bluuebunny/crossref_metadata_2025 huggingface dataset:
Pulmonary hypoplasia in chondrodystrophic mice
Authors: Seegmiller R. E. , Cooper C. A. , Houghton M. J. , Carey J. C.
Published: June 2005

Lungs of day‐18 fetal mice with hereditary chondrodysplasia (cho) were examined histologically and biochemically for pulmonary hypoplasia. Compared with normal littermate controls, the mutant's lungs were smaller by 37 (wet weight) and 22% (dry weight). Total DNA and protein per whole lung were decreased by 13 and 19%, respectively. The significantly smaller‐than‐normal terminal sacs observed in histological sections of the mutant's lungs corresponded with the greater difference (37%) in lung wet weight. The developmental mechanism for this disorder was further explored by examining the volumes of thoracic cavity and amniotic fluid. the volume of the thoracic cavity of newborn mutants was less than half that of controls, suggesting that the pathogenetic mechanism for the hypoplastic lungs in chondrodysplastic mice includes thoracic dystrophy. Measurement of the amniotic fluid volume revealed polyhydramnios in the mutant, thereby ruling out oligohydramnios as a mechanism. The relevance of this study to human pulmonary hypoplasia in short‐limb chondrodystrophy is discussed.
Developmental anomalies induced by all‐trans retinoic acid in fetal mice: I. Macroscopic findings
Authors: Yasuda Yoshiko , Okamoto Masaharu , Konishi Hiroyoshi , Matsuo Takuya , Kihara Takahide , Tanimura Takashi
Published: June 2005

The administration of a single dose of all‐trans retinoic acid on day 8 of gestation to pregnant mice, ICR strain, led to malformed fetuses in all of the litters. All‐trans retinoic acid (RA) was dissolved in olive oil and given in doses of 60 or 40 mg/kg of body weight. The control mice were given vehicle alone. Examination on day 18 of gestation of the fetuses exposed to 60 mg/kg showed various malformations, such as exencephaly, exophthalmus, micrognathia, agnathia, cleft palate, cleft lower lip, spina bifida, atresia ani, tail anomalies, agenesis of the kidneys, or hydronephrosis. In the fetuses exposed to 40 mg/kg, isolated cleft palate was much more common than in those exposed to 60 mg/kg. Double‐stained preparations of bone and cartilage showed cranio‐facial anomalies and axial skeletal anomalies: a‐ or hypogenesis of palatine or maxillary bones, tympanic ring, squamosal temporal bone or otic ossicles in cartilage, and fusion of basioccipital to basisphenoid and maxilla, zygomatic and mandibular bones; a‐ or hypogenesis of caudal vertebrae and supernumerary thoracic and lumbar vertebrae. These results indicate that anomalies comparable to those seen in the infants of mothers treated with isotretinoin, 13‐cis retinoic acid, during pregnancy can also be induced in mice and suggest that the site affected by RA may be neural crest cells, including those in the cephalic and caudal regions, and cells committed to somitic mesoderm in the trunk region.
Reproductive and teratogenic effects of fentanyl in Sprague‐Dawley rats
Authors: Fujinaga Masahiko , Stevenson Joseph B. , Mazze Richard I.
Published: June 2005

Female Sprague‐Dawley rats were administered fentanyl continuously using chronically implanted osmotic minipumps for 2 weeks before breeding and during the entire period of pregnancy. Three different fentanyl dosage regimens were emplyed, i.e., 10, 100, and 500 μg/kg/day. Reproductive indices were determined and the 1,046 offspring delivered at cesarean section were examined for external, visceral, and skeletal abnormalities. There were no major or minor reproductive abnormalities or teratogenic findings in any of the fentanyl‐treated groups. We conclude that fentanyl is devoid of adverse reproductive effects in this strain of rats up to dosages of 500 μg/kg/day administered by osmotic minipumps. From a methodologic point of view, osmotic minipumps facilitate study of the reproductive effects of narcotics as they allow delivery of dosages that ordinarily would not be tolerated without producing severe respiratory depression.
Congenital malformations and maternal smoking during pregnancy
Authors: Shiono Patricia H. , Klebanoff Mark A. , Berendes Heinz W.
Published: June 2005

The relationship between smoking during pregnancy and congenital malformations was studied in prospective studies of 33,434 live births in the Kaiser‐Permanente Birth Defects Study and 53,512 live births in the Collaborative Perinatal Project (CPP). In the Kaiser study, statistically significant positive associations (P < .05) were observed for ventral hernias, omphaloceles, and „other major gut abnormalities,”︁ but, for each comparison the estimates were based on one or two unexposed cases. Statistically significant negative associations were found for ventricular septal defects (odds ratio, 0.5 [95% confidnece interval, 0.2–0.96]), hydroceles (0.7 [0.6–0.9]), clubfoot (0.7 [0.6–0.9]), pigmented nevi (0.7 [0.6–0.9]), hemangiomas (0.8[0.7–0.98]) and Down syndrome (0.2[0.1–0.9]). To determine if the findings noted above were an artifact of multiple comparisons, seven of these nine malformations were analyzed by smoking status for women in the CPP. All but one of the associations were not confirmed in the CPP. Previously described associations between smoking and specific congenital malformations were also tested using data from the CPP. We conclude that smoking is unlikely to be responsible for a large increase in malformations at birth.
Uptake and blood pressure studies in the chick embryo following treatment with a teratogenic dose of dopamine
Authors: Borkowf Anne , Kolesari Gary L.
Published: June 2005

