bluuebunny/crossref_metadata_2025 huggingface dataset:
Isolated cleft palate in A/J mice after transitory exposure to drinking‐water deprivation and low humidity in pregnancy
Authors: Brown Kenneth S. , Johnston Malcolm C. , Murphy Peter F.
Published: June 2005

When pregnant A/J mice were deprived of drinking water and exposed to circulating dehumidified (dry) air for 72 h starting at gestation day 12, 39% of fetuses alive on day 17 had isolated cleft palate (CP), whereas treatment begun at day 11 gave 23% CP and at day 13 6% CP. A 48‐h exposure to dry air with deprivation of drinking water gave 7% CP. Deprivation of water alone for 72 h resulted in 12% CP and for 48 h gave 2% CP, not significantly above the 1% CP in controls. All treatments increased the fetal death rate but there was no evidence of an effect on the rate of cleft lip with or without cleft palate, a spontaneous defect in A/J mice. Extraembryonic membranes of day‐17 fetuses, after treatment from days 12–15, frequently showed strongly benzidine‐positivt pigment in the yolk‐sac cavity alongside the vitelline vessels. Only rarely vere small amounts of pigment observed in controls. It was thought to be old fetal blood. Fetal red cell and serum loss are discussed in relation to CP resulting from water deprivation and other teratogenic treatments.
Teratogenicity of methotrexate in mice
Authors: Skalko Richard G. , Gold Mark P.
Published: June 2005

The folic acid analogue methotrexate (MTX) was evaluated for its embryotoxic potential in ICR mice on day 10 (stage 18) of gestation. No malformations were produced at doses shown to be embryotoxic in humans, rats, rhesus monkeys, and rabbits (0.3–10 mg/kg), although a significant increase in resorption rate was observed in litters treated with 10 mg/kg. Doses between the LD10 and the LD50 (25 and 50 mg/kg) produced a parallel increase in intrauterine death and congenital defects.
Normal development of early human embryos: Observation of 90 specimens at Carnegie stages 7 to 13
Authors: Nishimura Hideo , Tanimura Takashi , Semba Reiji , Uwabe Chigako
Published: June 2005

1. A systematic analysis of the relation between 2 parameters of developmental stage — clinically assessed embryonic age and growth — was made for 90 human embryos at Carnegie stages 7–13 from healthy pregnancies. 2. The data showed remarkable individual variation in the relation between age and developmental stage of embryos at stages 11–13. It appears that the mean age for these stages in our specimens was a few days greater than the corresponding age in the currently cited standards, although a definite conclusion must await further studies. 3. The relation between body length and developmental stages in our embryos was not different from the corresponding standards presented by previous investigators. The relation of the number of somites to developmental stage and greatest length in 13 embryos at stages 9–11 was approximately in accord with that reported for several corresponding embryos by other investigators. 4. The oldest age for embryos at each stage in our data may have practical use in denying a causal relation between the exposure of pregnant women to an exogenous agent at such a stage and the subsequent appearance of specific malformations in their progeny.
A 63‐mm human fetus with radial Aplasia, tibial polydactyly, rib and vertebral fusions, and right aortic arch
Authors: Yasuda Mineo , Poland Betty J.
Published: June 2005

A female fetus of 63 mm crown‐rump length was examined. Aplasia of the left radius and thumb, preaxial polydactyly of the left foot, rib and vertebral fusions on the left side, right aortic arch, a small membranous ventricular septal defect, and a single umbilical artery were detected. The potential counseling value of detailed examination of small fetal specimens is stressed.
Effects of chronic low‐dose exposure of rat fetuses to methylmercury hydroxide
Authors: Mottet N. Karle
Published: June 2005

Near‐term fetal rats were examined for possible pathological changes produced by multiple low‐dose subcutaneous injections of methylmercury hydroxide during pregnancy. The near‐term maternal liver content of mercury served as an index of body content. At liver contents below 15 μg/g maternal and fetal mortality and fetal size were unaffected. The threshold of effect occurred at 15 μg/g maternal liver. From the threshold level to 75 μg/g (maternal toxic level) there was generally a dose‐response relation characterized by increasing maternal death, prenatal resorption, and fetal death, and decreasing fetal weight. Generalized fetal edema occurred at the maternal toxic dose level. No gross or microscopic malformations were found in the fetuses. Electron microscopy of samples of near‐term fetal lacrimal, submandibular, and parotid glands revealed no ultrastructural changes or necrosis. The development of behavioral characteristics in offspring of rats exposed to comparable levels of methylmercury was similar to the controls throughout 21 days of observation.
The effects of 5‐fluorouracil and 5‐fluorodeoxyuridine used alone and in combination with normal nucleic acid precursors on development of mice in lines selected for low and high expression of strong's luxoid gene
Authors: Forsthoefel Paulinus F. , Williams Mary Louise
Published: June 2005

Pregnant female mice selected for plus‐ and minus‐modifying genes of the limb‐skeleton effects of Strong's luxoid gene (1st) were injected ip on day 10 of gestation with 10 or 20 mg/kg 5‐fluorouracil (5‐FU) or 5‐fluorodeoxyuridine (5‐FUdR). The incidence and degree of expression of the effects (polydactyly, ectrodactyly, radial hemimelia, tibial hemimelia, pelvic girdle shifts, deformed caudal vertebrae) varied according to the teratogen and dose level. The addition of an equimolecular amount of thymidine, thymine, or uracil greatly potentiated the effects of 20 mg/kg 5‐FU, usually resulting in death of the embryos. The addition of an equimolecular amount of thymidine but not of thymine or uracil partly protected against the effects of 5‐FUdR. Both teratogens increased the expression of 1 st on the limb skeleton. The interactions of the teratogens with the major gene were inhibited by minus‐ and promoted by plus‐modifying genes of 1st. The effects of the teratogenic treatments may be mediated by cell death.
Occurrence of spontaneous hemorrhagic necrosis of the central nervous system in fetal hamsters
Authors: Keeler Richard F. , Young Stuart , Spendlove Rex S. , Douglas Dexter R. , Stallknecht Gilbert F.
Published: June 2005

