bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal toxicity: A possible etiological factor in embryo‐fetal deaths and fetal malformations of rodent‐rabbit species
Authors: Khera K. S.
Published: June 2005

Data from animal teratology studies were surveyed to determine whether embryo‐fetal mortality and fetal malformations result from a primary action of the agent on the conceptus or if they are secondary to maternal toxicity–a consequence of administration with high dose levels of test chemicals. A fairly strong association between embryo‐fetal mortality and maternal toxicity was revealed by analysis of data from hamsters, mice, rats, and rabbits in 234 studies of chemical and physical agents, of which 83 were conducted at both maternotoxic and nonmaternotoxic doses, 94 only at maternotoxic doses, and 49 at nonmaternotoxic doses. In the above studies, only nine chemicals (four each in hamsters and rabbits and one in rats) were reported to induce embryo‐fetal deaths at apparently nonmaternotoxic doses. These findings tend to suggest a contributory role for maternal toxicity in the induction of embryo‐fetal deaths. The previously reported hypothesis that certain fetal defects in mice may perhaps be caused by maternal toxicity was also found to be true in a review of data on hamsters, rats, and rabbits. Salient maternal toxicity‐associated fetal malformations were exencephaly, encephalocele, micro‐ or anophalmia, and fused ribs in hamsters and defective (fused, missing, or extra) ribs, vertebrae, and sternebrae, ex‐, an‐, or microphthalmia, and cleft palate in rats and rabbits. These malformations occurred at low frequencies, generally with no readily apparent dose‐response relationship. Presumptive evidence indicates that embryo‐fetal deaths, and the above‐mentioned fetal malformations in experimental animals, which in published literature are presently attributed to chemical induction for a large number of chemicals, may be a consequence of maternal toxicity per se.
Fetus‐in‐fetu: Report of a case
Authors: Yasuda Yoshiko , Mitomori Toshihiro , Matsuura Akio , Tanimura Takashi
Published: June 2005

A 5 month‐old female was brought to our clinic because of diarrhea and abdominal distension. A plain radiograph demonstrated a mass with a vertebral column in the right upper quadrant of the abdomen. At operation a mass was found to be retroperitoneal, well encapsulated, and connected to the abdominal aorta of the host by two small vessels; no other connections and adhesions were seen between the mass and the host. The ovaries, uterus, and other pelvic and abdominal viscera of the host were normal. The mass was diagnosed as a fetus‐in‐fetu. The fetus‐in‐fetu, encapsulated with an amniotic capsule, was covered with skin and had a top with long hair, two protuberances, an amniotic hernial sac, upper limbs with syndactylic fingers, a gluteal region, and lower limbs with polysyndactylic toes. A brain mass and a spinal cord were identified in the cranial cavity and the vertebral canal. Several spinal ganglia and a nerve plexus were found. A noselike structure,upper lip, maxillalike bone with teeth, tonguelike structure, intestines, ribs, bones of the extremities, and skeletal muscles were also identified. A cloacalike cyst was observed to have an opening in the external female genitalia. Microscopically, a small number of motor neurons were seen in the brain mass and the anterior horn of the spinal cord. In the spinal ganglia, ganglion cells were differentiated. The submucosal and myenteric plexuses were seen in the intestinal wall. Well‐differentiated muscle fibers were often accompanied with myelinated nerve fibers. Hematopoiesis was observed in the cranial bone marrow. The presence of the sex chromatin was confirmed in the nuclei of motor neurons and polymorphonuclear leukocytes. Thus, the present fetus‐in‐fetu, which was connected to the abdominal aorta of the host by two vessels, was a monozygotic twin which developed within its own amniotic cavity.
Ectopia cordis thoracalis with craniofacial defects resulting from early amnion rupture
Authors: Van Allen Margot I. , Myhre Selma
Published: June 2005

A 33‐week‐gestation fetus was evaluated as having ectopia cordis thoracalis, midline sternal cleft, frontonasal dysgenesis, a midfacial cleft, and amniotic bands. Fibrous bands were attached to the apex of the heart, face, and the brain. There were no associated limb defects or scoliosis. The findings in this fetus and those in the literature suggest that acute amnion rupture in the third week of gestation may be the cause of these defects. Mechanical teratogenesis by tissue bands adherent to the heart may lead to ectopia cordis. The changes seen in the thorax, face, and brain suggest pressure necrosis, incomplete morphogenesis, tearing and tethering by amnion, and compression as a cause for these defects. A spectrum of defects is found following amnion rupture with the abnormalities being dependent upon the timing of the event. Ectopia cordis with amniotic bands appears to have an etiology distinct from isolated ectopia cordis. This suggests several different etiologies for ectopia cordis.
Maternal factors in congenital limb‐reduction defects
Authors: Polednak Anthony P. , Janerich Dwight T.
Published: June 2005

Various maternal characteristics were examined in case‐control studies of limb‐reduction defects among live births in Upstate New York (i.e., New York State exclusive of New York City). In a study using birth records of 305 cases and 915 controls born in 1970–81, mean birth weight and gestation length were significantly lower in cases than in controls, and certain pregnancy complications (i.e., abnormal vaginal bleeding and diabetes mellitus) were reported more often in cases than in controls. Several subgroups of defects (i.e., isolated defects vs. multiple, long‐bone defects vs. other) were also compared with their respective controls. The subgroup with multiple (including nonskeletal) defects had the lowest mean birth weight and length of gestation.