We report on the ventricular pressor response and regional (head, heart, and body) uptake of dopamine hydrochloride (DA) following topical application of a teratogenic dose to the stage 24 chick embryo. Embryos treated with DA exhibited a significant increase in mean ventricular blood pressure (MVBP) at 0.5 and 1 hour after treatment when compared to salinetreated control embryos. The time of the elevated MVBP correlated with the time of the peak uptake of DA in the embryonic heart. Even though the level of DA in the heart remained high for 9 hours, there was no measurable increase in blood pressure beyond 1.5 hours, suggesting unresponsiveness to DA or perhaps conversion of DA to its metabolites. These experiments have correlated a physiologic response of a known cardiovascular teratogen to its uptake in the embryo.
Morphogenesis of isotretinoin‐induced microcephaly and micrognathia studied by scanning electron microscopy
Authors: Irving Delilah W. , Willhite Calvin C. , Burk Dorothy T.
Published: June 2005

Isotretinoin ingestion during the first trimester of human pregnancy can induce malformations of the skull, ears, face, central nervous system, eyes, palate, lungs, circulatory system, limbs, and digits. A single oral dose of isotretinoin on day 8 of gestation in hamsters induces a similar syndrome of congenital malformation. The present study concerned scanning electron microscopic (SEM) observation of embryonic and fetal hamster craniofacial structures at 4, 8, 12, 24, 48, and 72 hr after administration of an oral dose of 50 mg/kg isotretinoin or an equivalent volume of the vehicle. The variability in development among control embryos recovered 4 hr after treatment precluded objective assessment of pathologic change by SEM at very early time points. Craniofacial damage was obvious within 8–12 hr of isotretinoin treatment, and it included hypoplasia of the maxillary and mandibular processes of the first branchial arch, a rudimentary second arch, and apparent collapse of the forebrain. Equivalent fusion between the lateral nasal process and the maxillary process and between the medial nasal process and the maxillary process in treated and control embryos accounts for the very low incidence of cleft lip observed in fetuses. The terminal microstomia was not associated with excessive merging or overgrowth of the first arch components. Hypoplasia of the first arch can account for retinoid‐induced macrostomia and microstomia.
Diplomyelia: Caudal duplication of the neural tube in mice
Authors: Cogliatti S. B.
Published: June 2005

Diplomyelia (duplication of the neural tube or spinal cord) was studied histologically in nine cases of T/+ mouse embryos at 10–15 days of gestation. Grüneberg investigated T/+ fetuses and interpreted the extra neural tube to be notochord, but a reexamination of this material demonstrated that the interpretation is incorrect. Diplomyelia is produced in the mutations Fused, Kinky, vestigial tail, homozygous Brachyury, and t‐haplotype t9 and in the new mutation, NM 529, described here.
Campomelic syndrome: Concepts of the bowing and shortening in the lower limbs
Authors: Lazjuk G. I. , Shved I. A. , Cherstvoy E. D. , Feshchenko S. P.
Published: June 2005

A comprehensive study (bone roentgenography, arteriography, gross dissection, microscopy of the long bones, and biochemical study of proteoglycan‐aggregates in the hyaline cartilage) of the lower limbs in a fullterm stillborn with the campomelic syndrome was performed. Hyaline cartilage immaturity of the long bones, dysplasia of growth plates, focal shaft dysplasia, and a defective length of the posterior femur and crus muscles were revealed. The genesis of the bowing and shortening of the long bones in the lower limbs is discussed.
Embryotoxicity of sex steroidal hormones in nonhuman primates: II. Hydroxyprogesterone caproate, estradiol valerate
Authors: Hendrickx A. G. , Korte R. , Leuschner F. , Neumann B. W. , Poggel A. , Binkerd P. , Prahalada S. , Günzel P.
Published: June 2005

Two sex steroid compounds which have been used clinically for parenteral supportive therapy of pregnancy were examined for embryotoxic effects in rhesus and cynomolgus macaques. Hydroxyprogesterone caproate (HPC) alone or in combination with estradiol valerate (EV) were administered intramuscularly (i.m.) to pregnant monkeys at 7‐day intervals between 20 and 146 days of gestation and fetuses were examined following cesarean section at 150 ± 2 days. HPC alone was tested in both species at doses ranging from 0.01 × to 10 × the human dose equivalent (HDE); only rhesus monkeys were exposed to the HPC + EV combination at 0.1 × to 10 × HDE. Total embryole‐thality resulted following the administration of HPC alone and combined with EV at 1 × and 10 × HDE in rhesus monkeys; the level of abortions in cynomolgus monkeys exposed to HPC (0.1 × to 1 × HDE) was comparable to controls. A small number of nonspecific malformations and developmental variations observed in cynomolgus fetuses after HPC exposure were considered to be incidental findings. No anomalies were found in surviving rhesus monkey fetuses treated with HPC + EV. The results indicate that long‐term in utero exposure to the progestin, HPC, alone or in combination with EV in rhesus and cynomolgus monkeys, is embryolethal but not teratogenic at doses up to ten times the human therapeutic dose.
Anatomical defects associated with a feathering mutant (Ottawa naked) in domestic fowl
Authors: Fulton J. E. , Wenger B. S. , Wenger E. L. , Crawford R. D.
Published: June 2005

