogen interaction. Early exencephalic embryos showed delayed turning in one‐third of treated mutant crosses and less than a quarter of treated nonmutant crosses. Another one‐third of exencephalics, in treated mutant crosses only, had abnormally twisted hindbodies and appeared to be phenocopies of untreated homozygotes. Insulin treatment significantly slowed the rates of embryo turning and neural tube closure but did not affect somite number. Histologically, insulin did not appear to cause cell death, and mitotic index of mesoderm was unaffected. Only exencephalic embryos showed a significant reduction in neurectoderm mitotic index. Insulin caused a reduction in neurectoderm cell proliferation, delay in pattern of turning and delay in neural tube closure to the greatest extent in exencephalic embryos. It was postulated that extensive delays in turning could provide a mechanical basis for the failure of the neural tube to close.
Developmental pattern of cAMP, adenyl cyclase, and cAMP phosphodiesterase in the palate, lung, and liver of the fetal mouse: Alterations resulting from exposure to methylmercury at levels inhibiting palate closure
Authors: Olson Fred C. , Massaro Edward J.
Published: June 2005

Exposure to methylmercury (MeHg: 10 mg Hg/kg maternal body weight) on 126 (dayshours) of gestation significantly delays palate closure in the Swiss Webster CFW mouse. The cAMP content and activity of adenyl cyclase and phosphodiesterase (PDE) were measured in the tissues of control and MeHg‐induced cleft palates between 136 and 176 of gestation. Lung and liver were investigated similarly to determine if MeHg affected the adenyl cyclase system of the palate in a unique manner.

In control palatal tissue, cAMP levels increased sharply from 1322 (undetect‐able) to 146 (maximum). PDE activity increased similarly up to 142, but decreased 50% between 142 and 146. Since it has been reported that cAMP induces the synthesis of PDE, the difference in cAMP/PDE from 1322 to 142 and from 142 to 146 suggests the localization of relatively high levels of cAMP in at least two separate compartments. Between 146 and 1410, the adenyl cyclase activity of control palates decreased significantly. This rapid decrease suggests relatively high adenyl cyclase activity in the medial edge epithelial cells which undergo autolysis prior to shelf fusion (centered at 1415).

Maternal MeHg administration at 126 delayed the median time of palatal shelf rotation (1413) by 5 hours, and significantly altered the developmental pattern of the adenyl cyclase system. Thus, the increase in cAMP between 142 and 146 was abolished and the decrease in adenyl cyclase activity between 146 and 1410 was delayed by almost 20 hours. These changes may be manifestions of a MeHg‐induced delay in medial edge epithelial cell differentiation.

In a previous study, we observed that the fetal liver exhibits the highest MeHg concentration of all tissues. Since MeHg only slightly altered the adenyl cyclase system of the fetal liver compared to the lung and palate (in which MeHg uptake is considerably less), it may be that the effects of MeHg on palatal tissue are not due to a direct effect of MeHg on components of the adenyl cyclase system.
Congenital malformations in a post‐mortem series
Authors: Evans P. R. , Polani Nina
Published: June 2005

Of 8,390 children necropsies, 1,249 showed congenital malformations. Thirteen different malformations were recorded relatively often and are here designated as common. Of the necropsied children 914 had only one of these common malformations, and 140 more than one. A variety of less common anomalies was found in the remaining 195 necropsies. The 13 selected common malformations were analyzed statistically to establish whether there was significant clustering of them. Only five of the common malformations proved to be significantly associated. Both frequency and variability of complication differed considerably between groups of common malformations. There was an overall preponderance of males with the common anomalies but the different anomalies differed in respect to sex ratio.
Palate development in the mouse: A quantitative method that permits the estimation of time and rate of palate closure
Authors: Biddle F. G.
Published: June 2005

A quantitative technique is used to express the morphogenetic stages of palate development in the mouse in terms of gestational age and the normal probability distribution. The qualitative palate rating scale for mouse embryos was modified and the numbers of embryos that had reached the different palate stages at specific gestational ages were fitted to a cumulative multinomial frequency distribution by normal probability regression on gestational age. The median time for each stage can be estimated and the standard deviation of this time (slope of the probability regression) provides a measure of the rate of development. A/J and A.B6 F1 embryos (A/J maternal environment) differed significantly in median time but not in rate of development during a restricted examination time.
Differential staining of cartilage and bone in whole mouse fetuses by alcian blue and alizarin red S
Authors: McLeod M. Jean
Published: June 2005

The procedure described by Inouye ('76) for the staining of full‐term mouse fetal skeletons has been adapted for use with mouse embryos and fetuses of days 14–18 of gestation. The main adaptations for younger specimens involve a longer time in acetone, in lieu of skinning, and omission of the aqueous KOH step. These adaptations require more time but result in consistently good staining of intact specimens.
Agnathia, situs inversus, and associated malformations
Authors: Pauli Richard M. , Graham John M. , Barr Mason
Published: June 2005