In an interview study of 108 cases and 108 controls born in 1968–74, a history of maternal use of thyroid medication was a significant risk factor; possible explanations for this association are discussed.
Prevention of the eye closure defect in lgMl/lgMl fetal mice by thyroxine
Authors: Juriloff D. M.
Published: June 2005

The open‐eye birth defect of mice caused by the lgMl mutation was prevented by prenatal administration of thyroxine (T4) to the pregnant mother. Treatment on days 10 to 11 of gestation was most effective in preventing open‐eyes. A contrasting worsening of the defect was seen after treatment on day 14 of gestation. A dose‐response relationship for prevention appeared to be present up to a dose of 0.1 mg/mouse, after which 39% of fetuses had both eyes closed compared to 2% in controls. Higher doses appeared to give little or no further increase in beneficial effect. Scanning electron microscopy was used to compare thyroxine‐treated and untreated lgMl/lgMl and normal CBA/J day 16 or 17 fetal eyes. Mutant eye closure after thyroxine differed from untreated mutant in the growth of both upper and lower eyelids across the eye and in increased numbers of rounded periderm cells on the advancing lid edges. The underlying epithelial tissue layer appeared to fuse closed. The induced eye closure in the mutant was not normal, however. The periderm cell layer had disorderly fusion at the outer canthus, premature flattening, and failure to fuse in the inner canthus.
Reduction in the frequency of neural tube defects in splotch mice by retinoic acid
Authors: Kapron‐Brás Carolyn M. , Trasler Daphne G.
Published: June 2005

In the homozygous state, the splotch (Sp) gene causes spina bifida and exencephaly. Close to 25% of the embryos from Sp/ + × Sp/+ litters are affected. The frequency of these defects is significantly reduced by maternal treatment with 5 mg/kg retinoic acid on day 9 of gestation. There is no significant increase in the resorption frequency with this treatment, indicating that the fall in the frequency of neural tube defects is not due to differential mortality of the affected fetuses. The effects of retinoic acid are time specific, with treatment at different times on day 9 having the greatest influence on either the anterior or posterior neuropore. Treatment on day 8 with the same dose of retinoic acid causes an increase in both resorptions and neural tube defects, although only the increase in the former was significant.
Identification of the cellular retinoic acid binding protein (cRABP) within the embryonic mouse (CD‐1) limb bud
Authors: Kwarta R. F. , Kimmel C. A. , Kimmel G. L. , Slikker W.
Published: June 2005

Retinoic acid, a physiologically active metabolite of vitamin A, is a known animal teratogen. Among other malformations, limb abnormalities are produced and are attributed to a selective inhibition of differentiating prechondrogenic mesenchyme resulting in reduced or absent cartilage elements. Evidence is available that the cellular retinoic acid binding protein (cRABP) may be important in mediating the biological effects of retinoic acid. In this study, the cRABP has been identified by sucrose gradient sedimentation analysis in the gestation day 10 (Theiler stages 16–17) mouse forelimb bud, which contains retinoic‐acid‐sensitive prechondrogenic mesenchyme. Saturation analysis demonstrated values for the apparent dissociation constant (Kd) of 2.0 and 2.2 × 10−9 M and for the total specific binding capacity for [3H]‐trans‐retinoic acid of 24.5 and 25.6 pmoles per mg cytosolic protein. The binding specificity of the forelimb bud cRABP for all‐trans‐retinoic acid was demonstrated in competition assays using all‐trans‐retinol, all‐trans‐retinal, and 13‐cis‐retinoic acid. In addition, 13‐cis‐retinoic acid was demonstrated to have a lower affinity for the cRABP than all‐trans‐retinoic acid, a result which may be related to the lower teratogenic potency of the 13‐cis‐retinoic acid. Thus, the cRABP was demonstrated in the mouse forelimb bud at a time of susceptibility for the production of limb malformations by retinoic acid. The role of the cRABP in the mechanism of retinoic acid teratogenicity remains to be delineated.
Congenital Dandy Walker malformation associated with first trimester warfarin: A case report and literature review
Authors: Kaplan Lawrence C.
Published: June 2005

While the warfarin embryopathy is well defined, central nervous system abnormalities associated with gestational warfarin exposure require further definition. Based on the timing of warfarin exposure in humans, it has been proposed that second‐ and third‐trimester exposure predisposes to CNS abnormalities while first‐trimester exposure more typically is associated with the warfarin embryopathy. A case is presented of a liveborn male with Dandy Walker malformation, agenesis of the corpus callosum, and Peter anomaly of the right eye who was exposed to warfarin between the 8th and 12th weeks of gestation who had none of the stigmata of the warfarin embryopathy. His is the first known case of exposure confined to the first trimester, and the fifth case of Dandy Walker malformation among a total of 15 CNS cases associated with this drug. This case offers evidence that Dandy Walker malformation may represent a distinct complication of in utero first‐trimester exposure, and consideration of these particular abnormalities with exposure limited to a period prior to the known appearance of vitamin K‐dependent clotting factors suggests that warfarin has a direct teratogenic effect on central nervous system morphogenesis.
Congenital malformations associated with anencephaly in liveborn and stillborn infants
Authors: Sadovnick Adele D. , Baird Patricia A.
Published: June 2005

