bluuebunny/crossref_metadata_2025 huggingface dataset:
Anatomical Investigation of 39 Cases of Congenital Duplication in Calves
Authors: HIRAGA Takeo , ABE Mitsuo , IWASA Kenji , TAKE‐HANA Kazushige
Published: May 2008

Abstract The anatomical features of congenital duplication in the bovine calf encountered in 39 cases over eleven years in Hokkaido were investigated macroscopically. Among the animals studied, 14 were male, 20 female and 5 of unknown gender, and the anomaly was noted in 35 Holstein‐Friesians, 3 Japanese Blacks and 1 Hereford.

The duplications observed in this study were classified by four types: free asymmetrical, 4 (all 4 acardius); attached symmetrical, 25 (14 cranial duplication, 2 dipygus, 2 dicephalus dipygus, 5 thoracopagus, and 2 pygopagus); attached asymmetrical, 6 (1 parasitic dipygus, 4 notomelia, and 1 pygomelia); and miscellaneous, 4. The four acardii were holoacardii amorphi covered with skin and hair. Cranial duplication was subdivided into five types based on the number of eyes and ears. In symmetrical twins the anterior part of the body was affected in 16 out of 25 cases (64%), the posterior part in 2 out of 25 (8%) and both the anterior and posterior in 7 out of 25 (28%). All were mirror‐image duplicates on the various planes, and in some the internal organs had a center of symmetry. All four notomeli calves were female. Among the miscellaneous duplications, three were of the genital organs (male 1, and female 2) and one was a spinal cord duplication.
Development of Cerebellar Hypoplasia in Jaundiced Gunn Rats: A Morphological Study
Authors: TAKAGISHI Yoshiko
Published: May 2008

Abstract The developmental process of cerebellar hypoplasia was investigated in homozygous (j/j) Gunn rats (born from heterozygous (+/j) mothers) with hereditary hyperbilirubinemia by light microscopy of Epon‐embedded sections and Golgi preparations, electron microscopy and immunofluorescence with anti‐SlOO protein immune serum. No abnormalities were found in the cerebellar cortex at postnatal day 1. But at day 3, some Purkinje cells contained whorled membranous inclusions, enlarged Golgi cisternae and vesicles, and/or dilated endoplasmic reticulum. Membranous inclusions filled the cytoplasm of a large number of Purkinje cells at day 10. These severely damaged Purkinje cells died and disappeared by day 30. The remaining Purkinje cells contained only a few membranous inclusions at day 30. At the adult stage, membranous inclusions were no longer detected in the remaining Purkinje cells. In these Purkinje cells, the dendrites were poorly developed and primitive synaptic junctions with parallel fibers were occasionally found on the dendritic shafts even at the adult stage. The perisomatic processes were often present on the remaining Purkinje cell soma from day 18 to the adult stage and were in synaptic contact with climbing fibers.

The external granular layer was thinner in j/j than in +/j rats without hyperbilirubinemia at days 12 and 15 and disappeared at day 18 in j/j rats, i.e., earlier in j/j than in +/j rats. The molecular layer was thinner at day 10 and became slightly thicker thereafter. Cells in the molecular layer were scarce after day 12. The internal granular layer was thinner after day 12. An insufficient number of cells in the internal granular layer was apparent after day 12. Bergmann glia cells were hypertrophied after day 10 and filledthe spaces where Purkinje cells had disappeared. Subsequently, Bergmann fibers and astrocytes in the internal granular layer were hypertrophied after day 15.

Thus, in the developmental process of cerebellar hypoplasia in j/j Gunn rats, Purkinje cell damage preceded the histogenetic abnormalities of the cortex including astrocytic changes.
Teratology of Heavy Metals: Mercury and Other Contaminants*
Authors: INOUYE Minoru
Published: May 2008

Abstract Modern industrialization has introduced harmful metals into our environment, and there has been a good deal of speculation that heavy metals can cause teratogenesis. In fact many metals have been confirmed to have em‐bryotoxicity in experimental animals, but only a few elements (e.g., mercury, lead, etc.) are known to be human teratogens.

Liquid metallic mercury is hardly absorbed from the gastrointestinal tract. Inorganic mercury is also poorly absorbed, i.e., around 2% of ingested mercuric chloride is absorbed. Uptake of inorganic mercury by the fetus is very low. An experiment using mice revealed that a significant proportion of mercury is blocked in the yolk sack. Among the organic mercury compounds, the most accumulated knowledge pertains to methylmercury compounds. Methyl‐mercury is efficiently absorbed through the intestinal tract and skin. It crosses the human placenta with infantile blood levels in excess of the mother's blood, giving rise to a higher risk for the fetus. Pathological features of children's brains affected by prenatal methylmercury exposure are the outcome of disturbances in the development of the brain; microcephaly, dilated lateral ventricles, as well as derangement in the fundamental structuring of gray matter as the result of abnormal neuronal migration. Degeneration of already formed nerve cells is involved in some cases.

Lead has been shown to pass through the human placenta readily, and the concentration in the umbilical cord blood is 80‐90 % as high as that in the maternal blood. A large cohort study suggests that increased exposure to lead from the environment in the prenatal and early postnatal periods results in the deficit of mental development.