An autosomal recessive mutation (Ottawa naked, nk) that causes abnormal feathering, fusion of the third and fourth toes, and low viability has been reported previously in the chicken. In the present study mutant individuals were examined from three different stocks: the original one in which the mutant was found and two outbred F2 stocks. Defects of the tail region were observed in all mutants from the original stock (20/20) and in 64% (16/25) of the mutants produced from the outcrossed stocks. The severity of the defects ranged from mild distortion and scoliosis of the coccygeal vertebrae to absence of all vertebrae from the lumbosacral level caudad. Forty percent (16/40) of the mutants from the original stock lacked caudal portions of the kidneys to varying degrees. Edematous areas were observed in 22% (15/67) of the embryos examined at 14 days of incubation. Other defects observed in the mutant embryos but not studied in detail are abnormal patterning or absence of scales, absence of the caudal spinal cord in embryos with severe rumplessness, and failure of the three metatarsal bones to fuse into a single element. Since all structures affected in the mutants differentiate primarily from or may be dependent upon the mesoderm, it is suggested that the site of gene action lies within this germ layer. A decrease was observed in both incidence and severity of the various defects following outcrossing, which suggests the presence of modifiers that influence the expression of the trait.
Congenital malformations detected in 731 autopsies of children aged 0 to 14 years
Authors: Mattos Tamara C. , Giugliani Roberto , Haase Hugo B.
Published: June 2005

A retrospective study of 731 autopsies of children aged O to 14 years, performed in the Pathological Anatomy Service of the University Hospital of Porto Alegre from 1977 to 1982, was carried out to determine the frequency, type, and seriousness of congenital malformations. The subjects were divided into five age ranges: stillborn (6), 0 to 24 hours (42), 1 to 30 days (50), 1 to 12 months (24), and 1 to 14 years (9). The malformations were classified as single or multiple (presence of two or more independent defects), and their contribution to death was evaluated. Congenital malformations were detected in 131 autopsies (18%). In most cases the defects were single (91), and the most common ones involved the cardiovascular system (37) and the genitourinary system (21). In the patients with multiple malformations (40), the cardiovascular system (24) and the genitourinary system (19) were also most frequently involved. Defects of the osteoarticular system were also frequently encountered in patients with multiple defects (25), although most of them were deformations caused by mechanical factors. Proportionally, congenital malformations were most frequently detected in the 0 to 24 hour range, which also included the highest proportion of multiple defects in relation to single ones (1:1). Congenital malformations were considered responsible for death in 76% of the 131 cases (87% of the multiple defects patients and 60% of the single defect patients). We believe that the data collected in the present study may contribute to a better understanding of the role played by congenital malformations in child mortality.
Relative potency of four ethylene glycol ethers for induction of paw malformations in the CD‐1 mouse
Authors: Hardin Bryan D. , Eisenmann Carol J.
Published: June 2005

Time‐mated CD‐1 mice were orally dosed on gestation day 11 (plug = 0) with distilled water (control) or one of four glycol ethers at a dose of 4 mmol/kg: ethylene glycol monomethyl ether (EGME, 304 mg/kg), ethylene glycol dimethyl ether (EGdiME, 361 mg/kg), diethylene glycol dimethyl ether (diEGdiME, 537 mg/kg), triethylene glycol dimethyl ether (triEGdiME, 713 mg/kg). Fetuses were collected on gestation day 18, weighed, and examined for gross external malformations. Fetuses were cleared and stained to examine paws. There were no signs of treatment‐related maternal toxicity, and intrauterine survival was unaffected by glycol ether treatments. Fetal body weights were significantly reduced only in litters treated with EGdiME. There was no treatment‐related pattern of gross external malformations other than paw defects. Only triEGdiME failed to produce a significant incidence of malformations. Paw defects were present in 87.5% of EGME‐treated litters (68.5% of fetuses), 86.7% of EGdiME‐treated litters (33.8% of fetuses), and 77.8% of diEGdiME‐treated litters (39.7% of fetuses). Hindpaw defects predominated over forepaw, and syndactyly was the most common malformation. The incidences of oligodactyly and short digits were also significantly increased. The similarity of malformations produced by these methyl‐substituted glycol ethers is proposed to be attributable to in vivo conversion to a common teratogen, methoxyacetic acid.
TCDD‐Induced hyperplasia of the ureteral epithelium produces hydronephrosis in murine fetuses
Authors: Abbott B. D. , Birnbaum L. S. , Pratt R. M.
Published: June 2005

TCDD (2,3,7,8‐tetrachlorodibenzo‐p‐dioxin) has been recognized as a kidney and palate teratogen for many years. The etiology of the kidney abnormality has not been revealed, and there is some confusion about the exact nature of the defect. This study examines C57BL/6N fetal mouse kidneys from day 14 of gestation through day 17. Pregnant females received a single dose of 0 or 12 μg TCDD/kg by gavage on day 10 of pregnancy. Fetal urinary systems were examined on days 14, 15, 16 (A.M.), 16 (P.M.), and 17 (P.M.). The patency of the ureteric lumen was examined by injection of dye into the bladder. TCDD treatment did not delay or prevent breakdown of the ureteric membrane between days 15 and 16. On days 16 through 17, the ureteric lumina of TCDD‐exposed fetuses were narrow and tortuous when compared to the control lumens. Sections of ureter were observed by light microscopy. On day 15 the lumina of TCDD‐exposed ureters were occluded by epithelial cells. As a result of hyperplasia of the ureteric luminal epithelium, hydroureter and hydronephrosis became pronounced by day 17. We conclude that the kidney abnormality induced by TCDD is true hydronephrosis, which is defined as the accumulation of urine in the kidney due to obstructed outflow.
TCDD alters the extracellular matrix and basal lamina of the fetal mouse kidney
Authors: Abbott B. D. , Morgan K. S. , Birnbaum L. S. , Pratt R. M.
Published: June 2005