Records from the population‐based British Columbia Health Surveillance Registry were examined, and a total of 456 infants with anencephaly (181 liveborns, 275 stillborns) were identified. Registry records list up to four congenital malformations per individual, and the records of the study cohort were reviewed for the presence of additional malformations. A total of 12.7% of infants (14.4% liveborns, 11.6% stillborns) had congenital malformations in addition to anencephaly. The frequencies of specific congenital malformations (e.g., talipes, cleft lip and/or palate, omphalocele) in infants with anencephaly were compared with the frequencies of these malformations in the general population of liveborns. In addition, the types of additional congenital malformations in liveborn anencephalics compared to stillborns were looked at. The similarity suggests that it is not just the presence of these additional congenital malformations that leads to death in utero. The data provide further evidence for etiological heterogeneity in neural tube defects.
Gonadal development and fertility of mice treated prenatally with cadmium during the early organogenesis stages
Authors: Tam P. P. L. , Liu W. K.
Published: June 2005

Gonadal development was studied in mouse embryos that were exposed to cadmium during the early organogenesis stages. At 13.5 days, both the male and the female embryos had small genital ridges. Fewer primordial germ cells were found in the male embryos. In both sexes, many primordial germ cells were left outside the genital ridges, presumably as a result of retarded cell migration. In 16.5‐day embryos, the size of the testes and ovaries and the number of differentiating germ cells were reduced. Many germ cells degenerated during the differentiation to spermatogonia and meiotic oocytes. The perturbed gonadal development was less likely to be caused primarily by a defective hypothalamopituitary axis but was more a part of the general cadmium‐induced damage. The fertility of the male offspring was impaired by the prenatal cadmium insult, but the females were apparently fertile. The epididymal spermatozoa of the cadmium‐affected offspring showed a lower fertilizing capacity in vitro. The impaired fertility of the cadmium‐affected mice was the result of poor gonadal growth, paucity of germ cells, and defective maturation of the gametes.
Teratogenic effects of nigericin, a carboxylic ionophore
Authors: Vedel‐Macrander G. C. , Hood R. D.
Published: June 2005

Nigericin (Na+ salt) was given intraperitoneally at doses of 5.0 or 7.0 mg/kg on one of gestation days 7–12 to pregnant CD‐1 mice. Additional mice were injected ip with 2.5 mg/kg on day 11 or 12 only. Injections on single gestation days reduced fetal growth and increased prenatal deaths. Additional signs of toxicity to the conceptus included treatment‐related extra ribs and delayed ossification. Treatment was also associated with gross and skeletal malformations, such as median facial cleft, exencephaly, encephalocele, fused ribs, and anomalous vertebrae and exoccipitals. With the possible exception of the 5.0 mg/kg dose given on gestation day 8, nigericin doses associated with gross or skeletal malformations also resulted in observable maternal toxicity.
Methacrylic acid as a teratogen in rat embryo culture
Authors: Rogers John G. , Greenaway Jean C. , Mirkes Philip E. , Shepard Thomas H.
Published: June 2005

Using day 10 rat embryos cultured in vitro, we have shown that methacrylic acid is teratogenic at concentrations ranging from 1.2 to 2.1 mM. At these concentrations, methacrylic acid produced concentration‐dependent decreases in growth parameters, i.e., crown‐rump length, number of somites, and embryo protein content. In addition, methacrylic acid exposure produced malformed embryos characterized primarily by abnormal neurulation. Less frequent abnormalities included hypoplasia of the prosencephalon, edema, malpositioned heart, abnormal flexion, and dilated otic vesicles. Accompanying these abnormalities was an underlying increase in methacrylic acid‐induced cell death.
Suckling deficits in rat pups exposed to alcohol in utero
Authors: Rockwood Gary A. , Riley Edward P.
Published: June 2005

With the aid of a pair‐feeding procedure, two groups of pregnant Long‐Evans rats were fed a liquid diet containing 35% or 0% ethanolderived calories during days 6–20 of gestation. A third group was allowed free access to standard lab chow and water throughout pregnancy. At 6–7 or 9–10 days of age, suckling performance by male and female offspring representing the three prenatal treatment groups was examined. The test stimulus was a 6–10‐day postparturient, anesthetized dam in which milk letdown was prevented. Compared to both pair‐fed and lab chow controls, alcohol‐exposed animals exerted a lower maximum suckling pressure, spent less time suckling during the test session, and displayed an altered suckling pattern. These data are consistent with existing clinical and experimental evidence documenting sucking deficits following prenatal alcohol exposure and are discussed in terms of prenatal alcohol‐induced CNS impairment.
Strain differences in heat‐induced neural tube defects in mice
Authors: Finnell Richard H. , Moon Stephen P. , Abbott Louise C. , Golden Jeffery A. , Chernoff Gerald F.
Published: June 2005

Neural tube defects are common congenital anomalies affecting approximately 0.1% of liveborn infants. It is widely accepted that these disorders are of a multifactorial origin, having both a genetic and an environmental component to their development. In a study designed to elucidate the genetic factors involved in a mouse model of hyperthermia‐induced neural tube defects, it is apparent that a hierarchy of susceptibility exists among various inbred mouse strains. Female SWV mice were extremely sensitive to a 10‐minute hyperthermic treatment on day 8.5 of gestation, with 44.3% of their offspring having exencephaly. The other strains used in these studies (LM/Bc, SWR/J, C57BL/6J, and DBA/2J) all had less than 14% affected offspring. In experimental situations where the environment is held constant and the only difference between the strains in their genotype, it is assumed that the difference in response to a teratogen is genetically mediated. To test the hypothesis that several genes are involved, reciprocal crosses were made between strains of high, moderate, and low sensitivity. When this was done, the high sensitivity of the SWV strain was lost in the F1 hybrid, implying not only that multiple genes are involved, but that it is the embryo's genotype and not the maternal genotype that is the major factor in determining susceptibility to heat‐induced neural tube defects.
Major limb malformations following intrauterine exposure to ethanol: Two additional cases and literature review
Authors: Pauli Richard M. , Feldman Paula F.
Published: June 2005