Teratogenicity of many metal compounds such as aluminum, cadmium, chromium, indium, nickel, platinum, tellurium, thallium, ytterbium and zinc salts has been confirmed in experimental animals. Some metalloids (e.g., arsenic, selenium and lithium) appear to have teratogenic potential for humans.
Morphological Abnormalities in Experimental Teratology: Need for a Standardization of the Current Terminology
Authors: BELTRAME Diana , GIAVINI Erminio
Published: May 2008

The teratologist's main ethical aim in experimental procedures is to analyse specimens thoroughly so as to bring to light any potential adverse effects of the agent being tested after contact with the maternal organism. The results must be pondered, organized and expressed using agreed technical terms whose purpose is to reflect the exact scientific meaning of the findings. The analytical review must then be summarized, so as to present a clear but concise picture that is easily interpreted. However, there are many sources of differences between laboratories: the depth in which they analyse specimens and the weight they attribute to each finding; the way they organize and classify findings and – last but not least – the terms they use to describe them. All these factors may in the end influence judgements of the severity of an effect observed. Thus findings from different organisations are not always comparable. Considering, therefore, that most major laboratories and their staff have built up long years of experience, the time has surely come to seek some form of Operative and Co‐Operative standardization. This would not only assure the quality of work done everywhere, but also reach the aim, through uniformity of technical terminology, of a better understanding among non‐teratologists and easier agreement among teratologists.
Respiratory Failure in Newborn Rats with the Semilethal Mutation Fused Pulmonary Lobes as a Cause of Neonatal Death
Authors: AOYAMA Hiroaki , TERAMOTO Shoji , SHIRASU Yasuhiko
Published: May 2008

The present study aimed at elucidating the cause of pre‐weaning mortality of fpl/fpl rats having fusion of the right lung lobes with hypoplasia of the intermediate lobe and many other associated malformations. In the first experiment, fpl/fpl pups were examined for postnatal viability and growth. Cumulative mortality of fpl/fpl pups obtained from three types of mating pairs was 13.8–30.8% on day 0 of lactation and was raised to 41.9–76.7% on day 4. However, only few deaths were noted thereafter. Body weights of surviving fpl/fpl pups were significantly lower than those of +/‐ littermates through the lactation period. In the second experiment, moribund or dead fpl/fpl newborns at birth were closely examined for abnormalities in general condition and necropsied. Their lungs were weighed and examined for histological abnormalities. Several findings obtained from the fpl/fpl newborns demonstrated the occurrence of respiratory failure. They were decreased frequency of respiration, cyanosis, hepatization of the lung and inflation of the stomach by air. Lung weights of these newborns were significantly lower than those of +/‐ littermates. Histological examination of the lungs of dying fpl/fpl newborns revealed partial atelectasis occurred in the regions where fusion of lobes as well as hypoplasia of the lobe was grossly observed. In these lungs, however, epithelial maturation was apparently normal and hyaline membrane was not formed. These observations suggest that reduced gas‐exchanging capacity related to lung malformations leads fpl/fpl newborns to die of respiratory insufficiency in their early postnatal age.
Animal Model for Congenital Anomalies Induced by Chromosome Aberrations*
Authors: MIYABARA Shinichi
Published: May 2008

Abstract: Animal model for congenital anomalies induced by chromosome aberrations is explained in mice. Exencephaly is the most conspicuous external malformations among mice trisomies and partial trisomies. Characteristic cardiovascular malformations are observed in Ts 16, 13 and 14.

The association of persistent common atrioventricular (A‐V) canal in Ts 16 provides an excellent morphological homology to human trisomy 21. Observations on A‐V canal endocardial cushions of Ts 16 fetuses showed i) hypoplastic endocardial cushions, ii) delayed appearance of mesenchymal cells into cushions. and iii) failed fusion of endocardial cushions. The conotruncal malformations were observed in every fetus of Ts 16. Abnormal aortic arch was observed in about half of the cases. Further, the thymus was always hypoplastic. The combination of these anomalies suggests that Ts 16 had abnormal development similar to DiGeorge anomaly in these regions.

In enlarged hearts of Thp and twLub2, which have deletions on chromosome 17, the ventricular septum bulged so extremely into ventricle that the bilateral ventricular outflow tract was markedly obstructed.

From 14 days of pregnancy on, generalized edema was often observed in some of trisomic and ThP fetuses. Histological examination of Ts 16 and Thp fetuses demonstrated that the essence of the fetal edema was cystic hygroma, which is sometimes encountered in human fetuses with chromosome aberrations.

Investigations by an animal model with chromosome aberrations did offer new information which remains somewhat scanty in early embryonic stage.
Studies on Birth Defects and Twins in Japan*
Authors: IMAIZUMI Yoko
Published: May 2008

Abstract: In Japan, the overall incidence rates of birth defects among fetal deaths were 2.5% for singletons and 3.2% for twins during 1979–1985. The difference is significant at the 5% level. The incidence rate of anencephalus among fetal deaths during the period was higher in singletons than twins in each year, whereas the incidence rate of congenital hydrocephalus among twins was similar to that among singletons except in 1985. The concordance rates were 5.7% for anencephalus, 9% for spina bifida, and 15% for congenital hydrocephalus during the period. In two cases one twin had anencephalus and the other congenital hydrocephalus, and in one case one twin had anencephalus and the other spina bifida. Nationwide data on 112 sets of conjoined twins who died as fetuses or in the postnatal period during 1979–1985 were analysed. Female conjoined twins accounted for 60% of cases. The incidence rate of conjoined twins remained constant throughout the period except in 1985. The overall incidence rate was 10 per million births. A maternal age effect was found in mothers over the age of 40, where the highest incidence rate occurred. The incidence rate increased with birth order.
Micronutrients and Congenital Anomalies*
Authors: WATANABE Toshiaki
Published: May 2008