Lesions of hamster fetal neuraxial tissues, characterized by multifocal and coalescent zones of hemorrhage, edema, and necrosis in the cerebral mantle, brainstem, and spinal cord, were observed in experiments designed to test the teratogenicity of potato preparations. Retrospective and prospective data indicated, however, that the potato preparations were not responsible but that the disease occurred spontaneously in the colony and was associated with direct breeding contact of virgin females with certain males. Observations suggest that an infectious agent may be responsible, but no agent was recovered. Immunofluorescence assay of inoculated cultures indicated that reovirus was not present in affected fetal tissues.
Teratogenesis of acetazolamide in the CBA/J and SWV strains of mice. II. Genetic control of the teratogenic response
Authors: Biddle Fred G.
Published: June 2005

Three independently segregating loci appear to control the difference in response of CBA and SWV mouse embryos to the ectrodactyly‐inducing effect of acetazolamide. Response of the CBA embryo appears to depend on recessive genes for sensitivity being present in the homozygous condition at all 3 loci, and resistance to be conferred by the presence of a dominant allele at any one of the 3 loci. The genetic variability for the ectrodactyly response of the mouse is discussed in the light of the reported physiological factors necessary for acetazolamide‐induced ectrodactyly in the rat.
Teratogenic effects of the pyrimidine analogues 5‐lododeoxyuridine and cytosine arabinoside in late fetal mice and rats
Authors: Percy D. H.
Published: June 2005

Pregnant mice and rats were treated daily with 5‐iododeoxyuridine (IUDR) or cytosine arabinoside (CA) on 3 consecutive days, beginning on day 16 and 18 of pregnancy, respectively. Offspring were killed at 10 and 20 days of age and the cerebellum, eye, and kidney examined histologically. All offspring of mice treated with 400 mg/kg IUDR were stillborn or died within the first 48 h of life, and deaths occurred at other dosages in both species. In IUDR‐exposed mice and rats there was persistence of granule cells in the external granular layer, and scattered foci of microcystic tubular change in the renal cortices. In both species CA produced segmental cerebellar hypoplasia and focal microcystic renal cortical dysplasia. Retinal dysplasia occurred in rats exposed to 50 mg/kg. Lesions were concentrated in the central retina, corresponding with the stage of development at the time of administration of CA. The teratogenic effects of IUDR were minimal and were induced by dosages much higher than normally used in human medicine. On the other hand, lesions were more extensive in mice and rats exposed to CA. Thus, in addition to other known causes of congenital retinal dysplasia, defective development may be drug induced, in this case by the prenatal administration of CA.
Isolated absence of human carpal bones
Authors: Postacchini F. , Ippolito E.
Published: June 2005

An unusual instance of congenital isolated absence of carpal bones, in a 38‐year‐old woman, characterized by total lack of the scaphoid, lunate, and pyramidal and a massive fusion of the distal carpal row is reported. This condition is thought to have been the result of an embryogenetic error exclusively involving the portion of the autopodic blastema from which the carpus originates.
The use of in vitro procedures in teratology
Authors: Kochhar D. M.
Published: June 2005

The capabilities of investigators in the fields of teratology and toxicology are greatly enhanced by the use of tissue culture procedures in unraveling the mechanisms of drug action. Techniques currently available for the culture of postimplantation mammalian embryos permit evaluation of their metabolic responses to potential teratogens even when the length of time embryos survive and develop in culture is too short to allow a conventional teratologic survey of malformations. A simple procedure for culturing mouse embryos during early organogenetic stages is described in this report that will be of value to teratolegists; it avoids the requirements of special glassware and equipment by using ordinary capped test tubes which are rotated to maintain an efficient nutritional and gaseous environment. Some studies conducted with this procedure to monitor the metabolism of embryo during the first 24 h of culture are summarized. Another aspect of tissue culture, organ culture, provides further manipulative capability by which embryonic organs can be maintained for long periods of time during which they develop and differentiate to an extent that their morphological and biochemical responses to a teratogen can usually be made. Comparative effects of several teratogenic agents and the relative concentration of each that produces a similar degree of response are summarized. It is concluded that organs are more sensitive to teratogens in culture than they are in vivo, and that different teratogens possess enough specificity to isolate their simple growth‐retarding effect from the role they play in disturbing other specific developmental events.
The embryotoxicity of ytterbium chloride in golden hamsters
Authors: Gale Thomas F.
Published: June 2005

Two experiments were performed to assess the embryotoxicity of intravenously administered ytterbium chloride in golden hamsters: (1) 50, 75, 100, or 150 mg/kg ytterbium chloride were injected early on the 8th gestation day; (2) 100 mg/kg ytterbium chloride were administered at 4 different times during the critical period of organogenesis in this species (7th day, 4 PM; 8th day, 8 AM or 4 PM; 9th day, 8 AM). The pregnant females were killed on the 12th, 14th, or 15th gestation day and the frequency of resorptions was determined, and surviving offspring were studied for the presence of external and internal malformations as well as skeletal damage. Relatively few externally visible malformations and no significant internal malformations were produced. Damage to the skeletal system included fused and supernumerary ribs, and many different sites of poor ossification. Maximal susceptibility to these effects occurred on the 8th day.
Association of cleft lip and atrial septal defect in mice: A preliminary report
Authors: Fraser F. Clarke , Rosen Joel
Published: June 2005