Two children are reported in whom major limb malformations were identified and whose mothers had consumed large quantities of alcohol in the first trimester of pregnancy. In one there was complete amelia of the upper limbs, while the other had preaxial polydactyly of both hands. These cases, taken together with previously reported instances of major limb anomalies following intrauterine ethanol exposure, as well as animal investigations that have demonstrated virtually identical limb malformations following ethanol administration, suggest that maternal ethanol abuse may be causally related to these limb malformations. We suggest that interruption of blood supply to the developing limb may be caused by ethanol exposure and may result in all of the various limb malformations described.
Atelencephalic microcephaly in a 21‐week human fetus
Authors: Siebert Joseph R. , Warkany Josef , Lemire Ronald J.
Published: June 2005

Atelencephalic microcephaly, a rare and extreme disorder, is known morphologically by only six cases. Derivatives of the telencephalon are absent or dysplastic, while more caudal structures are normal or mildly deformed. A more extensive form, aprosencephaly, involves structures of the diencephalon and may be associated with holoprosencephalic facies. Extracranial anomalies may be present in both atelencephaly and aprosencephaly. We describe the seventh and youngest specimen, a 21‐week female with atelencephaly. Maternal and gestational histories were unremarkable; the fetus was obtained by therapeutic abortion following diagnosis of a severe cranial malformation by ultrasound. A small and depressed, but intact, calvarium covered the brain. The forebrain was rounded and showed fused hemispheres, absent gyri, olfactory bulbs, and tracts. Caudal structures were mildly deformed. An oval mass of bone filled much of the middle cranial fossa. By light microscopy, several dysplastic changes were apparent in the forebrain. Ventricles were not present; small round cells resembling those of the germinal matrix were prominent in the forebrain. Pyramidal tracts were absent at all levels. The process responsible for these changes cannot be established with certainty; the changes are, however, in keeping with previous damage, such as that accepted for other encephaloclastic disorders. The insult in atelencephaly presumably occurs after closure of the rostral neuropore; earlier damage, with more widespread consequences, is possible for aprosencephaly. As with other destructive processes, etiology in atelencephaly and aprosencephaly is most likely heterogeneous.
Frequent occurrence of polyovular follicles in ovaries of mice exposed neonatally to diethylstibestrol
Authors: Iguchi Taisen , Takasugi Noboru , Bern Howard A. , Mills Karen T.
Published: June 2005

The occurrence of polyovular follicles (PF) was examined at 10‐34 days of age in the ovaries of BALB/cCrgl female mice given five daily injections of 0.1μg diethylstilbestrol (DES), 2μg DES, 100 μg progesterone (P), 137 μg 17α‐hydroxyprogesterone caproate (HPC), 20 μg testosterone (T), 20 μg 5α‐dihydrotestosterone (5α‐DHT), or oil vehicle alone starting on the day of birth, and of C57BL/Tw females given five neonatal injections of 1 μg DES, 20 μg 17β‐estradiol (E2), 50 μg 5α‐DHT, 50 μg 5β‐DHT, or the vehicle alone. Ovaries of 30‐day‐old C57BL mice given five daily injections of 1 μg DES starting at 3–25 days of age were also examined. PF incidence (% of PF per ovary) and PF frequency (% of mice with PF) were significantly greater in BALB/c mice receiving injections of DES, P, HPC, and T than in the controls. In DES‐treated mice at 34 days, PF incidence (2–13 oocytes/follicle) was 120–340 times higher than in the controls. BALB/c mice treated with T, P, and HPC showed PF incidence (two to four occytes/follicle) three‐ to six‐fold higher than in the controls. In 30‐day‐old C57BL mice treated with T, E2, and DES, PF incidence also increased by two‐ to 50‐fold. 5α‐DHT and 5β‐DHT failed to increase PF incidence. PF incidence was significantly increased only when neonatal DES treatment was begun on days 0 to 3, but was reduced when started at days 10–25. In DES‐treated C57BL mice aged 10–30 days, PF incidence was significantly higher than in the age‐matched controls.
Further characterization of the distribution and metabolism of nitrofen in the pregnant rat
Authors: Brown T. J. , Manson J. M.
Published: June 2005