Abstract: Insufficient as well as excessive amounts of essential micronutrients such as vitamins and minerals are known to be deleterious to developing embryos in mammals. However, no detailed analysis of the effects of biotin deficiency on mammalian embryos has been reported. We demonstrated that maternal biotin deficiency produced a high incidence of external and skeletal malformations in mice, although the dams showed no clinical signs of biotin deficiency during gestation. The prominent malformations were craniofacial and limb malformations such as cleft palate, micrognathia, and micromelia. A dose‐response relationship was observed in the incidences of the respective malformations. The formation of secondary palatal processes and limb buds was delayed at midgestation in these biotin‐deficient mouse embryos, probably leading later to cleft palate and limb malformations. When the teratogenicity of biotin deficiency was compared in three mammalian species, striking species and strain differences were detected.

Excess retinoids are embryotoxic and teratogenic in mammals, causing especially high incidences of craniofacial and limb malformations. We examined the mechanism of action of retinoic acids (13‐cis‐, 4‐oxo‐13‐cis‐, and all‐trans‐) on the craniofacial tissues of mouse embryos using whole embryo culture and primary cell culture. In cultured embryos, retinoic acids caused overall embryonic growth retardation, particularly in the facial processes (maxillary, mandibular, and nasal). Histological examination of mouse embryos at midgestation showed that cranial neural crest cells were not migratory and demonstrated pyknotic nuclei in the mesenchyme adjacent to the epithelium in nasal processes. Biochemicalanalysis revealed that retinoic acids also inhibit DNA synthesis and the proliferation of mesenchymal cells in facial processes, a finding that is relevant to the mechanisms of retinoic acid‐induced craniofacial malformations.

It is proposed that the role of micronutrients in embryonic growth and development should be evaluated at the cellular level using whole embryo culture and embryonic cell culture.
Analysis of Sex Differences in Skeletal Ossification and Variations in Near‐term Mouse Fetuses
Authors: MANAKA Yukiko , WATANABE Toshiaki , ENDO Akira
Published: May 2008

Abstract: When the degree of skeletal ossification and the incidence of skeletal variations were compared between male and female fetuses in mice according to body weight, males had more ossification centers in sternebrae than did females, while ossification of thoracic and sacrococcygeal vertebral bodies tended to be more advanced in females. Also, more rudimentary ribs tended to appear in females and more extra ribs appeared in males.
Development and Intrauterine Fate of Normal and Abnormal Human Conceptuses
Authors: SHIOTA Kohei
Published: May 2008

Using the data from the Kyoto Collection of Human Embryos, three main topics related to normal and abnormal development of human embryos are discussed.

1) Wide variability was noted in developmental stage of human embryos at any given gestational age. This was true not only for the estimated ovulation age but also for ‘coital’ age in single coital cases. Such diversity in human prenatal development may be, at least in part, ‘normal’ biological variability and it should be taken into account when assessing the teratogenic risk of environmental agents to human embryos.

2) At the early postimplantation period prior to major organogenesis, the percentage of morphologically abnormal embryos is high (> 30%), which supports the clinical finding that a substantially large proportion of human conceptuses are eliminated at an early stage of pregnancy, often without the knowledge of the mother. The fate of undifferentiated abnormal embryos is not certain and should be studied.

3) Life‐table estimates for normal and abnormal human conceptuses showed that more than 10% of all embryos recognizable at 5 weeks gestation are malformed or ‘potentially’ malformed. Because of selective intrauterine death of malformed embryos and fetuses, the proportion of the malformed drops to 2.4% by age 8 weeks and 1% at term. The cumulative intrauterine mortality rate of malformed conceptuses was estimated to be 93%, while the corresponding rate for normal conceptuses was 18%.
Comments on the Draft 11 of EC Guideline on Detection of Toxicity to Reproduction for Medicinal Products
Authors: TANIMURA Takashi
Published: May 2008

Abstract In order to contribute to international harmonization on reproductive and developmental toxicity studies of pharmaceutical drugs, European Community (EC) has introduced the drafts of guidelines for the tests in succession. The draft 11 was announced on June 21, 1991 and the Committee on the Guidelines of Reproductive and Developmental Toxicity Studies, Japanese Teratology Society reviewed it on July 12, 1991. Six general and 50 individual comments were drawn up. It is hoped that through hot international discussion with supporting scientific data, the true international harmonization of the guidelines on reproductive and developmental toxicity studies will be achieved.
Systemic Lupus Erythematosus and Congenital Anomalies, Focusing on Neonatal Lupus Erythematosus and Anti‐SS‐A/SS‐B Antibodies*
Authors: HASHIMOTO Hiroshi , TAKASAKI Yoshinari , HIROKAWA Kaoru
Published: May 2008

