bluuebunny/crossref_metadata_2025_split huggingface dataset:
Embryotoxicity of Ethanol and Acetaldehyde: Direct Effects of Mouse Embryo in Vitro
Authors: HIGUCHI Yoshiki , MATSUMOTO Nobuo 
Published: May 2008

AbstractDirect embryotoxic effects of ethanol (EtOH) and acetaldehyde (AcH) on mouse embryos during early organogenesis were studied using the whole embryo culture method. Mouse embryos (Jcl‐ICR) were cultured for 48 hours from day 8 & 1/2 to 10 & 1/2 (embryonic age; plug day = day 1) with EtOH‐ or AcH‐supplemented medium. Final concentrations of EtOH ranged from 5 mM to 1 M, whereas those of AcH ranged from 0.4 μM to 400 mM. Exposure to EtOH at 500 mM or more caused early death. Growth and development in EtOH‐exposed embryos were retarded as indicated by the dose‐dependent decrease measured by several embryonic growth parameters. The most common EtOH‐induced anomaly was exencephaly and it was observed remarkably in the 66 mM or more exposed group. Exposure to AcH at 40 μM or more caused early death. Growth and development in AcH‐treated embryos were retarded as a function of dosage. The most common AcH‐induced anomaly was the deformation complex of the neural tube such as transparent and prominent rhombencephalon and remarkable shortening of the posterior part of the body, with or without cyst formation. This deformation complex was observed remarkably in the 0.8 μM or more exposed group. It can be said by these results that AcH is approximately 10000 times more embryotoxic than EtOH in the early organogenetic period and both EtOH and AcH disturb the normal closure of the neural tube, but each compound affects the closure process in a different way and/or developmental stage.
Strain Differences of Postnatal Development of Righting Reflex, Traction and Motor‐Coordination, and Emotional Behavior in Rats
Authors: ASANO Yuzo , KOBAYASHI Takashi , HIGAKI Koh 
Published: May 2008

AbstractLitters from the non‐treated dams in Sprague‐Dawley (SD) and Wistar rats which are used most frequently in reproduction studies were observed for strain differences concentrating on the behavioral development during the early postnatal stage. During the period before the eyelids open, the Wistar rats showed significantly earlier development of postural reflex and traction than the SD rats. However, during the period after eyelids open, the significant difference between these two strains disappeared. The numbers of fallings from a rotorod, ambulation, and rearing in the SD strain significantly increased as compared with those in the Wistar strain. These findings suggest that proper caution should be paid to the developmental period for observing the postural reflex and traction response for the particular strain.
Teratogenicity of Azosemide, a Loop Diuretic, in Rats, Mice and Rabbits
Authors: HAYASAKA Ikuo , UCHIYAMA Kaoru , MURAKAMI Kazuo , KATO Zenji , TAMAKI Fumikazu , SHIBATA Tadashi , SUGAWARA Tsutomu , HAYASHI Motohide 
Published: May 2008

AbstractTeratogenic effects of azosemide, a loop diuretic, were investigated in rats, mice and rabbits. Azosemide was given orally to pregnant rats, mice and rabbits during organogenesis. The pregnant animals were killed at term and their fetuses were examined for external, visceral and skeletal abnormalities. In rats, azosemide at 10–30 mg/kg/day did not affect intrauterine growth, resorptions and rates of external and visceral malformations. Treatment with 90 mg/kg/day resulted in a significant increase in skeletal abnormalities such as wavy ribs, bent scapula and bent humerus. However, the skeletal abnormalities observed in term fetuses could not be found in adult offspring, indicating that they were temporary. In mice, 1250 mg/kg/day of azosemide caused maternal death, abortion, and retarded maternal and fetal weight. Treatment with 200–500 mg/kg/day did not induce fetal mortalities, external and visceral malformations. Skeletal abnormalities increased in dose‐dependent fashion. The type of abnormalities was identical to that encountered in rat fetuses. Furosemide as a positive control also produced similar types of skeletal abnormalities in mouse fetuses. In rabbits, azosemide did not have embryolethal or teratogenic effects even at the highest dose (6 mg/kg/ day), which caused maternal death.Treatment for a different 3‐day period and then a different day during organogenesis in rats and mice showed that the sensitive period was days 15–17 of gestation with a peak on day 16 in rats, and days 12–15 with a peak on day 13 in mice.
Immunological Defects in a Bis(dichloroacetyl) diamine Induced Malformation Complex in Rats Closely Resembling the DiGeorge Syndrome
Authors: OKISHIMA Takahiro , EIZURU Yoshito , MINAMISHIMA Yoichi , OHDO Shozo , HAYAKAWA Kunio 
Published: May 2008