Two infants with a striking pattern of associated malformations including agnathia, situs inversus, renal agenesis and ectopia, and multiple vertebral and rib abnormalities are described. It appears that these two infants represent a previously unrecognized malformation association that involves far more than developmental arrest of the mandibular arch. It is conceivable that a single defect at a very early stage in development could account for the multiple manifestations seen.
The teratogenicity of cytochalasin D and its inhibition by drug metabolism
Authors: Fantel A. G. , Greenaway J. C. , Shepard T. H. , Juchau M. R. , Selleck S. B.
Published: June 2005

Pregnant rats received intraperitoneal injections of cytochalasin D (CD) on gestational days 7–11. Doses of 400 μg/kg were only minimally and nonsig‐nificantly teratogenic, leading to 2 exencephalic fetuses among the 111 fetuses delivered. By contrast, embryos exposed to CD in vitro on day 10 showed significant frequencies of neural tube abnormalities when exposed to CD concentrations at or above 3.1ng/ml. These embryos also exhibited significantly decreased protein, somite counts, and crown‐rump lengths.

In order to understand this apparent discrepancy between the teratogenicity of CD in vivo and in vitro we performed experiments to determine whether drug metabolism could inhibit the teratogenicity in vitro. Male rats were pretreated with a mixture of polychlorinated biphenyls as cytochrome P‐450 inducers, and their livers were used to prepare a microsome‐rich fraction (S‐9). This S‐9 fraction, plus a source of reducing equivalents (NADPH), significantly inhibited the teratogenicity of CD. The teratogenicity was restored by the omission of NADPH, and was partially restored with the addition of carbon monoxide.

These results led us to conclude that the teratogenic effect of CD can be inhibited by drug metabolism in vitro; additionally, it is likely that some or all of this drug metabolism may depend on cytochrome P‐450. We further speculate that CD may be inactivated in vivo by these same systems, explaining the discrepancy between the teratogenicity of CD in vivo and in vitro.
Effect of ethinyl estradiol on development of mouse fetuses
Authors: Yasuda Yoshiko , Kihara Takahide , Nishimura Hideo
Published: June 2005

Pregnant ICR/JCL mice were given orally 0.02, 0.2, or 2.0 mg/ kg body weight/day of ethinyl estradiol in olive oil or vehicle alone on day 11 through day 17 of pregnancy. Pregnant mice of another group received a single oral dose of ethinyl estradiol on day 8 or day 11 of pregnancy. A lethal effect on fetuses of both groups with single and continuous exposure to ethinyl estradiol was observed in a dose‐response relationship. Growth suppression of fetuses was only found at term in a dose‐response relationship following continuous exposure to ethinyl estradiol. Hypertrophic nipples were seen in 42% of surviving female fetuses prenatally exposed to 2.0 mg/kg of ethinyl estradiol singly on day 11 of gestation. There was not an increase in other congenital malformations in any of the treated groups. These findings indicate that administered ethinyl estradiol can affect the developing mouse embryo but the embryotoxic doses in the mouse are substantially greater than the usual therapeutic or contraceptive doses in the human.
Limb development in mouse embryos. III. Cellular events underlying the determination of altered skeletal patterns following treatment with 5′fluoro‐2–deoxyuridine
Authors: Knudsen T. B. , Kochhar D. M.
Published: June 2005

A potent inhibitor of thymidylate synthetase, 5–Fluorodeoyxyuridine (FUdR), produced dose‐ and stage‐dependent skeletal defects in embryos of mice injected during early development (10th‐13th day). The dose of 25 mg/kg was teratogenic producing few resorptions and little reduction in fetal weight. Hindlimbs were much more sensitive to the drug than were the forelimbs and showed dose‐dependent long bone reductions. Specific long bone reductions occurred after treatment on the 11th or 11.5 day and were accompanied by preaxial polydactyly; treatment on the 12th or 12.5 day produced high incidence of ectrodactyly but no long bone reductions. Limbs were insensitive on the 13th day of development and beyond. Limb buds in organ culture demonstrated a direct action of FUdR on undifferentiated mesenchymal cells, incurring what has been previously termed “thymineless” cell death. Dose‐dependent reduction of viable cell number led to a reduction in chondrogenic expression in vitro–more so in the hindlimb than the forelimb. Similar occurrence of cell death was also noted after in utero exposure, and here, it was followed by a process of recovery. The recovery phase was characterized by the formation of a distal synchronized cell population derived from undamaged subridge cells leaving damaged cells at the proximal extent of the subridge zone. Limb segments maintained their temporal sequence of differentiation, and their regulatory capability was related to the time allotted for repopulation of the subridge zone. We propose that a faster growth during early development of the elements of the hindlimb versus analogous ones of the forelimb allows the former less time for regulation–and hence, higher sensitivity to antiproliferative agents such as FUdR.