SLE is a representative autoimmune disease which develops preferentially in women of childbearing age. Its frequent occurrence makes the coincidence of SLE and pregnancy an important clinical problem. SLE is thought to be multifactorial disease. A familial prevalence was found to be 3% which was significantly higher when compared with Japanese prevalence of SLE. When women with SLE become pregnant, the fetus is at high risk and is adversely affected showing the high prevalence of fetal loss. Antiphospholipid antibodies were thought to be one of the causative factors. Ne‐onetal lupus erythematosus (NLE) including lupus like skin lesions and congenital complete heart block (CCHB) is associated with maternal anti‐SS‐A and SS‐B antibodies. The disease resolves with normalization of the maternal antibodies by the 8th month after delivery with the exception of the CCHB which is almost universally irriversible. When the sera from 4 maternal patients with NLE and 32 patients with normal delivery were analyzed by immunoblotting using recombinant 60 and 52 kD SS‐A, and SS‐B purified from calf thymus extract, the frequency of anti‐52 kD SS‐A and SS‐B in patients with NLE was significantly higher than that of patients with normal delivery. Anti‐SS‐A/SS‐B antibodies may react with the SS‐A/SS‐B antigens in fetal heart tissue as fetal levels of IgG increases which is almost simultaneously as when the SS‐A/SS‐B antigens appear in the fetal heart tissue. The pathogenesis of tissue damage mediated by autoimmune mechanisms specifically dependent on the biology of pregnancy is recognized to be due to passively acquired autoimmune injury.

congenital complete heart block,

anti‐SS‐A antibodies,

anti‐SS‐B antibodies.
Diaphragmatic Hernia Induced in Rat Fetuses by Administration of Bisdiamine
Authors: TASAKA Hiroyasu , TAKENAKA Hitoshi , OKAMOTO Naomasa , KOGA Yasunori , A Minora HAMAD
Published: May 2008

Administration of N, N'‐bis (dichloroacetyl)‐l,8‐octamethylenediamine, bisdiamine, to pregnant Donryu rats on a single day of gestation induced unilateral and bilateral diaphragmatic hernias in fetuses with high incidence. The protruded liver was not covered with a serous membrane or a muscular layer. Incidence of unilateral diaphragmatic hernia on the left side was high when bisdiamine was administered on day 9 or 13 of gestation, and that on the right side was high when administered on day 12 of gestation. Incidence of bilateral diaphragmatic hernia was high when bisdiamine was administered on day 12 of gestation. Differences in sensitivity to hernia formation according to day of bisdiamine administration between right and left sides may reflect differences in developmental chronology between the two sides. Two distinct times for induction of left diaphragmatic hernia might be attributed to at least two different mechanisms. The present model is expected to help analyzing not only anatomical characteristics of congenital diaphragmatic hernia but also possible mechanisms responsible for their development.
Correlation of Active Folate Availability with Effects of Folic Acid on Pyrimethamine Teratogenesis in Rats
Authors: TSUNEMATSU Kunitoshi , SHIMODA Minora , HAYAMA Toyoaki
Published: May 2008

Oral administration of pyrimethamine (PYR) 3.6 mg/kgBW/day to the pregnant rats from day 11 to day 15 of gestation caused malformations in all the fetuses, but concomitant intraperitoneal administration of folic acid (ip FA) 50 mg/kg/day inhibited the incidence of malformations by 25%. On the other hand, the same dose of oral FA (in feed) had an opposite effect on PYR teratogenesis; the incidences of malformed fetuses were 0% in the PYR 1.6 group, but 100% in the PYR with oral FA group. The plasma levels of 5‐methyltetrahydrofolic acid (5MF), a principal transfer form of folate, were measured after single oral administration of PYR with or without FA (ip or oral) in non‐pregnant female rats. The area under the plasma concentration‐time curve (AUC) after the concomitant administration of PYR with ip FA was larger than that after PYR alone. This result indicated that the available 5MF for the peripheral tissues was increased by the concomitant administration of ip FA. The AUC after the concomitant administration of PYR with oral FA was smaller than that after PYR alone. These results suggested that ip FA increased the available 5MF to ameliorate, but oral FA decreased the availability to aggravate the PYR teratogenesis.
Frequency of Spontaneous Axial Skeletal Variations Detected by the Double Staining Technique for Ossified and Cartilaginous Skeleton in Rat Fetuses
Authors: IGARASHI Eiki , KAWAMURA Nobuyuki , OKUMURA Haruko , HOTTA Kei , OKAMOTO Takafumi , INAOKA Miyuki , TAKESHITA Shuji , YASUDA Mineo
Published: May 2008

The purpose of the present study was to determine the frequency of spontaneous axial skeletal variations detectable by the double staining technique in Crj: CD (SD) and Crj: Wistar rat fetuses. In addition, the frequencies of unossified skeletal variations were compared between SD and Wistar rats, and between same strain male and female rat fetuses. Fifteen types of the variations were detected. There were strain differences (4 types) and sex differences (3 types) in the frequencies of the variations. With the aid of double staining technique, skeletal variations such as supernumerary ribs or deformed ossification centers detected by the single staining technique could be classified in detail into many types. This study showed that the double staining technique improved detectability of skeletal variations and facilitated their evaluation in developmental toxicity studies.
Findings and Possibilities in Teratology1,2
Authors: SCHUMACHER Gert‐Horst
Published: May 2008

Abstract Reports of malformations are already documented in the writings of Assyrian and Babylonian astrologists dating back 1800 before our chronology. Historically, a significant source of informations are pamphlets. These publications started in Germany in the 15th century to disseminate news.