Newborn A/J and CL/Fr mice with congenital cleft lip usually have an atrial septal defect of the secundum type, often associated with cyanosis. Their littermates without cleft lip rarely have a septal defect. The atrial septal defect results from a delay in growth of the atrial septum primum.
The role of β‐adrenergic activity in the production of cardiac and aortic arch anomalies in chick embryos
Authors: Hodach Richard J. , Hodach Albertina E. , Fallon John F. , Folts John D. , Bruyere Harold J. , Gilbert Enid F.
Published: June 2005

The sympathomimetic amines isoproterenol, epinephrine, norepinephrine, and phenylephrine are structural derivatives of β‐phenylethylamine and have proportionately different effects on α‐ and β‐adrenergic receptors. Chick embryos in ovo were each administered a single dose of one of these compounds at concentrations ranging from 0.4 × 10−9 to 20 × 10−9 mol/5 μl saline during Hamburger and Hamilton stages 20–27. In other experiments embryos were pretreated with the β‐antagonist propranolol and subsequently administered isoproterenol, 743 cardiovascular anomalies were produced. The production of cardiovascular anomalies was proportional to the degree of β‐adrenergic activity of each drug. The frequency of anomalies was significantly reduced by pretreatment with propranolol. At all concentrations tested the anomaly rate was greater in chick embryos receiving an experimental compound than in controls. The general types of anomalies included aortic arch defects, ventricular septal defect, double outlet right ventricle, aortic hypoplasia, and truncus arteriosus. These results demonstrate that activation of the β‐adrenergic receptor mechanism is directly related to the cardiovascular anomalies produced in the chick embryos.
Teratologic evaluation of Δ9‐tetrahydrocannabinol in mice, including a review of the literature
Authors: Fleischman Robert W. , Hayden David W. , Rosenkrantz Harris , Braude Monique C.
Published: June 2005

Pregnant CD1 mice received 5, 15, 50 and 150 mg/kg/day of Δ9‐THC in sesame oil on days 6–15 of gestation orally by gavage and were killed about one day before expected delivery. Treatment had no effect on maternal weight gain, prenatal mortality rate, fetal weight, and the frequency of gross external, internal, and skeletal abnormalities.
Effects in mice of high and low environmental temperature on the maternal and fetal toxicity of 2‐sec‐butyl‐4,6‐dinitrophenol (dinoseb) and on disposition of [14C]‐dinoseb
Authors: Preache Maurline M. , Gibson James E.
Published: June 2005

Swiss‐Webster female mice were treated with 2‐sec‐butyl‐4,6‐dinitrophenol (dinoseb) and maintained in an increased environmental temperature (32°C) for 24 h or a decreased temperature (0–6°C) tor 1.5–4 h. In two experiments animals maintained at low temperature were kept wet during the cold exposure, to enhance the reduction in body temperature, by rinsing them with water at approximately 30 min intervals. Results from nonpregnant females indicated that increased temperature lowered the LD50 for single injections of dinoseb from 20.2 to 14.1 mg/kg and that reduced temperature for 4 h had no effect on the LD50 A 24 h exposure to 32°C enhanced the effect of 3 daily dinoseb treatments of pregnant mice, it increased maternal mortality, decreased fetal body weight, and increased frequency of fetal anomalies. Fetal body weight and the frequency of malformations were the same in groups exposed to low temperature and maintained at room temperature. Disposition of [14C] dinoseb was also determined in nonpregnant mice exposed to temperatures of 0, 24, and 32°C. The periods of environmental temperature studied (3–24 h) had no effect on the rate of disappearance of dinoseb from plasma or other tissues examined.
Prenatal effects of ochratoxin a in hamsters
Authors: Hood Ronald D. , Naughton Michael J. , Hayes A. Wallace
Published: June 2005

Pregnant golden hamsters were injected ip with 2.5–20 mg/kg ochratoxin A on one of gestation days 7–10. The largest dosages when given on day 7, 8, or 9 increased prenatal mortality and on day 9 diminished fetal growth. Malformations, such as micrognathia, hydrocephalus, short tail, oligodactyly, syndactyly, cleft lip, micromelia, and heart defects occurred, but no skeletal malformations were noted. These results add to the prenatal effects of ochratoxin A previously reported in mouse, rat, and chicken embryos.
Tolbutamide treatment of pregnant mice: Repeated administration reduces fetal lethality
Authors: Belisle Robert J. , Long Sally Y.
Published: June 2005

Pretreatment of pregnant BALB/c mice with several low doses of tolbutamidc protected against the fetolethal effects of a high dose. Pregnant mice were given single ip injections of 400 mg/kg in saline on day 13; 100 mg/kg/day on clays 10, 11, 12, and 13; or 100 mg/kg/day on days 10, 11, and 12 and 400 mg/kg on day 13. On day 16 the single‐treatment group had a significantly higher resorption rate than any other group. Fetolethality was not related to hypoglycemia. The protective effect of pretreatment may have been due to induction of maternal microsomal enzymes.
Genetically mediated induction of drug‐metabolizing enzymes associated with congenital defects in the mouse
Authors: Lambert George H. , Nebert Daniel W.
Published: June 2005