Nitrofen (2,4‐dichloro‐4′ ‐nitrodiphenyl ether) is an herbicide with potent teratogenic activity in rodent species. The present study was an extension of previous efforts to characterize the distribution and metabolism of nitrofen in pregnant rats. Following a single p.o. exposure to radiolabeled compound on day 10 of pregnancy, maternal and embryonic tissues were collected at intervals from 1.5 to 72 hours. Radioactivity was accumulated and retained in maternal fat for over 72 hours. Peak levels were reached in other maternal organs at 3–12 hours. The half‐life in maternal plasma was estimated to be 42 hours. Radioactivity was first detected in the embryonic compartment at 3 hours and continued to increase through the 72‐hour time point. HPLC analysis indicated that the parent compound is initially deposited in maternal fat and after 48 hours redistributes to other maternal organs and to the embryo. The 5‐hydroxy derivative was the major nitrofen metabolite found in maternal tissues, while the 4′‐amino and 4′‐acetylamine derivatives were found at lower levels and all exhibited single‐phase kinetics. The parent compound alone was found in the embryo, and levels increased gradually as nitrofen redistributed from the fat at 48 hours after exposure. The results of this and other studies of nitrofen metabolism in pregnant rats suggest that its teratogenicity is not mediated via generation of mutagenic intermediates through nitroreduction of the parent compound. Rather, the embryo is exposed to the parent compound alone and appears to be a deep compartment for accumulation of nitrofen.
The embryolethality and teratogenicity of acrolein in cultured rat embryos
Authors: Slott Valerie L. , Halves Barbara F.
Published: June 2005

Acrolein, a three‐carbon unsaturated aldehyde, is teratogenic to rats in vivo following intraamniotic administration but has been reported not to be teratogenic in vitro in the rat whole embryo culture system. In this study the effects of acroleion on rat embryos cultured in the standard medium consisting of rat serum were assessed over a narrow‐concentration range. Additionally, a comparison was done of the effects of culture in a serum medium vs. a serum‐free medium. In the serum medium acrolein caused 100% embryolethality at 140 μM and was found to be teratogenic in the concentration range of 80–120 μM. In the serum‐free medium acrolein was 100% embryolethal at 20 μM and was teratogenic in the range of 5–15 μM. The EC50 for malformations in the serum medium was 137 μM, whereas that for embryolethality was 115 μM; the EC50s for malformations and embryolethality in the serum‐free medium were 2.8 μM and 8.3 μM, respectively. Malformations were observed in the brain, facial area, and heart in addition to blebs and twisted or kinked bodies. Decreases in yolk sac diameter, crown–rump length, head length, number of somites, morphological score, and protein content were observed within the teratogenic ranges in each type of medium. Thus acrolein is teratogenic and embryolethal in vitro as well as in vivo. Dissociation between embryolethality and teratogenicity was seen in the serum‐free medium. The slope of the acrolein log concentration‐response curve in the serum‐free medium was twice that in the serum medium, indicating that acrolein may have a different mechanism of action in this medium.
Neural tube defects: A review of human and animal studies on the etiology of neural tube defects
Authors: Campbell L. Rebecca , Dayton Delbert H. , Sohal G. S.
Published: June 2005

Although neural tube defects are a common congenital anomaly, their etiology is not known. Human studies have emphasized the pathology and epidemiology of the defects and suggest that in the majority of cases the etiology is multifactorial. Factors which appear possibly to be important are genetic predisposition, maternal illness, and fetal drug exposure. Animal studies have utilized naturally occurring neural tube defects and teratologically induced lesions. No animal model has been convincingly established as the equivalent of human neural tube defects. However, animal models have allowed investigation of the mechanisms of suggested human teratogens and determination of the pathogenesis of naturally occurring animal defects. Their most important contribution has been in furthering the understanding of the normal mechanisms of neural tube closure. It may be through this understanding that the etiology of human neural tube defects will be determined.
Increased mortality and aneuploidy in embryos from rabbits injected with Newcastle disease virus at the time of ovulation and conception
Authors: Maroun Leonard E. , Degner Marykay , Mourey Mary Elizabeth , Rowan Dighton F. , Amankwah Kofi S.
Published: June 2005

In the rabbit, ovulation and conception occur during an 8–10 hour period immediately following mating (“reflex ovulation”). We report here that live Newcastle disease virus (NDV; an avian paramyxovirus) injected into rabbits immediately following mating resulted in a high frequency of embryo death at a wide range of developmental stages. When measured at midterm, a greater than threefold increase in embryo mortality was observed (24.7% vs. 6.8%). Aneuploidy of a small acrocentric chromosome was observed in three of 60 live midterm embryos recovered from NDV‐injected does. No aneuploidy was observed in 52 live midterm embryos from control, saline‐injected does. These observations suggest that the NDV‐exposed rabbit can provide a useful model for the study of the teratological effect of virus exposure occurring at or about the time of meiosis, ovulation, and conception.
Sirenomelia and anencephaly in one of dizygotic twins
Authors: Schwaibold H. , Oehler U. , Helpap B. , Böhm N.
Published: June 2005

The combination of sirenomelia and anencephaly was observed in a stillborn dizygotic twin. A review of the literature revealed no other patients reported to have both conditions. Various explanations concerning the genesis of sirenomelia, and also the combination with anencephaly, are discussed.
Teratogenic effects on the CD‐1 mouse embryo exposed to concurrent doses of ethanol and aspirin
Authors: Guy Julia F. , Sucheston Martha E.
Published: June 2005