For most congenital anomalies the causes are unknown. The majority of developmental defects have a multifactorial etiology and are induced interactions of environmental and genetic factors. In order to examine the effect of noxae the development of mammals is subdivided into several segments.

On the base of guidelines which were issued by the Food and Drug Administration (FDA) in 1966 the principles of in‐vivo teratogenicity testing procedures are discussed. As a rule reproduction toxicological investigations are carried out on mice, rats and rabbits. Special attention is to be payed on dose limits, mode of application, toxicokinetics of the test agents, morphological criteria and specific disorders of developmental rhythm.

Stimulating factors for the use of in‐vitro tests are the increasing number of chemical substances. Advantages and disadvantages of in‐vitro technique are discussed. Some of the actual in‐vitro models are presented, such as monolayer culture, organoid culture, organ cultures, “whole embryo” culture. It is concluded that in‐vivo experiments cannot be replaced by in‐vitro systems, but its usefulness in teratological research has been proven.
Mirror Movements of Hind Limbs of the Rat with Experimentally Induced Lumbosacral Agenesis
Authors: INAGE Akihiko
Published: May 2008

Abstract Neuropathological and electrophysiological studies were designed to clarify the pathomechanism of motor disturbance in the hind limbs of rats with sacral agenesis. The model animals were obtained from mother rats which had been treated with trypan blue on day 8 of gestation. Mirror movements in the hind limbs were observed in 7 out of 56 rats with lumbosacral agenesis. The conus medullaris in rats with lumbosacral agenesis ended at the level between Th13‐L1 vertebra, whereas that in normal cases terminated between L3‐4. The spinal cord of the lumbosacral region was hypoplastic and dysplastic particularly in the ventral half. Anterior horn cells were sporadic and there were no apparent median fissure in the spinal cord of the lumbosacral region. On the other hand, any abnormality was not found in the brain, the brain stem, and the spinal cord of the cervicothoracic region. Horseradish peroxidase (HRP) was injected into the unilateral hind limbs. In segments of the anomalous spinal cord, HRP‐labeled neurons in the anterior horn were found not only on the injected side but also on the other side. In electrophysiological examination, F' wave was recorded on the non‐stimulated side with longer latency and duration compared with that of the stimulated side. These morphological and physiological findings indicated that the mirror movements in the hind limbs of the model animals may arise from developmental errors of motor nervous pathway, with some deficient inhibitory mechanism in the upper neural system.
Significance of the Minor Alterations of the Axial Skeleton in Rat Foetuses. A Short Review
Authors: STAZI Anna V. , MACRI Caterina , RICCIARDI Claudio , MANTOVANI Alberto
Published: May 2008

Abstract The toxicological significance of different kinds of minor alterations in the axial skeleton of foetal rat is still a matter of debate. These changes can be better evaluated by means of the double staining technique for cartilage and calcified tissue, which helps to distinguish between deficient calcification and actual structural changes. Sternebral alterations are a frequent finding in prenatal toxicity studies, while in humans they are seldom observed. However, very few data exist for the rat with regard to their persistence and/or consequences in postnatal life. Abnormalities of the vertebral bodies might be functionally important, but comparatively little attention has been given to them in prenatal toxicology. By contrast, the little significance of wavy ribs, potentially reversible alterations, has been extensively studied. The transiency of extra ribs in the rat might be a species‐specific feature, but they have been reported to cause health problems in humans. It is important to recognize a dose‐dependent trend both for specific minor changes and for general parameters (e.g., sternebral alterations). Finally, the range of prevalences in historical controls may be an insensitive parameter, due to the wide variability between different control groups. This range could be better replaced by the average prevalence ± Standard Deviation.
Micromass Culture of Midbrain Cells and its Relevance to in Vitro Mechanistic Studies*
Authors: TSUCHIYA Toshie , ETO Kazuhiro , BURGIN Heinrich , KISTLER Andreas
Published: May 2008

Abstract The relationship between ethylenethiourea (ETU)‐induced malformations of cultured rat whole embryos and the alterations of midbrain (MB) cells was investigated and species‐specific ETU‐induced alterations between rat and mouse MB cells were determined.

Herefore, we developed new methods for monitoring teratogenic activities in serum fluids without heat treatment. The serum samples were prepared from rats and mice given ETU, and ETU‐teratogenicity was evaluated in both species. We determined that the different sensitivity of the midbrain of the rat and mouse may be the main reason that ETU was teratogenic in rats but not in mice.

Next, we showed that MB‐cultures are unsuitable for estimating the teratogenic potential of arotinoids. MB differentiation was adversely affected only at concentrations which caused cell death.