Various polycyclic aromatic compounds induce certain monooxygenase activities, including aryl hydrocarbon (benzo[a]pyrene) hydroxylase (EC 1.14.14.2), and cytochrome P1‐450 in the liver and many nonhepatic tissues of the mouse. This induction process is controlled by the Ah locus. Genetic differences that have been shown in the past to be associated with the Ah locus include an increased susceptibility to chemical carcinogenesis, mutagenicity in vitro, and drug toxicity – manifested as hepatic necrosis, aplastic anemia, or shortened survival time. Pregnant mice received a single injection of 3‐methylcholanthrene or 7,12‐dimethylbenz[a] anthracene between day 5 and day 13 of gestation, and the uterine contents were examined on day 18. Striking increases were observed in the incidence of MC‐1 and DMBA‐induced resorptions and congenital malformations in the aromatic hydrocarbon “responsive” C57BL/ 6N inbred strain, and of DMBA‐induced resorptions in the “responsive” C3H/HeN and BALB/cAnN strains – when compared with the similarly treated genetically “nonresponsive” AKR/N strain. These data suggest but do not prove that an association exists between the Ah locus and developmental toxicity, i.e., teratogenesis. Although numerous teratogenic differences among inbred mouse strains have previously reported, this study is unique in that the genetic differences in teratogenicity observed were predicted in advance on the basis of known differences among these strains in polycyclic hydrocarbon metabolism regulated by the Ah locus.
Environmental heat stress effects in the hamster
Authors: Umpierre Carmen C. , Dukelow W. Richard
Published: June 2005

Exposure of Syrian hamsters for two twenty‐minute periods at 40°C on a single day of pregnancy (ranging from day 6 to day 13) resulted in differing teratogenic effects. Maximum resorption (52.6%) was seen with treatment on day 7 whereas the highest rate of malformation (51.9%) was observed with treatment on day 9. Cranial defects predominated with treatment early in pregnancy (highest incidence on day 9) while limb defects were not observed with any treatment administered before day 9. Exencepaly occurred with treath ments on days 6 and 8, with a single case after treatment on day 10. Cleft lip and cleft palate were observed with treatment on days 9 and 10.

These studies illustrate the usefulness of the Syrian hamsters in teratological studies and characterize some of effects exerted after mild heat treatment at varying stages of pregnancy.
Effects of methyl mercury on murine fetal amino acid uptake, protein synthesis and palate closure
Authors: Olson Fred C. , Massaro Edward J.
Published: June 2005

Methylmercury (MeHg: 5 mg Hg/kg maternal body weight) in 0.13 M NaCl, 0.01 M NaH2PO4‐Na2HPO4, pH 7.4 (PBS) administered to gravid CFW mice on day 12, hour 6 (126) of gestation induced a high incidence of cleft palate in fetuses examined on days 156 (72%), 166 (62%) and 176 (40%). Palate closure (100%) in PBS control animals occurred by 1410.

One day post MeHg administration, total fetal protein was decreased 22% while DNA content was unaltered. Protein was maximally decreased (28%) on 146 and, thereafter, returned toward control levels. Alterations in DNA content followed a similar pattern; but the maximal decrease (32%) occurred on 156.

The rate of fetal protein synthesis was depressed 5% at 129 and between 20% to 26% from this time to 136 (end of observation). The agreement between the calculated decrease in protein synthesis (19%) and the measured decrease in protein content (22%) suggests that a reduction in protein synthesis is responsible for the decreased fetal protein content.

Pacental blood flow and fetal water space, measured with 3H – H2O at 1218, were not affected by MeHg treatment. However, fetal free amino acid concentrations at 1218 were generally decreased (alanine, 23.0%; valine, 9.7%; methionine, 22. 6%; isoleucine, 12.0%; leucine, 18.2%) while uptake of the non‐metabolizable amino acid, 14C‐cycloleucine, was decreased 23%. From this, it is concluded that the growth inhibitory effects of MeHg are related, at least in part, to impaired placental/fetal transfer of amino acids.
Digital anomalies in the embryonic mouse limb cultured in the presence of excess vitamin A
Authors: Nakamura Harukazu
Published: June 2005

Forelimb buds of days 10 to 12 ICR/JCL mouse embryos were cultured on a liquid medium consisting of 90% Eagle's MEM and 10% fetal calf serum. Experimental explants were exposed to retinol (10 iu/ml) for the first 24 hours of culturing. In the control explants, chondrified metacarpals and proximal phalanges increased in number as the age of the donor limb bud increased. All treated explants cultured on the experimental medium showed abnormal development compared with the controls. Lesions caused by vitamin A shifted from proximal to distal limb segments as the age of donor limb bud increased.
The effect of high doses of retinoic acid on prenatal craniofacial development in Macaca nemestrina
Authors: Yip Janice E. , Kokich Vincent G. , Shepard Thomas H.
Published: June 2005

Eight pregnant Macaca nemestrina were administered from 7.5 to 10 mg/kg retinoic acid by mouth from day 20 to 44 of gestation. All fetuses exhibited craniofacial abnormalities. The craniofacial complex was studied in detail utilizing gross photography, silver nitrate impregnation, radiography, alizarin staining, and histologic processing. Nearly all the bones of the craniofacial complex were affected; the zygomatic bone and the mandible were most severly altered. Premature fusion of the coronal suture occurred in all the specimens, and there was a clockwise rotation of the craniofacial complex on right lateral view. In general, the bones of the affected fetus were smaller and less well developed than in the control specimen. The abnormal specimens in the present investigation resembled the Treacher‐Collins syndrome in humans, and may be the result of defective neural crest cell migration in the first and second branchial arches.
The association of spinal retroflexion with limb anomalies
Authors: Bowden Releigh A. , Stephens Trent D. , Lemire Ronald J.
Published: June 2005