Human fetal alcohol syndrome characteristics have been seen in the mouse fetus by several investigators who dosed the dam with only one or two doses of alcohol. The purpose of this study was to determine if the fetal effects of acute doses of alcohol (ethanol) are altered by aspirin. CD‐1 mice were given two IP doses of a 25% v/v solution of 95% ethanol/saline (2.5 hours apart) and intubated with 250 mg/kg aspirin. The treatment regimen, begun at 8 days, 4 hours gestation, consisted of either aspirin pretreatment 1 hour before or posttreatment 1 hour after the ethanol. Control animals were treated similarly and included vehicle only, ethanol/vehicle, and aspirin/vehicle groups. One group was untreated. On gestational day 18, the dams were killed and the uterine horns were examined for live, dead, and resorbed fetuses. The live were weighed and examined for external malformations and either skeletal or visceral abnormalities. With the litter as the unit of analysis, no significant difference was found in the number of dead and resorbed among groups. There was a significant difference (P <.01) in average fetal weight in the aspirinpreteated group. When the total number of fetuses affected was considered, the aspirin pretreatment group showed significantly (P <.05) more external and visceral malformations. The skeletal examination revealed a significant (P <.05) difference in anomalies plus delayed ossification in both groups treated with the aspirin/ethanol combination. No significant differences were seen in any category in the groups receiving aspirin alone or ethanol alone. These results indicate and additive effect of aspirin and ethanol on the developing CD‐1 mouse fetus.
Teratology studies of ametantrone acetate in rats and rabbits
Authors: Petrere Judith A. , Kim Sang‐Nam , Anderson John A. , Fitzgerald James E. , De La Iglesia Felix A. , Schardein James L.
Published: June 2005

Ametantrone acetate is an antineoplastic drug chemically described as 1,4‐bis [[2‐[(2‐hydroxyethyl)‐amino]ethyl]amino]‐9,10‐anthracenedione diacetate salt. The drug has activity against leukemia and solid tumors 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. Daily doses of 1.5, 3.0, and 6.0 mk/kg were administered IP to pregnant rats on days 6 through 15 of gestation, and 0.2, 0.4, and 0.8 mg/kg to rabbits on days 6 through 18. Dose‐related weight loss occurred in both species during treatment as well as in the entire gestation period. Maternal and fetal parameters were evaluated upon uterotomies in rats on gestation day 20 and rabbits on day 28. In both species, there was dose‐related blue discoloration of abdominal viscerae and of skin at injection sites. In rats, fetal malformations and developmental variations were comparable between treated and control fetuses. However, the incidence of fetal malformations was increased in rabbits given 0.4 and 0.8 mg/kg but not at 0.2 mg/kg. Based on these data, ametantrone was considered teratogenic at dose levels of 0.4 mg/kg and above in rabbits.
Prevention of polydactyly manifestation in Polydactyly Nagoya (Pdn) mice by administration of cytosine arabinoside during pregnancy
Authors: Naruse Ichiro , Kameyama Yoshiro
Published: June 2005

Male mice heterozygous for the dominant polydactyly gene Pdn (Polydactyly Nagoya) were crossed with normal or heterozygous females of the same strain. Pregnant females were treated with 5 mg/kg of cytosine arabinoside (Ara‐C) on day 12 of gestation. The offspring were removed on day 18 of gestation and examined for external malformations, and the fore‐ and hindlimbs were examined by means of bone‐ and cartilage‐stained cleared specimens.

In +/+ x Pdn/+ matings, Pdn/+ fetuses, bearing preaxial polydactyly of the distal phalangeal type in the hindlimb and deformity of the 1st digit in the forelimb, were obtained in about 50% of the nontreated group. In treated fetuses, however, the incidence of polydactyly and deformity of the 1st digit decreased to 1.4 and 10.1%, respectively. Nontreated Pdn/Pdn fetuses exhibited preaxial polydactyly of the duplicated or triplicated metacarpal/metatarsal type both in the fore‐ and hindlimbs. In the treated Pdn/Pdn fetuses, the number of preaxial extra digits decreased in both limbs. Some hindlimbs of the treated Pdn/Pdn fetuses exhibited five metatarsals, normally.

In the vitally stained specimens at 6 and 24 hours after injection of Ara‐C, preaxial marginal necrotic zones (fMI) were observed in almost all of the treated embryos from +/+ × Pdn/ + matings. However, approximately half of the embyros did not exhibit fMI in the nontreated control group at the same stage. Those embryos deficient in fMI were regarded as Pdn/ +.

These findings indicated that a subteratogenic dose of Ara‐C prevented the genetic expression of polydactyly in almost all Pdn/+ and some cases of Pdn/Pdn mice. In addition, the fMI had an important role in the morphogenesis of preaxial polydactyly of distal phalangeal type in Pdn/+ mice.
Effects of the volatile anesthetic halothane on fertilization and early development in the sea urchin Lytechinus variegatus: Evidence that abnormal development is due to polyspermy
Authors: Hinkley Robert E. , Wright Brent D.
Published: June 2005

The volatile anesthetic halothane, when present at fertilization, dose‐dependently increases the incidence of abnormally developing sea urchin embryos at the first cell division. Microscopic examinations of eggs stained with aceto‐orcein or the DNA fluorochrome bisbenzimide and direct observations on isolated sperm aster complexes show that halothane induces polyspermy (multiple sperm entry) when present at fertilization. Experimental evidence suggests that anesthetic‐induced polyspermy involves impairment of both the fast (electrically mediated) and slow (morphological) blocks to multiple sperm entry. These observations clearly show that relatively brief exposures to halothane at fertilization cause polyspermy and that this effect is almost certainly responsible for the ensuing abnormal development observed at the first cell division.
6‐mercaptopurine‐induced alterations in mineral metabolism and teratogenesis in the rat
Authors: Amemiya Kenjie , Keen Carl L. , Hurley Lucille S.
Published: June 2005