Finally, we demonstrated that the embryolethal action of new herbicides is not detectable in the micromass teratogenic test. However, the V79 colony assay may be useful for preliminary screening of embryolethal effects of herbicides.
Tongue Papillae Anomaly in Anencephalic Fetuses
Authors: LEE Suk Keun , LEE Chong Heon , LIM Chang Yun , CHI Je Geun
Published: May 2008

Abstract Eighteen cases of anencephalic fetuses were examined to explore the abnormal growth of the tongue papillae. All 18 cases consistently showed severe hypoplasia of the tongue papillae and taste buds. The filiform papillae showed the most severe hypoplasia. Both epithelial ingrowth and crypt formation of the tongue papillae were retarded from as early as gestational age 19—20 weeks, thus the filiform papillae became greatly arrested showing smooth surfaced and thick keratinized epithelium. The fungiform papillae decreased in number and were of abnormal size. The direction of the papillae was occasionally reversed. The taste bud of the fungiform papillae was markedly hypoplastic and was often missing. Meanwhile the vallate papillae were relatively well developed although frequently abnormal in shape. The distribution of the taste bud was irregular, and several taste buds were observed on the top of the vallate papillae. The taste buds were generally hypoplastic, and some of them showed degenerative or cystic change. In conclusion the tongue papillae, indicative of a highly proliferative epithelium, seem to be definitely affected by the generalized growth retardation in anencephalics.
New Approach in Behavioral Teratology—Experimental Study on FAS *
Authors: OMOTO Miyako
Published: May 2008

ABSTRACT Fetal alcohol syndrome is known as an effect given by mothers. In connection with this, we so far observed rats from physical, biochemical, histological, and functional standpoints. Recently we observed synaptogenesis in brain together with behavior and learning ability of rats. Ethanol was given to mother rats during pregnancy and nursing periods, and learning ability of their offspring at 12 weeks of age was studied by the radial arm maze method. Also synaptogenesis in the hippocampus CA1 was observed at 2, 7, 14, 21, and 70 days of age by quantitative electron microscopy. The offspring were significantly deficient in learning ability tested with the maze compared with offspring of mother rats not exposed to ethanol. Densities of all synapses in the strata radiatum and lacunosum‐moleculare of CA1 in the hippocampus became significantly lower at every time of the observation. Both axo‐spinous and axo‐shaftic synapses significantly decreased. Thus we found that observations of learning ability agreed with observations of synaptogenesis in the hippocampus CA1 which has important association with memory. This fact suggests that both observations will be of great value in the research in behavioral teratology.
Clinical Features of Congenital Contractural Arachnodactyly
Authors: OGINO Toshihiko , KATO Hiroyuki , OHSHIO Itaru , TAKAHARA Masatoshi
Published: May 2008

ABSTRACT Clinical features of 11 cases of congenital contractural arachnodactyly (CCA) were reported. Eight cases were male and 3 cases were female. Family history was positive in 6 cases of 3 families. As for hand deformity, flexion of the finger, adduction of the thumb and shortening of the palmar skin were observed in all cases, arachnodactyly in ten cases, flexion contracture of the finger joint in 6 cases. Dolichostenomelia and crumpled ear deformity were associated in all cases, spinal deformity in 6 cases, flexion contracture of the lower extremities in 5 cases, micrognathia in 2 cases and high palate, strabismus, pectus excavatum and polydactyly of the fifth toe in one case. Arachnodactyly was not an essential feature of CCA. Existence of multiple camptodactyly with or without arachnodactyly and/or ulnar drift of the fingers, and crumpled ear deformity were important findings for differential diagnosis of CCA. There was no association of cardiovascular anomalies in this series. CCA without ocular and cardiovascular involvement must be a definite clinical entity and should be distinguished from the other forms of marfanoid habitus.
Palatal Slit and Cleft Palate in Rats Treated with a Glucocorticoid 1. Teratogenicity of Dexamethasone
Authors: ISHIZUKA Yasuo , WATANABE Chiaki , WADA Azusa , SAITO Yoshiaki , NAGAO Tetsuji , MIZUTANI Masahiro
Published: May 2008

The sensitive period and the dose‐response characteristics for dexametha‐sone‐induced cleft palate and palatal slit in rats were examined. Pregnant rats were injected subcutaneously with dexamethasone in a single dose of 2–6 mg/kg on one day between day 8 and 16 of the gestational period or once each day for two successive days (days 14 and 15 of gestation). All animals were euthanized on day 20 of gestation and the palatal condition of their fetuses was inspected after fixation under a dissecting microscope. The sensitive stage of palatal slit and cleft palate induction was determined and the dose‐response relationship was analyzed by the log‐probit transformation method.

No maternal lethality was elicited in any of the treatment groups. High frequencies of palatal slit and cleft palate were induced when dexamethasone was administered as a single dose on any individual day from day 12 to day 14 of gestation. Omphalocele and general edema were also found to be significantly more frequent in the high‐dose group treated on days 12–14 of gestation. All groups treated showed a reduction in fetal body weight. The response data for palatal slit and cleft palate after administration of dexamethasone fitted to similar linear regression slopes, suggesting a similarity in the underlying mechanisms for palatal slit and cleft palate induction in rats. ED50 values were 3.48 mg/kg for palatal slit and 6.64 mg/kg for cleft palate. These findings indicate that dexamethasone treatment is effective in inducing palatal slit and cleft palate in rats, as well as in mice. Key words: glucocorticoid, dexamethasone, palatal slit, cleft palate, sensitive stage, doseresponse, rats
Magnetic Resonance imaging of Rat Fetuses
Authors: IGARASHI Yo , HASEGAWA Kenichi , OTSU Shinichi , KAWANISHI Hiroaki
Published: May 2008