The teratogenic effects of the dioxin 2,3,7,8‐tetrachlorodi‐benzo‐p‐dioxin (TCDD) have previously been studied in several species, and hydronephrosis has been reported to be a frequent abnormality in near‐term fetuses. C57BL/6N female mice, given 12 μg/kg TCDD, P.O., on day 10 of gestation were killed on days 14, 15, and 16; fetal kidneys were collected and prepared for either immunofluorescent localization of several extracellular matrix components (ECM) or transmission electron microscopy (TEM). The TCDD‐treated and control kidneys showed the same pattern of staining for fibronectin, but TCDD‐treated kidneys displayed a diminished overall intensity. The intensity of laminin and type IV collagen immunofluorescence also appeared to be decreased, and deviations in the pattern of antibody binding were detected for differentiating TCDD‐treated nephrons. Binding of the laminin antibody to the basal lamina was decreased in the parietal layer of Bowman's capsules in more advanced stages of differentiation. TEM analysis focused on the basal lamina of the tubules and Bowman's capsule. In TCDDD‐exposed kidneys, ECM componets adjacent to differentiating nephrons were less abundant, and the basal lamina of the developing Bowman's capsules had a diminished lamina densa. The earliest nephrons to develop display these defects and comprise the first functional filtration units of the metanephric kindney. These ultrastructural changes noted in TCDD‐exposed nephrons may promote proteinuria, a condition normally observed in the developing kidney when the filtration barrier is immature.
A stage‐dependent effect of ethanol on 9.5‐day rat embryos grown in culture and the role played by the concomitant rise in osmolality
Authors: Clode A. M. , Pratten M. K. , Beck F.
Published: June 2005

The effects of ethanol on the rat embryo undergoing organogenesis in vitro have been studied. We have shown that embryopathy is dependent on the stage of development at which explanted embryos were treated. The early neural plate (presomite) stage was highly sensitive to a 4‐hour exposure of 300 mg/% ethanol, whereas embryos explanted 5 hours later, at the late head‐fold (two to six somites) stage grew normally under the same conditions. We have also established that raised serum osmolality, associated with ethanol in serum, is responsible for some but not all of the teratogenic effect. This was shown by mimicking the rise in osmolality with hyperosmotic serum, containing glycerol, NaCl, or concentrated Hanks' salts. Dilution of this osmotic effect by the addition of distilled water in part reversed these embryopathic effects.
Valproic acid
Authors: Lammer Edward J. , Sever Lowell E. , Oakley Godfrey P.
Published: June 2005

Valproic acid use during pregnancy results in an absolute risk for spina bifida of 1–2%. This increased risk is comparable to the recurrence risk for neural tube defects and warrants informed counselling and access to prenatal diagnosis. There is no substantial evidence that valproic acid use increases the risk for other specific major malformations above the increased risk due to maternal epilepsy. Valproic acid may cause a characteristic pattern of minor facial malformations. Further definition and confirmation are required, and the magnitude of the risk needs to be determined. There are inadequate data to assess the magnitude, if any, of the risks for postnatal growth abnormalities and developmental disabilities associated with the use of valproic acid during pregnancy. Birth‐defect monitoring programs and international collaboration among the staffs of monitoring programs played a major role in determining that valproic acid is a human teratogen.
Amyoplasia congenita‐like condition and maternal malathion exposure
Authors: Lindhout D. , Hageman G.
Published: June 2005

This report concerns an amyoplasia‐like condition in a case with maternal exposure to malathion during the 11th to 12th week of pregnancy. Malathion is an agent acting on the neuromuscular system. The possibility of a causal association is discussed.
Cytotoxic effects of ethylene glycol monomethyl ether in the forelimb bud of the mouse embryo
Authors: Greene J. A. , Sleet R. B. , Morgan K. T. , Welsch F.
Published: June 2005

The role of cytotoxicity in digital maldevelopment in CD‐1 mouse embryos was examined following dosage with ethylene glycol monomethyl ether (EGME) on gestation day (gd) 11. Patterns of cell necrosis in the forelimb buds of embryos collected from dams given EGME orally at doses of 100, 250 or 350 mg/kg were characterized by staining with Nile blue A. Cell death was induced in the mesenchymal tissue and to some extent in the limb bud ectoderm, including the apical ectodermal ridge in a dose‐related manner. The area of preaxial physiological cell necrosis was enlarged by EGME, and the shape of the limb buds was altered 24 hr after treatment. Preaxial tissue and the predigital chondrocyte condensations were reduced or missing following 250 and 350 mg EGME per 1 kg. Light and electron microscope evaluations of forelimb buds revealed the presence of phagocytic vacuoles and condensed, fragmented cytoplasm, which indicate cytotoxicity, as early as 2 hr following EGME, a maximum effect being observed 6 hr after the dose was administered. Although the severity of the cytotoxic response appeared to be dose‐related, comparison with the incidence of digital malformations in near‐term fetuses indicates that the loss of mesenchymal tissue is partially compensated for as formation of the limb progresses.
Developmental toxicity of ethanol in Drosophila melanogaster
Authors: Ranganathan Sulabha , Davis D. Gale , Hood Ronald D.
Published: June 2005