The spectrum of conditions in which retroflexion of the spine occurs includes anencephaly, iniencephaly, and Klippel‐Feil syndrome. It was suggested by Gilmour ('41) that a continuum may exist linking the latter two entities. The present paper attempts to reopen this question by reporting two specimens which have none of the above conditions, yet have spinal retroflexion and limb malformations. Combined with other isolated case reports, they show that spinal retroflexion can arise over a variable period of time.
Cleft palate in domestic animals: Epidemiologic features
Authors: Mulvihill John J. , Mulvihill Charlotte G. , Priester William A
Published: June 2005

Among 331 animals with cleft palate in a veterinary clinic‐hospital population, cats, mixed breed dogs and German Shepherd Dogs had low risk for cleft palate; high rates were seen in English Bulldogs, some small purebred dogs and Charolais cattle, where cleft palate occurred as part of a syndrome of multiple malformations. Many of the epidemiologic characteristics resemble features of cleft palate in humans and suggest animal breeds suitable for exploration as animal models for use by experimental teratologists, development biologists, and clinicians.
Hypervitaminosis A and matrix alterations in maxillary explants from 16‐day rat embryos
Authors: Sauer George J. R. , Evans Carlotta A.
Published: June 2005

Hypervitaminosis A in treated pregnant rats has been shown to interfere with normal palatal closure and fusion, as demonstrated by the presence of cleft palates in offspring. The observation that palatal shelves of excess witamin A exposed fetuses are stunted and delayed in rotation suggests that vitamin A may inhibit a biochemical event crucial to the successful contact of the palatal shelves. Maxillary explants from 16 day Wistar rat embryos cultured in the presence or absence of 30 IU/ml retinyl palmitate were analyzed for DNA, glycosaminoglycan, and collagen synthesis. Maxillary explants cultured in vitamin A‐containing medium showed an inhibition in DNA, GAG, and collagen synthesis in comparison to control explants. Excess vitamin A in the culture medium of maxillary explants also resulted in a reduction of intermolecular cross‐links in collagen. The possible significance of the results in terms of cleft palate and normal secondary palate formation is discussed.
Maternal characteristics and hypospadias: A case‐control study
Authors: Polednak Anthony P. , Janerich Dwight T.
Published: June 2005

Various characteristics were compared among mothers of 99 singleton male live births (in Upstate New York, 1970–1974) with hypospadias and mothers of 99 singleton male live births, matched for maternal age, race, and residence. Maternal (and paternal) education, maternal height and weight, and the frequency of maternal diseases did not differ between cases and controls. Mean age at menarche was significantly later, but delayed menarche (16 years) was not more frequent, in case vs. control mothers. In the latest year during which the mother was neither pregnant nor taking oral contraceptives, menstrual cycles were significantly more often asymptomatic in case vs. control mothers, implying a higher frequency of anovulatory cycles in case mothers. This suggests the need for further studies on menstrual symptoms. Among case‐control pairs with a previous pregnancy, the first pregnancy was less likely to have resulted in a male fetus in case vs. control mothers. Maternal use of exogenous sex hormones (oral contraceptives, hormone therapy, and hormone pregnancy tests) during the index pregnancy did not differ significantly between cases and controls, but the relative risk of 3.50 for hormone pregnancy tests (seven cases vs. two controls) was noteworthy in view of the results of previous studies.
Cardiovascular malformations associated with administration of prenalterol to young chick embryos
Authors: Bruyere Harold J. , Matsuoka Rumiko , Carlsson Enar , Cheung Matthias O. , Dean Roxanne , Gilbert Enid F.
Published: June 2005

Prenalterol (levo‐1‐[4‐hydroxyphenoxy]‐3‐isopropyl‐amino‐2‐propanol), a new stimulant of cardiac β‐adrenergic receptors in man, induces cardiovascular malformations when topically administered to 2½‐through 5½‐day chick embryos (Hamburger‐Hamilton stages 17–27). Ventricular septal defects (VSD) located in the middle portion of the conal septum and classified as the simple, punched‐out type VSD without septal malalignment were the predominant malformations observed throughout the developmental period tested. Arch malformations of the aortic circulation were also observed throughout the test interval, while anomalies of the pulmonary system were observed only at Hamburger‐Hamilton stages 17 and 26–27. At stage 25 prenalterol demonstrated an acute toxicity significantly less than (1/50–1/20) epinephrine (P = .035 at concentrations of 8–10 mM) but was relatively equipotent with epinephrine in producing cardiovascular malformations. The effective median concentrations of the two agents were comparable (0.5–1.0 mM). The spectra of malformations induced by prenalterol and epinephrine were qualitatively similar. Malformations included absence of the right and/or left third aortic arch (innominate arteries), persistent remnant of the left fourth aortic arch, and VSD. These results support a previously proposed theory by these investigators that hyperstimulation of cardiac β‐adrenergic receptors in the chick embryo produces cardiovascular malformations.
Differential response of heterozygous curly‐tail mouse embryos to vitamin A teratogenesis depending on maternal genotype
Authors: Seller Mary J. , Perkins Kathleen J. , Adinolfi Matteo
Published: June 2005