The internal structures of rat fetuses on day 18.0 of pregnancy were studied by magnetic resonance imaging in 1‐mm sagittal slices. Each organ was represented as white to gray images different in tone according to the 1H proton content and the relaxation time. In solid organs, portions with high cell density were seen as white areas and those with low cell density as gray areas. In the tubular organs, the margins were imaged as white and the lumina as gray.
Clinical Features of Congenital Ankylosis of the Digital Joints of the Hand
Authors: OGINO Toshihiki , TAKAHARA Masatoshi , KATO Hiroyuki , SUGIMOTO Yoshihiro , ISHII Seiichi
Published: May 2008

ABSTRACT: Clinical features and roentgenographic findings of 37 patients (65 hands) with congenital ankylosis of the digital joints, including symphalangism and other types of congenital ankylosis of the joints, were analyzed. Congenital ankylosis of the digital joints was divided into four types according to the clinical features as follows; Type A (typical symphalangism), 13 cases, Type B (symphalangism without associated anomalies), 6 cases, Type C (symphalangism associated with hypoplasia of the affected digit), 10 cases and Type D (symphalangism as a part of syndrome), 8 cases. Roentgenographic findings of the affected joints were divided into 4 types, such as normal type (Type I), narrow type (Type 2), flat type (Type 3) and bony ankylosis (Type 4). There seems to be 4 types of joint development in congenital ankylosis of the digital joints. In Types 1 and 2, the joint space of the affected joint and the secondary ossification center looks normal. The joint seems to develop normally in Type 1, but the condyle of the affected joint becomes flat in Type 2. In Type 3, the joint space is narrow in infancy, the secondary ossification center fuses with the proximally located phalanx and finally the affected joint develops bony ankylosis. In Type 4, there is osseous fusion of the affected joint at birth. Key words: hand, joint, symphalangism, tarsal coalition, carpal coalition
Bronchial Branching Abnormalities and Emphysema‐like Changes in Mutant Rats Having Congenital Lobation Anomalies in the Lung
Authors: AOYAMA Hiroaki , FUJII Sakiko , TERAMOTO Shoji
Published: May 2008

ABSTRACT The present study aimed at investigating in fpl/fpl mutant rats survived to adulthood 1) whether bronchial branching abnormalities were the primary defects of pulmonary lobation anomalies, and if this was the case, 2) whether these anomalies could lead to respiratory dysfunction. Examination of corrosion casts made from the malformed lungs of adult fpl/fpl rats revealed a variety of branching abnormalities in the right bronchial tree, such as ventral ramification of the middle lobar bronchus, abnormal curvature of the intermediate lobar bronchus, and positional abnormalities of the middle lobar bronchus and first segmental bronchus of the intermediate lobar bronchus, while reduction in the number of segmental bronchi was the only minor abnormality found in the left lung. These results conformed to our previous observations in which the main manifestation of the fpl mutation was restricted to the right lung lobes, and indicated that the primary defect of this malformation was bronchial branching abnormalities. In these rats, stenosis of the trachea, right and left principal bronchi, and some lobar and segmental bronchi also became evident by calipering their circumference. Histopathological examination of the lungs revealed abnormally expanded airspaces accompanied by destruction of alveolar walls and macrophage infiltration in aged fpl/fpl rats. These observations suggest that fpl/fpl rats suffer emphysema‐like respiratory dysfunction with advancing age from pulmonary lobation anomalies conforming to tracheal and bronchial malformations.
Clinical Features and Operative Findings of Congenital Flexion Deformity of Multiple Digits
Authors: OGINO Toshihiko , ISHII Seiichi , KATO Hiroyuki
Published: May 2008

ABSTRACT Thirty‐six cases with congenital flexion deformities of multiple digits were classified into six types such as congenital contractural arachnodactyly, distal arthrogryposis, Freeman‐Sheldon‐like syndrome, congenital aplasia of the extensor muscles of the digits, ulnar drift type and multiple camptodactyly type. Many common clinical features of the hands were observed among these deformities. In eleven cases, 18 hands were treated surgically and were followed up for more than a year. During surgery, complete correction or signigicant reduction of the deformity was achieved in most cases. From these operative findings, it was assumed that the main cause of congenital flexion deformity of multiple digits was contracture of the palmar skin and retaining ligaments of the skin. At follow up, complete correction was achieved in 10 hands, and incomplete or minimal correction in eight hands.
Lethal Multiple Pterygium Syndrome with Complete Intestinal Duplication
Authors: Kim Eun Kyung , Chi Je Geun
Published: May 2008

ABSTRACT We present an autopsy case of a 23‐week female abortus with the cardinal signs of lethal multiple pterygium syndrome (LMPS), including multiple pterygia with congenital joint contracture, fetal hydrops, cystic hygroma and intrauterine growth retardation. In addition, she had complete tubular intestinal duplication, not yet reported in this group of conditions.
Transplacentally‐Administered Enalapril Inhibits the Spontaneous Constriction of the Ductus Arteriosus in the Newborn Rat
Authors: TAKIZAWA Tatsuya , ARISHIMA Kazuyoshi , YAMAMOTO Masako , SOMIYA Hiroaki , SHIOTA Kohei
Published: May 2008