Ethanol was tested for teratogenicity in Drosophila melanogaster. Treatment consisted of rearing the fly larvae in media containing initial ethanol concentrations of 0%, 4%, 8%, or 14% by weight. Emerging flies were inspected for gross malformations. A low frequency of malformations was seen among controls (0.82%), increasing to 10.36% of emerging adults at the highest ethanol dose. The most common malformation involved the legs (segments missing or distorted or complete absence) and wings (uninflated, distorted, or absent). Less frequent defects included fused or missing mouth parts and missing halteres. Also, by exposing staged larvae to ethanol and examining the emerging flies, developmental stage sensitivity of Drosophila was investigated in terms of timing of treatment initiation. The results suggested that the incidence of defects increased with length of exposure. These results support the assumption that ethanol itself is the causative agent in ethanolinduced developmental toxicity and further support the use of Drosophila for developmental toxicity screening.
Experimental hyperphenylalaninemia in the pregnant guinea pig: Possible phenylalanine teratogenesis and p‐chlorophenylalanine embryotoxicity
Authors: Kronick Jonathan B. , Whelan Donald T. , McCallion David J.
Published: June 2005

Maternal hyperphenylalaninemia (HPH) due to deficient phenylalanine (Phe) hydroxylation is a recognized human teratogen associated with an increased incidence of intrauterine growth retardation, microcephaly, congenital heart disease, and mental retardation. There are no previous reports of experimental HPH during organogenesis. Sustained HPH was produced in pregnant guinea pigs by adding 3.5% Phe and 1.0% para‐chlorophenylalanine (pCPA), an inhibitor of Phe hydroxylase, to standard guinea pig chow. Animals consumed the supplemented test diets from gestation day 1 until killed on gestation day 17. Examination of day 17 embryos revealed that embryonic mortality was associated only with maternal pCPA administration and was independent of the degreee of maternal HPH. Embryonic malformation was associated with maternal HPH as well as maternal pCPA administration. Both maternal HPH and pCPA administration were associated with embryonic growth retardation. There was no association between maternal food intake or plasma tyrosine levels and embryonic abnormality or mortality. Both Phe and tyrosine were found to be concentrated in gestation day 17 yolk sac fluid when compared to maternal plasma Phe and tyrosine. The association of embryonic malformation and maternal HPH is consistent with human data. The embryotoxicity of pCPA requires further study and highlights the necessity of appropriate controls in models of experimental HPH.
Atelencephalic microcephaly: Craniofacial anatomy and morphologic comparisons with holoprosencephaly and anencephaly
Authors: Siebert Joseph R. , Kokich Vincent G. , Warkany Josef , Lemire Ronald J.
Published: June 2005

This is the first detailed report of the craniofacial anatomy of atelencephaly. Comparisons were made with a control specimen and others with holoprosencephaly, anencephaly, and anencephaly with holoprosencephalic facial features. In the atelencephalic fetus, severe microcephaly, flattened calvaria, and partial synostosis of the metopic suture were apparent. The cranial fossae were much smaller than usual; lesser wings of the sphenoid were folded into a rounded basal mass. Facial features were pronounced, and orbits were hyperteloric, lowset, and rounded. Ethmoidal cartilages, nasal bones, and maxillary structures were distorted and elongated. The secondary palate was displaced inferiorly and cleft. Because major components of the craniofacial complex were generally present, although misshapen, changes in the atelencephalic skull seem to be deformations rather than malformations. Differences in the cranial morphology of associated disorders–holoprosencephaly and anencephaly–can be construed as aberrations of separate developmental fields. Relationships between atelencephaly and these fields are unclear.
Atypical malformations in an infant exposed to warfarin during the first trimester of pregnancy
Authors: Ruthnum P. , Tolmie J. L.
Published: June 2005

We report a dysmorphic female infant whose mother took warfarin in therapeutic doses during the first 6 weeks of pregnancy. At birth the infant was small for dates and had a triangular facial appearance, micrognathia, microglossia, short fingers and toes, and hypoplastic nails. A skeletal survey revealed hypoplastic distal phalanges in the fingers and toes; there was no epiphyseal stippling. The pattern of malformations present in this infant may either represent the earliest teratogenic effects of warfarin or the fortuitous association of exposure to warfarin and unexplained dysmorphic features.
Structure– toxicity relationships of the tetramethylated tetralin and indane analogs of retinoic acid
Authors: Howard W. Brian , Willhite Calvin C. , Sharma R. P.
Published: June 2005

The teratogenicity of retinoids containing either tetramethylated tetralin (Ro 13‐6307 or Ro 13‐2389) or tetramethylated indane (Ro 13‐4306) ring system substitutions was compared to the teratogenic potency of all‐trans‐retinoic acid. Single oral doses, administered to Syrian Golden hamsters at 10:00 A.M. on day 8 of gestation, induced a syndrome of malformations identical to that induced by treatment with all‐trans‐retinoic acid. These retinoids failed to induce signs of maternal hypervitaminosis A at doses associated with a significant teratogenic response. The tetramethylated tetralin retinoids and indane retinoid were 18 and 2.4 times as embryotoxic on a molar basis, respectively, as all‐trans‐retinoic acid. Introduction of a supplementary ring in the side‐chain restricted polyene chain flexibility and maintained the hydrophobic plane of the chain. The present results are consistent with previous studies showing that the presence of or biotransformation to a free acid congener was necessary for retinoid teratogenic activity in hamsters and that increasing conformational restriction of acidic retinoids increased teratogenic potency.
Acardiac fetus in a triplet pregnancy
Authors: Landy Helain J. , Larsen John W. , Schoen Michael , Larsen Melissa E. , Kent Stephen G. , Weingold Allan B.
Published: June 2005