Around 60% of mice homozygous for the curly‐tail gene have neural tube defects (NTD). F1 hybrids between curyl‐tail mice (ct) and a nongenetically predisposed A strain (A) do not have NTD. Vitamin A increases the penetrance of the ct gene at doses that hardly cause any NTD in A mice. The susceptibility to vitamin A of the F1 hybrids, derived from ct female × A male and A female × ct male crosses, was examined. Either 10, 20, or 40 mg/kg was injected into the mother on the eighth day of pregnancy. The F1 hybrids did develop NTD, and there was a dose response. The number with NTD was roughly intermediate between that found in the two pure parental crosses. However, there was a significant difference in response according to whether the ct or the A was the mother, more F1 embryos having NTD in the former situation. Also, significantly more of the female F1 hybrids had NTD when the ct was the mother than when the A was the mother, but for the males, the number with NTD was the same in both crosses. The number of intrauterine deaths of F1 hybrids, seen as resorptions in each reciprocal cross, was not intermediate but matched that of the pure parental strain of the mother involved in the hybrid cross. It is concluded that gene‐environment interaction has been demonstrated, together with both a maternal effect and a contribution of the fetal genotype in the liability to produce NTD in response to vitamin A.
Palatal slit: A new spontaneous defect of the palate of C57BL/6 mice
Authors: Kusanagi Takao
Published: June 2005

A hitherto undescribed palatal defect, here named “palatal slit,” was observed during a teratological study of C57BL/6 fetuses. The defect, involving a failure of fusion of the premaxilla and palatal shelves, corresponds to stage 7 in normal palate closure. Adult C57BL/6 mice have been observed with the defect, so it does not represent a developmental delay that is repaired postnatally. Genetic factors of an unknown nature seem to be involved in the occurrence of palatal slit, which does not appear to be related developmentally to cleft palate. Some preliminary information on the defect is reported here.
Reduction of caffeine teratogenicity in mice by inducing maternal drug metabolism with β‐naphthoflavone
Authors: York Raymond G. , Randall Joan L. , Scott William J.
Published: June 2005

The effect of stimulating maternal drug metabolism on caffeine teratogenicity was investigated in C57BL/6J (cytochrome P1‐450 inducible) and AKR/J (cytochrome P1‐450 noninducible) mice. The inducing agent, β‐naphthoflavone (β‐NF) in corn oil, was administered intraperiotoneally (IP) to dams at 20 or 80 mg/kg/d on days 9 and 10 of gestation. Teratogenic injections of 175 mg/kg/d caffeine in deionized water were administered IP on days 11 and 12 of gestation. All dams were sacrificed on day 18 of gestation, and fetuses were fixed for razor blade sectioning and skeletal examination. Caffeine, without maternal metabolism stimulation, caused similar types and rates of malformations in both strains of mice. Inducing drug metabolism during pregnancy with β‐NF protected the embryos from the congenital toxicities of large injections of caffeine. Reductions in embryolethality, limb malformations, and hematoma formation were evident in the inducible strain but not in the strain incapable of being induced. A dosage of eighty mg/kg/d was more effective than 20 mg/kg/d β‐NF in decreasing malformations, suggesting that stimulation of metabolism and caffeine‐induced teratogenicity are inversely related. Rapid elimination of caffeine resulting from increasing drug metabolism with the concomitant decrease in toxicity would indicate that caffeine, and not a metabolite, is the toxicant.
Effects of hyperketonemia on mouse embryonic and fetal glucose metabolism in vitro
Authors: Horton W. E. , Sadler T. W. , Hunter E. S.
Published: June 2005

The ketone body β‐hydroxybutyrate (B‐OHB) has been shown to be teratogenic to early‐somite mouse embryos, although the mechanism responsible for these defects has not been determined. In an attempt to define this mechanism, the present study investigated the normal pattern of both glucose and B‐OHB utilization in the developing embryo and fetus. Furthermore, the metabolic interaction of these two substrates, i.e., the potential for B‐OHB to inhibit glycolysis, was studied. All studies compared early and late embryonic periods of development as well as fetal stages. The results show that the early embryo relies almost exclusively on glycolysis for energy metabolism and suggests that there is an increasing importance of the Krebs cycle with increasing gestational age. Similarly, the early embryo has a low capacity to metabolize B‐OHB, whereas later gestational stages display a greater rate of utilization. Finally, there appears to be no inhibition of glycolysis by B‐OHB (via so‐called “substrate interactions”) during early embryonic stages. However, the compound significantly inhibits glycolysis during later embryonic and fetal stages. These studies suggest that the teratogenicity of B‐OHB in the early embryo is not due to its effects on modulating glycolysis, although this mechanism may be operating at later periods of gestation.
The interference of naloxone hydrochloride in the teratogenic activity of opiates
Authors: Jurand A.
Published: June 2005

Diamorphine hydrochloride, methadone hydrochloride, and the synthetic enkephalin analogue FK 33‐824 are potent teratogens for the central nervous system in mouse embryos. They induce the “neurotropic syndrome of malformations,” which is restricted to the central nervous system if administered during the critical period of neural tube closure. Pretreatment with corresponding equimolecular doses of the antagonist naloxone hydrochloride applied 30 minutes before treatment with the opiate agonists abolishes the major severe malformations, i.e., exencephaly, craniorachischisis, and brachyury, and reduces the number of cases of kinking of the spinal cord. Dilation of the fourth brain ventricle remains unaffected.