ABSTRACT Pregnant Wistar rats were given orally enalapril maleate (EM), an angiotensin‐converting enzyme (ACE) inhibitor, 15–60 min prior to Caesarean operation and the diameter of the ductus arteriosus (DA) in the newborn rats was calibrated at intervals after delivery. The caliber of the DA in control newborn rats gradually decreased to less than 10% of the initial value by 90 rnin after delivery. The DA calibers of the newborn rats treated with 50 or 200 mg/kg EM in utero were larger than the controls at any time interval up to 90 rnin and the difference from the control value was significant for at least 30 rnin after delivery when the drug was given to the dam 30 rnin prior to Caesarean section. The present study has demonstrated that transplacentally‐administered enalapril inhibits the spontaneous constriction of the neonatal rat DA and supports the view that ACE inhibitors should not be used late in pregnancy.
Analysis of Palatogenesis in the Mouse with Exencephaly Induced by Cadmium Chloride
Authors: SATO Toshio J.
Published: May 2008

ABSTRACT It has been revealed that exencephalic mouse embryos were resistant to cleft palate induction when they were exposed to several teratogens known as cleft palate inducing agents. In the present study, palatogenesis in exencephalic mouse embryos, which were not exposed to cleft palate inducing teratogens, was observed. A single dose of 6 mg CdCl2/kg body weight was intraperitoneally injected into pregnant Jcl:ICR mice at day 7.5 of gestation (plug day = day 0). Embryos were dissected from uterus at day 13.5 to 15.5, and the secondary palate was observed with a dissecting microscope or a scanning electron microscope (SEM). Of live embryos, 71.5% had exencephaly. Palatal shelves of exencephalic embryos were elevated earlier than non‐exencephalic embryos, and there seem to be two modes of palatal fusion in exencephalic embryos. (1) “Parallel‐shape.” The anterior part of shelves were elevated at day 13.5. Distance between the opposite medial edges of both shelves decreased at the posterior part, and this closing proceeded to the anterior part, where the shelves began to fuse. (2) “V‐shape.” The posterior part of palatal shelves became closer at day 14.0 or day 14.25. The medial edge of both shelves began to fuse at this part, and this fusion proceeded anteriorly. The anterior parts of the shelves were elevated, and the medial edge of the anterior shelves was fused independently. It is suggested that these alterations of palatogenesis in exencephalic embryos are related to inhibitive mechanism(s) against cleft palate induction. Key words: palate, neural tube defects, skull, mice, cadmium
Variations in Palatal Rugae in Near Term Fetuses from Untreated Jcl:ICR Mice
Authors: YASUDA Mineo , OHYA Ryoji , SATO Toshio J.
Published: May 2008

ABSTRACT The oral surface of the mouse palate has eight or nine pairs of transverse ridges, or rugae. Abnormalities in the pattern of palatal rugae have been reported in mutant mice and mice exposed to teratogens in utero. The purpose of this study was to describe control data of ruga variations for proper definition of “anomalous” ruga patterns. Jc1:ICR mice on gestation day 18 were killed, and the fetuses were fixed in Bouin's solution. Fetal palates were examined under a dissecting microscope. In total, 251 fetuses from 19 dams were observed. Among these fetuses 88% had one or more variations in the palatal rugae. Common variations were supernumerary anterior to the fourth ruga, division, and lateral bifurcation, and these were regarded as variations in the “normal” range. Variations rare in fetuses from untreated dams were shortness, fusion, cross, and supernumerary posterior to the fifth ruga, and these should be defined as “anomalous” ruga patterns in teratology experiments. Key words: mouse, palate, rugae, developmental toxicity test
Molecular Genetic Techniques for Prenatal Diagnosis*
Authors: SUZUMORI Kaoru , TANEMURA Mitsuyo , ADACHI Ritsuko
Published: May 2008

Abstract Recently, molecular genetic techniques have been rapidly incorporated into routine clinical as well as laboratory medicine, and genetic diseases including inborn errors of metabolism have come to be diagnostically viewed as changes in DNA. Molecular genetic techniques have the advantage that rapid and accurate analysis can be made with a small amount of samples in comparison with analysis at the protein level by conventional biochemical techniques. They are, therefore, clinically used today not only for the diagnosis of various genetic diseases but also for the detection of infection, including viral infections, in the outpatient clinic. They have also been applied to fetal diagnosis, and are bringing about major changes in prenatal medicine.
Growth Hormone (GH) Treatment in Achondroplasia*
Authors: OGAWA Masamichi , MORI Osamu , ASAI Toshi
Published: May 2008

ABSTRACT Achondroplasia, a form of short stature with short limbs, is the most common disease among osteochondrodysplasia. The growth pattern of patients with achondroplasia is unique compared with the normal standard. At birth, patients' heights are within normal limits and height velocity is normal during the first year in most patients. Thereafter, it declines to the 3 percentile line and remains low until 8 years of age. The peak height velocity is much lower during puberty in these patients than in the normal and contributes to short stature in achondroplasts. Extremely short stature lowers quality of life, therefore, various medications have been tried to promote growth in achondroplasts but in vain. GH is now produced in sufficient quantity utilizing recombinant DNA technique.

Since encouraging results have been obtained in the GH treatment of various kinds of short stature without GH deficiency, e.g., Turner's syndrome, intrauterine growth retardation, non‐endocrine short stature, etc., achondroplasia has been also considered as a candidate for GH treatment.

There have been only a few studies on GH treatment in achondroplasia and the number of subjects studied is small. However, satisfactory growth‐promoting effects have been demonstrated in these studies although observation periods were short and side effects have not been reported. Further studies are necessary to confirm the optimal dosage and administration method on final height and side effects in long‐term use of GH.