The acardiac monster represents one of the most severe but rare congenital anomalies. It occurs only in multiple gestations associated with vascular anastomoses between the affected fetus and its co‐twin. The prenatal diagnosis of an acardiac fetus must be suspected in any multiple gestation in which cardiac activity cannot be documented sonographically in a growing fetus. We report an acardiac fetus occurring in a spontaneously conceived triplet pregnancy. A review of the literature, including pathogenetic theories and sonographic reports, is discussed.
Evaluation of a temporal increase in ventricular septal defects: Estimated prevalence and severity in northeastern New York, 1970–1983
Authors: Spooner Eric W. , Hook Ernest B. , Farina Matthew A. , Shaher Reda M.
Published: June 2005

A marked increase or “epidemic” in ventricular septal defects (VSD) in recent years has been reported by the Center for Disease Control. Many pediatric cardiologists believe that this increase is simply a reflection of more intensive diagnosis and evaluation of infants throughout the country. Yet to our knowledge there has been no objective evidence for this explanation. We evaluated this possibility by considering records on live births occurring in 1970–1983 in the counties surrounding Albany, New York. In that period a single group of pediatric cardiologists has been evaluating all infants with suspected or confirmed cardiac defects in this area. We limited this analysis to ventricular septal defects unassociated with any cardiac syndrome complex. Thus, VSDs occurring as part of cyanotic heart disease or other complex cardiac “syndromes” were excluded. Consistent with the reported national trend, the estimated prevalence rate of ventricular septal defects diagnosed under 1 year of age in this period has increased from 1.0 per 1,000 live births in 1970 to 4.0 per 1,000 in 1983. Several factors indicate that this rise resulted from more intensive diagnoses at earlier ages in this period: (1) for all patients with VSD, the median age at diagnosis fell from 251 days in 1970 to 25 days in 1983; (2) the most severe VSDs (based on an index derived from pathophysiologic data) were constant from 1972 afterward at an estimated rate of about one per 1,000 (although the estimated rates were lower than this in 1970 and 1971) while the milder defects rose from an estimated rate under 0.5 per 1,000 to over 3.0 per 1,000 in this interval; (3) changes in diagnostic criteria for VSD occurred, so that a murmur thought to be innocent in 1970 might, if heard later in the interval, lead to a diagnosis of VSD; (4) echocardiography began in the latter part of the interval, and the sharpest increase in the estimated rate of VSD occurred after its introduction in 1977 in our area; (5) the prevalence of complex VSD remained relatively stable throughout the period, being 0.4 per 1,000 live births in the first 3 years of the study and 0.5 per 1,000 in the last 3 years; (6) there was an increase in diagnoses of spontaneous closure of VSDs from 7% in 1970 to 32% in 1983. All of these factors are consistent with the view that the increase of VSD resulted from changes in ascertainment due to changes in methods and criteria for diagnosis of this defect.
Strain differences in teratogenic susceptibility to trypan blue between WM and BDIX rat strains
Authors: Hoshino Kiyoshi , Oda Sen‐Ichi , Fukui Yoshihiro , Kameyama Yoshiro
Published: June 2005

Female rats of WM (Wistar‐Mishima)/Nem strain were mated with WM/Nem (group W) or BDIX/Nem males (group WB), and BDIX/Nem females were mated with BDIX/Nem (group B) or WM/Nem males (group BW). On day 8 of gestation, pregnant females were treated intraperitoneally with 1% aqueous solution of trypan blue at a dose of between 20 and 120 mg/kg of body weight. On day 20 of gestation, fetuses were examined for external, visceral, and skeletal malformations.

In group W, fetal mortality increased dose dependently at doses higher than 20 mg/kg, and incidences of external, visceral, and skeletal malformations were significantly higher than control at doses of 30 mg/kg and more. In group B, fetal mortality and the incidence of external malformations were significantly higher than control only in the group treated with 120 mg/kg, and no significant increase of visceral and skeletal malformations was shown. It was confirmed that BDIX strain is much more resistant to trypan blue teratogenicity than WM strain.

In group BW, nearly the same teratogenic effects were shown as in group W in terms of fetal mortality and incidence of malformations. However, in group WB, teratogenic effects were not so remarkable as in group BW, suggesting patroclinous effects in teratogenic susceptibility to trypan blue. In group BW, sex differences in teratogenic susceptibility were found; male fetuses were more susceptible to trypan blue than females.
Niridazole metabolism by rat embryos in vitro
Authors: Fantel A. G. , Person R. E. , Tracy J. W. , Juchau M. R.
Published: June 2005

We report the results of studies on the reductive activation of the schistosomicidal agent, niridazole (NDZ). Intact rat embryos in vitro reduced this compound, generating a stable metabolite in the presence of 5% O2. By contrast, embryo and yolk sac homogenates or liver microsomes appeared to require anaerobiasis. Malformation incidence–specifically, axial asymmetry–showed a strong correlation with nitroreductase activity rates when the latter were modulated by oxygen tension.