It is suggested that the mechanism of interference in the teratogenicity of the opiates by naloxone hydrochloride reported here is based on competition for opiate receptors. In general, these observations are regarded as evidence that the pharmacological affinity of opiate agonists to receptors in the central nervous system is responsible for the malformations caused by them in this system.
Potentiation of acetazolamide induced ectrodactyly in wistar rats by vasoactive agents and physical clamping of the uterus
Authors: Ugen Kenneth E. , Scott William J.
Published: June 2005

The vasoactive agents serotonin, ergotamine, and nicotine potentiate acetazolamide induced forelimb ectrodactyly (missing digits) in Wistar rats. These vasoactive agents administered alone do not produce forelimb ectrodactyly and are not known to be inhibitors of carbonic anhydrase. Additionally, physical clamping of the uterine horns in addition to oral acetazolamide administration increases the frequency of forelimb ectrodactyly, suggesting that decreased uterine blood flow can potentiate acetazolamide teratogenesis. Since the vasoactive agents used in this study are reported to possoss uterine vasoconstrictive activity, a decrease in uterine blood flow is a plausible mechanism for the potentiative ability of these agents.
Strain differences between C57BL/6 and SWV mice in time of palate closure and induction of palatal slit and cleft palate
Authors: Kusanagi Takao
Published: June 2005

Palatal slit, which occurs spontaneously in C57BL/6 (C57BL) mice, is increased in frequency among C57BL fetuses from dams treated with triamcinolone acetonide, but is not induced in SWV fetuses. On the other hand, C57BL is more resistant than SWV to left palate induction by triamcinolone. Using these C57BL and SWV mice, the relation of palate stage and chronological age was examined from 1 P.M. on day 14 to 9 A.M. on day 16 in untreated embryos, and the condition of the palate after triamcinolone treatment on day 12 was examined at 9 A.M. on day 16. In untreated embryos, horizontalization and fusion of the palatal shelves occurred earlier in C57BL than in SWV embryos, but fusion of the primary palate with the secondary palate occurred later. After triamcinolone treatment, the development of the palate was delayed in both C57BL and SWV embryos. These results suggest that the times of normal palate closure are related to the differences between C57BL and SWV mice in their susceptibilities to palatal slit and cleft palate induction and that triamcinolone produces palatal slit and cleft palate by delaying palate closure.
Umbilical vein variations: Review of the literature and a case report of a persistent right umbilical vein
Authors: Ricklan D. E. , Collett T. A. , Lyness S. K.
Published: June 2005

A case of a ligamentum teres formed from an obliterated right umbilical vein is described. It passed to the right branch of the portal vein. The quadrate and left lobes of the liver were not separated by the usual fissure. Very few cases of anomalous umbilical veins or persistent right umbilical veins have been recorded. Of these, several have been recorded only in the umbilical cord, while in others the persistent right umbilical vein has been found intra‐abdominally, in an extrahepatic position, and passing directly to the right atrium or to the inferior vena cava. Its presence is generally associated with severe congenital abnormalities, in contrast with the present case. In view of the high incidence of congenital defects associated with aberrant or accessory umbilical veins, when these are detected either in the umbilical cord or in the abdomen by umbilical phlebography, it is suggested that the patient should be carefully investigated for other congenital abnormalities.
Long‐term changes in medication during pregnancy
Authors: Harjulehto Tiina , Aro Timo , Saxén Lauri
Published: June 2005

The Finnish Register of Congenital Malformations, established in 1963, rendered possible the study of changes in medication during pregnancy. The study consisted of 659 control mothers who had delivered a healthy child during the years 1964–1984. The data of this long‐term follow‐up study were collected by interviews at Maternal Health Care Centers after delivery and were completed by filed antenatal data. The results show a continuous decreasing trend in the usage of analgesics and tranquilizers but not in the usage of antiemetics, antibiotics, and vitamins. We believe that in Finland the publicity aimed at unnecessary medication during pregnancy has affected both the mothers and the health personnel.
Teratogenicity of the antiallergic Sm 857 SE in rats versus rabbits
Authors: Nishimura Michiyo , Kast Alexander , Tsunenari Yasuo , Kobayashi Shoji
Published: June 2005

Sm 857 SE is an antiallergic drug chemically described as 11‐Oxo‐11H‐pyrido(2,1‐b)quinazoline‐2‐carboxylic acid that has activity against allergic bronchoconstriction in animal models. The purpose of this study was to investigate the teratogenic potential in pregnant rats and rabbits when administered during the critical period of organogenesis. The drug was suspended in aqueous 0.25% carboxymethylcellulose (CMC) solution. Daily doses of 20, 90, or 400 mg/kg were given orally by gavage to rats on days 7 through 17 of gestation and to rabbits on days 6 through 18. Two additional studies were done in rats dosed with 400 mg/kg, and with 90, 200, or 400 mg/kg, respectively. Doses of 20, 90, and 200 mg/kg had no meaningful effects on maternal animals of either species or on their offspring. A dose of 400 mg/kg was maternally toxic in rats as shown by the effects on body weight and food consumption. Among pregnant rabbits, two deaths and three miscarriages occurred at this dose. In rats, 400 mg/kg caused embryonic death, retarded fetal development, and two specific malformations, namely microphthalmia and vertebral‐costal defects. A mild teratogenic action of 400 mg/kg also occurred in the first additional study but not in the second one. There was, however, one anophthalmia in a rat fetus of the 90 mg/kg group. In rabbits, no embryotoxic or teratogenic effects were observed. These species differences were explained by the concentration and protein binding in maternal serum as well as by the relatively high concentration of 14C‐Sm 857 SE in the rat fetus.
Effects of temporary cooling, and of different explantation and storage conditions, on the subsequent development of post‐implantation rat embryos in vitro
Authors: Kachilele S. G. , New D. A. T.
Published: June 2005

