bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractThe 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

AbstractThe 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.
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.
Development and Intrauterine Fate of Normal and Abnormal Human Conceptuses
Authors: SHIOTA Kohei 
Published: May 2008

AbstractUsing 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%.
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

AbstractSLE 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

AbstractAdministration 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

AbstractOral 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

AbstractThe 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.
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.
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

ABSTRACTThe 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

ABSTRACTThe 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.
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.