Data presented here suggest that when embryos are exposed to NDZ under conditions of low oxygen in vitro, redox cycling ensues with molecular oxygen serving to oxidize early reduction products. This process continues, regenerating the parent compound until oxygen is depleted locally. The basis of this localized depletion is unknown, but inability of the immature supply system to replete oxygen or demand by precociously aerobic tissues may be involved. Once local anaerobiasis is attained, further reduction could generate toxic metabolites capable of covalently binding cellular macromolecules. Localized hypoxia represents another potential mechanism of dysmorphogenesis.
Time‐lapse photographic study of neural tube closure defects caused by xylocaine in the chick
Authors: Lee H. , Bush K. T. , Nagele R. G.
Published: June 2005

Sequential changes in the morphology of early chick embryos were, for the first time, photographically recorded. Embryos were explanted at stage 8 (four‐somite) or 9– (six‐somite) of development using New's technique and grown in nutrient medium (thin albumen) with or without a teratologic dose (200 μg/ml) of xylocaine. They were photographed using a Nikon Diaphot inverted microscope equipped with both phase‐contrast optics and photomicro‐graphic accessories maintained in an incubator. It was found, among other things, that a characteristic neural tube closure defect often seen in the midbrain and anterior portion of the hindbrain of xylocaine (200 μg/ml)‐treated chick embryos was a consequence of failure of the neural tube to withstand the tension generated by the rapidly expanding cephalic region, which occurred, regardless of the stage at explantation, when corresponding control embryos had advanced to stage 10+ (11‐somite) of development.
Genetics of susceptibility to 6‐aminonicotinamide‐induced cleft palate in the mouse: Studies in congenic and recombinant inbred strains
Authors: Karolyi Jill , Erickson Robert P. , Liu Sharon
Published: June 2005

In a search for genetic differences in susceptibility to cleft palate, congenic and recombinant inbred strains of mice were treated with 6‐aminonicotinamide or control injections. Of six loci tested, only the chromosome segment marked by N‐acetyl transferase was found to affect susceptibility to 6‐aminonicotinamide‐induced cleft palate. This chromosome segment is known to affect glucocorticoid‐induced cleft palate and phenytoin‐induced cleft lip with or without cleft palate in these strains of mice.
Histological comparison of the effects of the splotch gene and retinoic acid on the closure of the mouse neural tube
Authors: Kapron‐Brás Carolyn M. , Trasler Daphne G.
Published: June 2005

The splotch gene (Sp) and all‐trans retinoic acid (RA) interact to cause spina bifida in mouse embryos. To investigate the mechanisms of action of the two, the spinal regions of Sp homozygotes, RA‐treated wild‐type, and control wild‐type embryos were examined histologically by light microscopy on day 9 of gestation. The mean numbers of cells per section in the neural tube, mesoderm, and notochord were determined, along with the percentages of mitotic and pyknotic nuclei and the numbers of migrating neural crest cells. As well, the effect of Sp and RA on the extracellular matrix was studied histochemically with Alcian blue staining for glycosaminoglycans. The main defect in Sp homozygotes was a marked reduction in the number of migrating neural crest cells and the amount of extracellular matrix around the neural tube. Retinoic acid, on the other hand, caused a number of disruptions in the embryo, including abnormalities in the position of the notochord and the shape of the neural tube. Sp and RA delay neural tube closure and thus cause neural tube defects, through different mechanisms. However, the combined effects of the gene and teratogen on the embryo lead to a greater inhibition of neural tube closure than when either is present separately.
Retinoic‐acid‐induced limb malformations resulting from apical ectodermal ridge cell death
Authors: Sulik Kathleen K. , Dehart Deborah B.
Published: June 2005

Pregnant C57B1/6J mice were treated with single oral doses of 400 mg/kg 13‐cis retinoic acid (RA, isotretinoin, Accutane) in sesame oil at 9 days, 12 hours postfertilization. Among the live 16‐day fetuses from ten treated mothers, 46% (26/56) had limb malformations including small fifth digits, preaxial and/or postaxial oligodactyly, and preaxial or postaxial polydactyly. Fetuses with preaxial digit deficiencies also had absent or malformed radii. Scanning electron microscopic and light microscopic analyses of the sequence of developmental alterations leading to these malformations demonstrated abnormalities in the apical ectodermal ridge (AER). Excessive cell death in the AER of 27–30 somite enbryos (12 hours after treatment) appears to play a major role in the pathogenesis of the limb malformations observed. Previous investigations of retinoid‐induced limb malformations have concentrated on later exposure times. Evidence from this study in addition to that from previous teratologic and clinical investigations has led to the hypothesis that 13‐cis RA results in excessive cell death in regions of programmed cell death and subsequent malformations of affected regions.
Developmental toxicity evaluation of Bendectin in CD rats
Authors: Tyl Rochelle W. , Price Catherine J. , Marr Melissa C. , Kimmel Carole A.
Published: June 2005

Bendectin, composed of doxylamine succinate and pyridoxine HCl (1:1), is an antinauseant previously prescribed for nausea and vomiting during pregnancy. The present study examined the maternal and developmental effects of Bendectin (0, 200, 500, or 800 mg/kg/day, po) administered to timed‐pregnant CD rats (36–41/group) during organogenesis (gestational days [gd] 6–15). At death (gd 20), all live fetuses were examined for external, visceral, and skeletal abnormalities. At 500 and 800 mg/kg/day, maternal toxicity included reduced food consumption during treatment and for the gestation period, increased water consumption in the posttreatment period, reduced weight gain during treatment, and sedation; water consumption was reduced during treatment and for the gestation period, and maternal mortality (17.1%) was observed only at the high dose. Developmental toxicity included reduced prenatal viability (800 mg/kg/day) and reduced fetal body weight/litter (500 and 800 mg/kg/day). In addition, reduced ossification of metacarpals (800 mg/kg/day), phalanges of the forelimbs (500 and 800 mg/kg/day), and of caudal vertebral centra (all doses) was observed. No increase in percent malformed live fetuses/litter was observed. The proportion of litters with one or more malformed fetuses was higher than vehicle controls only at 800 mg/kg/day, with short 13th rib (to which the test species is predisposed) as the predominant observation. By contrast, a positive control agent (nitrofen, 50 mg/kg/day, po, 14 dams) produced 85% malformed fetuses/litter with the predominant malformation being diaphragmatic hernia. In conclusion, the incidence of litters with one or more malformed fetuses was increased only at a dose of Bendectin which produced maternal mortality (17.1%) and other indices of maternal and developmental toxicity (see Discussion).
Physical anomalies and developmental delays in nonhuman primate infants exposed to weekly doses of ethanol during gestation
Authors: Clarren Sterling K. , Astley Susan J. , Bowden Douglas M.
Published: June 2005