Rat embryos explanted at head fold stage were stored under various levels of hypothermia prior to culture. The storage media were Hanks' Balanced Salt Solution (BSS), 50% rat serum with 50% Dulbecco's Modification of Eagle's Medium (standard medium), or 100% rat serum. The media were gassed with 5% O2/5% CO2/90% N2 or 20% O2/5% CO2/75% N2. Subsequent development of embryos after storage at temperatures between 10°C and 30°C for 5 hr in Hanks' BSS, or for 5–10 hr in standard medium or serum, was similar to that of controls. Some embryos developed well even after storage for 48 hr in standard medium. Development was poorer after storage at 0°C or 5°C, and after storage at all temperatures in ungassed Hanks' or standard medium (pH >8.0). Differences in oxygen level had little effect. For routine explantation at room temperature in (ungassed) phosphate‐buffered saline solutions such as Hanks', it is recommended that the delay before transferring the embryos to the culture incubator not exceed 2–3 hr.
Congenital defect rates among spontaneous abortuses: Twenty years of monitoring
Authors: Shepard Thomas H. , Fantel Alan G. , Fitzsimmons Jack
Published: June 2005

A 20‐year study of 1,124 spontaneously aborted embryos and fetuses found 214 (19.0%) to have a localized defect or identifiable syndrome. No clear trend of change over time was noted. The rate is compared with other studies of spontaneously aborted specimens and is approximately ten times higher than in newborns. Forty (3.6%) had neural tube defects and 30 (2.7%) had a clinically recognized chromosomal phenotype. Fifteen had Turner's phenotype, four trisomy 18, and 11 triploidy. Amniotic bands occurred in eight. Two had bilateral renal agenesis. Thirty had some form of facial cleft.
Effect of a high systemic background level of vitamin a on the teratogenicity of all‐trans‐retinoic acid given either acutely or subacutely
Authors: Nolen Granville A.
Published: June 2005

Groups of 12 Charles River CD virgin female rats were either supplemented with 25,000 IU/kg of vitamin A palmitate or not during the first 8 days of pregnancy and in the first experiment given a single dose of either 5 or 10 mg/kg of all‐trans‐retinoic acid (RA) on day 9 of pregnancy. In a second experiment, similar groups were given either 4 or 8 mg/kg RA daily from day 6 through day 15 so that each treatment with RA was given to vitamin A supplemented rats or nonsupplemented rats. The high systemic background of vitamin A increased the teratogenicity of the 10 mg/kg dose of RA given on day 9 by 50%, but reduced the teratogenicity of the 8 mg/kg dose given on days 6–15. The reasons for this paradox are discussed and related to the human propensity to self‐medicate with megadoses of vitamins.
Effect of 6‐mercaptopurine on 65Zn distribution in the pregnant rat
Authors: Amemiya Kenjie , Hurley Lucille S. , Keen Carl L.
Published: June 2005

The effect of 6‐mercaptopurine (6‐MP) on the distribution of gavaged 65Zn in maternal and embryonic tissues of Sprague‐Dawley rats was examined 24 hr after injection of the drug on day 13 of pregnancy. 6‐MP injection resulted in a significantly higher retention of counts of 65Zn in maternal liver and lower counts in maternal plasma, uterus, placenta, and embryo than in controls. Compared to controls, gel chromatography of maternal liver from 6‐MP injected dams showed higher counts associated with a protein peak of molecular weight 6,000–8,000, the approximate molecular weight of the zinc‐binding protein metallothionein. These results support the idea that the zinc deficiency, which is observed in day 21 fetuses from dams injected with 6‐MP during midgestation, may be the result of a drug‐induced sequestering of zinc into maternal liver followed by a decrease in maternal plasma zinc and subsequent reduction in fetal zinc uptake. We suggest that this 6‐MP‐associated redistribution of zinc into maternal liver may be due to induction of maternal metallothionein synthesis by the drug.
Congenital malformations in rats with the semilethal mutation fused pulmonary lobes
Authors: Aoyama Hiroaki , Nakashima Nobuaki , Teramoto Shoji , Shirasu Yasuhiko
Published: June 2005

It has been demonstrated that an autosomal recessive gene, fused pulmonary lobes (fpl), causes fusion of the right pulmonary lobes with several associated malformations and a high incidence of death in homozygous newborns (Aoyama et al. Teratology 1988; 37:159–166). The aim of the present study was to investigate whether the deaths of fpl/fpl newborns were caused by functional abnormalities of the malformed lung or other associated malformations. Day‐20 fpl/fpl and fpl/ + fetuses were weighed and examined for gross abnormalities. The lungs of selected fetuses were further examined for histological abnormalities. A wide variety of associated external, visceral, and skeletal anomalies as well as relatively lower body weights than those of phenotypically normal fpl/ + littermates were observed in the fpl/fpl fetuses. The associated anomalies consisted of hematomas and/or subcutaneous hemorrhages in the head, truncus and limbs, eyelid anomalies, CNS defects, lobation anomalies of the liver, hypoplasia of the spleen, partial absence of the skull bones, and dorsi‐ or ventriflexion of the phalanges of the limbs. Among them, CNS defects and partial absence of the skull bones were considered to be possible causes of newborn deaths. However, the incidence of these malformations was approximately 10% and was lower than the neonatal mortality, which had been estimated to be approximately 50% in the previous study (Aoyama et al. Teratology 1988; 37:159–166). The lungs of fpl/fpl fetuses consistently had hypoplasia of the intermediate lobe and fusion of the right pulmonary lobes. No histological changes suggesting postnatal respiratory insufficiency were found in the lungs of day‐20 fpl/fpl fetuses, and the cause of newborn death remains unclear.