The relationship between 6‐mercaptopurine‐induced alterations in mineral metabolism and the teratogenic effects of the drug were investigated. Pregnant Sprague‐Dawley rats were fed diets containing 4.5, 100, or 1,000 μg Zn per 1 g diet. On day 11 of gestation, dams were given intraperitoneal injections of 6‐mercaptopurine (27.5 mg/kg). At term, dams fed the 1,000‐μg Zn per 1 g diet showed fewer drug‐induced deleterious effects on reproduction and embryogenesis than did those fed lower levels of zinc. Mineral analysis of maternal and fetal tissues revealed pronounced effects of 6‐mercaptopurine on metabolism of zinc, copper, iron, calcium, and magnesium. The results of this study indicate that 6‐mercaptopurine teratogenesis may be due in part to drug‐induced changes in mineral metabolism.
Distribution, metabolism, and fetal uptake of pentavalent arsenic in pregnant mice following oral or intraperitoneal administration
Authors: Hood Ronald D. , Vedel‐Macrander Ginger C. , Zaworotko Michael J. , Tatum Fred M. , Meeks Robert G.
Published: June 2005

Pregnant CD‐1 mice were treated with 20 (i.p.) or 40 (p.o.) mg/kg sodium arsenate on gestation day 18 (plug = day 1). Individual fetuses, pooled placentas and maternal blood, urine, liver, and kidneys were obtained from three or more litters at intervals up to 24 hours following treatment. Acid‐digested samples were analyzed for total arsenic by hydride generation atomic absorption spectrophotometry. The rate of arsenic elimination from maternal samples was not influenced by administration route. First‐order elimination followed a brief period of distribution, and the biological half‐life was approximately 10 hours. Arsenic was found in most samples, with mean peak concentrations expressed as μg As/gm (wet wt.) or /ml (values listed are post‐treatment sampling times in minutes or hours and concentrations for i.p. and for p.o. treated groups, respectively) as follows: fetuses–2, 3.5; 6, 0.8, placentas–2, 9.3; 1, 2.3, blood–10 minutes, 6.9; 1, 2.0, urine–1, 712; 2, 342, kidney–20 minutes, 25.4; 1, 11.0, liver–0.5, 7.9; 1, 11.7. By 24 hours, arsenic levels in fetuses and placentas had declined to 0.22 μg/gm and 0.74 μg/gm for i.p. and 0.33 μg/gm and 0.57 μg/gm for p.o. treatments, respectively. Fetal arsenic uptake and loss were more rapid following i.p. than p.o. treatments, and although the i.p. dose was only half that used p.o., peak fetal As+5 was almost fivefold higher following i.p. treatment. These results agree with the finding that oral dosing of pregnant mice with arsenate has less effect on the conceptus than does treatment by injection. Arsenic metabolites (mono‐ and dimethyl arsenic) were quantitated in fetuses and ranged up to 83% of total fetal arsenicals by 24 hours.
Studies of the effect of 0.4‐Gy and 0.6‐Gy prenatal X‐irradiation on postnatal adult behavior in the Wistar rat
Authors: Jensh Ronald P. , Brent Robert L. , Vogel Wolfgang H.
Published: June 2005

Thirty‐four pregnant Wistar rats were X‐irradiated on the 9th or 17th day of gestation at a dosage level 0.4 Gy or 0.6 Gy or were sham‐irradiated. All mothers were allowed to deliver their offspring, and litters were limited to a maximum of eight on day 2. On day 30, 224 offspring were weaned and raised until 60 days of age, at which time testing began. Each rat randomly received, in random order, three of the following six behavioral tests: Water T‐maze, Conditioned Avoidance Response, Forelimb Hanging, Activity Wheel, Swimming, and Open Field. There were no statistically significant differences between the irradiated and control groups for maternal weight or weight gain or mean litter size, although the litter size of the 17th day 0.6‐Gy group was slightly lower. Among offspring irradiated with 0.6 Gy on the 17th day, 3‐day‐old neonates' weights were significantly reduced. Offspring irradiated on the 17th day with 0.6 Gy exhibited higher Conditioned Avoidance Response 5th‐day and retest avoidance scores than did the controls. There were also significant sex differences in responses within the irradiated and control groups for several tests, which were unrelated to radiation exposure. The results of this study indicate that low‐level X‐irradiation during the fetal period of rat gestation results in neonatal growth retardation and subtle behavioral alterations that may be manifested in adult life. Growth retardation may be the most sensitive indicator of suble effects that result from low‐level prenatal exposure to X‐rays.
Effects of metabolic factors in the diabetic state on the in vitro development of preimplantation mouse embryos
Authors: Zusman Igor , Yaffe Perhiya , Ornoy Asher
Published: June 2005

The effects of insulin, glucagon, β‐hydroxybutyrate, and acetoacetate on the in vitro development of preimplantation mouse embryos were studied. In controls, 24% of blastocysts failed to develop successfully when grown for 72 h in Eagle's medium supplemented with 10% fetal calf serum. Insulin at concentrations of 1.0 and 2.0 IU/ml of culture medium interfered with development in 62–63% of the blastocysts. Preimplantation embryos showed a threshold pattern in their reaction to glucagon: its addition in concentrations of 0.0015 mM (5 μg/ml) did not significantly inhibit blastocyst development, while concentrations of 0.003 mM (10 μg/ml) inhibited 70% of blastocysts. The embryotoxic effects of ketone bodies were manifested only in relatively high doses. β‐hydroxybutyrate was embryotoxic at concentrations greater than 5 mg/ml, and its effects were dose dependent: 48 mM (6 mg/ml) inhibited 45% of blastocysts, while 80 mM (10 mg/ml) arrested 87% of embryos from further development. Acetoacetate at concentrations of 0.1 mM (10 μg/ml) inhibited the development of 50% of the blastocysts, and its effects were not dose dependent: concentrations of 1 mM (100 μg/ml) inhibited development in 63% of the embryos. The combination of the diabetic metabolic factors in relatively low concentrations was highly embryotoxic, especially when accompanied by hyperglycemia.
Craniofacial dysmorphogenesis following hypervitaminosis A in mice
Authors: Kay Elizabeth D.
Published: June 2005