Ethanol was orally administered once per week to 54 gravid pigtailed macaques (Macaca nemestrina) in doses of 0.0, 0.3, 0.6, 1.2, 1.8, 2.5 or 4.1 gm/kg from the 1st week in gestation or in doses of 2.5, 3.3, or 4.1 gm/kg from the 5th week. Mean maternal mean peak plasma ethanol concentrations (MPPEC) ranged from 24 ± 6 mg/dl at the 0.3 gm/kg dose to 549 ± 71 mg/dl at the 4.1 gm/kg dose. Thirty‐three viable infants were followed from birth to 6 months of age and assessed for growth, health, congenital anomalies and developmental rate. Facial anomalies, growth deficiency, or central nervous system dysfunction were found in 57% of the alcohol‐exposed animals. No animal showed all the features of the human fetal alcohol syndrome. Ten of the twelve animals (83%) with mean MPPEC above 140 mg/dl had evidence of a teratogenic impact. The animals with full gestational exposure to ethanol and mean MPPEC between 140 and 249 mg/dl had much more severe and consistent cognitive abnormalities than the animals with delayed gestational exposures, even though the latter were exposed to mean MPPEC between 260 and 540 mg/dl. Conclusions from this study included: 1) ethanol‐related behavioral teratogenesis occurred without accompanying physical anomalies, 2) measurable teratogenic effects from weekly exposures occurred only at intoxicating doses of ethanol, and 3) early gestational exposure to ethanol appeared to be more damaging to cognitive function than later and considerably greater alcohol exposure.
Developmental variation of the diaphragm and liver in fischer 344 rats
Authors: Lu C. C. , Mull R. L. , Lochry E. A. , Christian M. S.
Published: June 2005

The nature and frequency of a developmental variation of the diaphragm and liver in Fischer 344 rats are described. Totals of 20, 98 and 55 (25 for caesarean‐sectioning and 30 for natural delivery) mated female rats were used for Experiments 1, 2, and 3, respectively. Each rat was intubated (gavage) with either an aqueous suspension of 0.2% METHOCEL®, 0.25% methyl cellulose, or distilled water as a single daily dose from days 6 through 15 (inclusive) of gestation. On the 20th day of gestation, a caesarean‐section was performed, and the uterine contents of each rat were examined. A gross necropsy was performed on the pups of 30 mated female rats on day 21 postpartum. The visceral examinations conducted on these fetuses and pups included an evaluation of a developmental variation in the diaphragm and liver. The variation consisted of a thin fibrous central tendon of the diaphragm with an area of liver (0.5–3 mm diameter) that protruded within the thin central tendon of the diaphragm. The incidence (mean % of fetuses affected per litter) of the diaphragm/liver developmental variation was 9% and 11% for METHOCEL®‐ and water‐treated groups, respectively. A thin central tendon was present in the diaphragm of all fetuses of methyl cellulose‐treated dams; these fetuses did not have a raised area of the liver present within the diaphragm's central tendon. However, in a few weaned pups of the Fischer 344 rats in this study, liver protruded within the central tendon of the diaphragm. The incidence of the diaphragm/liver developmental variation differed with the vehicles used, and it has never been observed in the Sprague‐Dawley or Wistar rat fetuses examined by us.
Glutathione status and the incidence of neural tube defects elicited by direct acting teratogens in vitro
Authors: Harris Craig , Stark Kevin L. , Juchau Mont R.
Published: June 2005

Valproic acid (VPA), cytochalasin D (CD) and 7–hydroxy–2–acetylaminofluorene (7–OH–AAF) each caused abnormal closure of the anterior neuropore in rat embryos cultured in vitro in the absence of an exogenous bioactivation system. Morphological comparisons showed that although all three compounds prevented normal neural tube closure, each did so in a distinctive manner. Modulation of GSH in cultured rat conceptuses was evaluated to determine whether common responses occurred relative to the ability of different chemicals to elicit neural tube defects. Malformation incidence in embryos (10–14 somites) varied widely following exposure to CD (44%), 7–OH–AAF (29%) or VPA (17%). The incidence of CD‐elicited malformations was increased by 50% following GSH depletion by L‐buthionine‐S, R‐sulfoximine (BSO) and was decreased by nearly 60% when the cysteine pro‐drug 2–oxothiazolidine–4–carboxylate (OTC) was added to the culture medium. GSH modulation also exerted significant effects on the incidence of abnormal neurulation caused by VPA or 7–OH–AAF. A relatively low incidence of open neural tubes produced by VPA or 7–OH–AAF alone was shown to be a function of the state of maturation in the embryos. Conceptuses cultured in the presence of VPA or 7–OH–AAF from an earlier gestational age (6–10 somites) showed 2–3 fold increases in the number of embryos with open neural tubes. Differential alterations in protein and DNA content were observed among embryos and yolk sacs after various treatments indicating possible differences in the site of embryotoxicity. These results demonstrate the role of GSH status on the capacity of three chemically diverse compounds to elicit abnormal neurulation in cultured rat embryos and suggest some possible mechanisms by which normal neurulation may be compromised.