Malformations of the temporomandibular joint (TMJ), zygomatic arch, middle ear ossicles, and mandibular musculature following hyper‐vitaminosis A were described in fetal mice. Pregnant mice (Mus musculus) were each given a 0.2‐ml solution of corn oil containing 10,000 IU of retinol palmitate by gavage on day 8.7. Thirty‐eight fetal heads were collected and hemisected. The left hemiheads were serially sectioned, stained, and examined histologically. Right halves were cleared and double‐stained with alizarin red and alcian blue. The craniofacial morphologies of the test mice were found to vary from normal to maximally involved (feature unidentifiable) even among littermates. Both inter‐ and intralitter variation were discussed. Errors in chondrogenesis were determined to have produced the variety of dysmorphologies observed. Changes in Meckel's cartilage affected both the TMJ and ossicles; the presence of ectopic cartilages affected the zygomatic arch; and the musculature was affected secondary to skeletal system changes. Several modes of vitamin A interference leading to craniofacial dysmorphogenesis have been proposed in the literature. It was determined that proposals implicating altered cellular differentiation were the most compatible with the in vivo data recorded here and elsewhere.
Embryotoxicity of sex steroidal hormone combinations in nonhuman primates: I. Norethisterone acetate + ethinylestradiol and progesterone + estradiol benzoate (Macaca mulatta, Macaca fascicularis, and Papio cynocephalus)
Authors: Hendrickx A. G. , Korte R. , Leuschner F. , Neumann B. W. , Prahalada S. , Poggel A. , Binkerd P. E. , Günzel P.
Published: June 2005

Two sex steroid hormone combinations which have been used clinically as tests for detection of early pregnancy were examined for embryotoxic effects in macaques and baboons. Norethisterone acetate and ethinyl estradiol (NEA + EE) were orally administered to rhesus and cynomolgus monkeys and baboons at dosages ranging from one to 1,000 times the human dose equivalent (HDE) during days 20–50 of pregnancy. Progesterone and estradiol benzoate (P + EB) were delivered by two to six intramuscular injections to rhesus and cynomolgus monkeys between gestational days 20 and 35 at 0.1–25 × HDE. Fetuses were examined following cesarean section at 100 ± 2 days (NEA + EE) or at term (P + EB). The results showed increased embryolethality over controls at 100–1,000 × HDE (NEA + EE) and at 10 and 25 × HDE (P + EB). Besides growth retardation, isolated cases of minor nongenital malformations were observed only in cynomolgus monkeys following treatment with both hormone combinations mainly at embryolethal dose levels and were considered spontaneous in nature. Virilization of female cynomolgus fetuses following NEA + EE treatment was manifested as two cases of clitoral enlargement in the 300 × HDE group and two cases of increased anogenital distance with reduced vaginal opening in the 1,000 × HDE group. The highest dose of NEA + EE was also maternally toxic, as two maternal deaths occurred at the end of the treatment period. One dead female cynomolgus fetus exposed to P + EB (10 × HDE) also exhibited masculinized external genitalia. The results support epidemiologic and laboratory data which indicate that sex steroid exposure during early pregnancy does not induce nongenital teratogenicity.
Shakespeare, genetics, malformations, and the Wars of the Roses: Hereditary themes in Henry VI and Richard III
Authors: Hook Ernest B.
Published: June 2005

The four plays in the Henry VI‐Richard III sequence well illustrate Shakespeare's recognition of hereditary influences upon the human condition. The inheritance of physical characteristics as manifest particularly by resemblance between fathers and sons is noted frequently. The absence of such resemblance is cited occasionally as evidence of illegitimacy. Personality traits are also viewed as inherited, although less consistently and there are important exceptions. Physical and mental traits when not derived from parents are ascribed to “nature” in the sense in which the term is often used today. Such traits are seen as being congenital or inborn even if not obviously “hereditary.” Important exceptions to this are provided by the characters of the two lead characters in the play sequence. The weak‐willed Henry VI is markedly different from his father, grandfather, and son who were all valiant, warlike, and brave. Shakespeare never explains this abrupt difference among generations. And the source of the evil character of Richard III is somewhat ambiguous. It seems most likely that in the first three plays of the sequence Shakespeare intended Richard's villainousness to be perceived as innate, caused by the same forces of nature that produced Richard's deformities (which are not further explained). But when Shakespeare wrote Richard III and gave more conscious consideration to what was now his central character he invoked an “environmentalist” explanation. Richard now is presented, albeit somewhat inconsistently, as evil in response to social ostracism because of his ugly deformities. This rather modern interpretation of the social origins of the personality of the deformed is particularly striking because it goes beyond anything in Shakespeare's historical sources, although Francis Bacon, a con‐temporary of Shakespeare, also recognized the effect of social forces upon the personality of the deformed.