ABSTRACT: Spleen cells from newborn rats with bisdiamine‐induced congenital malformation were examined for subpopulation of lymphocytes and responsiveness of the lymphocytes to phytohemagglutinin (PHA), concanavalin A (ConA) and lipopolysaccharide (LPS). T cells, but not B cells, were significantly diminished in the drug‐treated newborn rats. Proliferative response of the lymphocytes to PHA and ConA, but not to LPS, was significantly depressed in the drug‐treated newborns. Thus a defect in cell‐mediated immunity was suggested to be associated with the congenital anomaly.It is tempting to consider that this bisdiamine‐induced malformation can be another animal model for the DiGeorge syndrome.
The Production of Cardiovascular Malformations with Combined Use of Antisera to Kidney and Fetal Heart
Authors: MIYATA Koichiro , YAMAMOTO Eiji , TAKESUE Tetsuo , MUNAKATA Shuzo , NINOMIYA Makoto , ONO Seigo 
Published: May 2008

ABSTRACT: Wistar rats were administered rabbit anti‐fetal‐rat‐heart serum (AFHS) alone on day 9 of gestation or in combination with sub‐teratogenic doses of rabbit anti‐rat‐kidney serum (AKS).The results showed that the incidence of cardiovascular malformation was low (4.3%) when AFHS alone was administered. However, the incidence markedly increased to 42.4% when a small dose (O.lml/lOOg) of AKS was given on day 9 followed by 0.9ml/lOOg of AFHS on day 10. Ventricular septal defects, aortic arch anomalies, and double outlet right ventricle were the most common cardiovascular malformations observed. These results were similar to our previous finding using adult rat heart antiserum, and suggest that AFHS alone is not teratogenic, but when combined with a sub‐teratogenic dose of AKS it becomes teratogenic and organ specific.
Prospects of the Reproductive Toxicology: With Special Reference to the Developmental Hazards Due to the Treatment at the Stages from Prefertilization to Implantation*
Authors: TANIMURA Takashi 
Published: May 2008

ABSTRACT  With the definition of teratogenicity was expanded in terms of developmental stages when the agent acts and types of developmental anomalies induced, the concept of reproductive toxicity or developmental toxicity has been established. These new terms are essentially the synonym; the former gives the prime emphasis on the parent generation while the latter on the longer phase of developmental stage of the offspring.It has been generally stated that the environmental agents which act before the onset of organogenesis will bring the embryo either death or normal growth. However, some affect the preimplantation embryos with resultant congenital anomalies. Moreover, it has been demonstrated that various developmental defects can be induced by a premating treatment to males, some of which may have been caused by mechanisms other than mutagenicity. On the other hand, oogenesis in females takes a very long time and it is often difficult to determine when these environmental agents act before or after pregnancy. Recent episodes of herbicides (Agent Orange) and vaginal spermicides were introduced as examples.Pharmaceutical drugs, chemicals given to humans intentionally at a relatively large amount in a limited duration, have been requested to be tested in laboratory animals on the possible developmental defects in offspring even when given prior to organogenesis. In Japan, at the test administered prior to and in the early stages of pregnancy (segment I study), it is recommended not only to examine fertility of the parent generation but also to observe the development of offspring as long as practically possible.In the symposium held at the 24th Annual Meeting of the Japanese Teratology Society, significance of developmental failures of the offspring induced by environmental factors given to the parents and during the preimplantation period was critically discussed.
Cultrure and Transfer of Embryos as a Testing System for Embryo‐toxicity of Chemicals*
Authors: MATSUMOTO Nobuo , SPINDLE Akiko , KATAYAMA Susumu , KUBO Harumi 
Published: May 2008

ABSTRACT  Culture system of mouse embryos from 2‐cell stage to early post‐implantation stage was established. To assess the growth and development of embryos, morphological, biochemical and cytogenetical endopoints were settled as follows:1. Blastocysts formation (Day 4 of culture) after treatment of 2‐cell, 4 to 8‐cell and morula.2. Retention of blastocoel fluid on Day 5 of culture after treatment of blastocysts on Day 4 of culture.3. Formation of trophblast outgrowth, discrete inner cell masses (ICMs), and ICMs differentiating into the primary endoderm and ectoderm (two‐layer ICMs) on Day 9 of culture.4. Inhibitory effects on incorporation of 3H‐thymidine into DNA and of L‐(35S) methionine into protein of embryonic cells after treatment with chemicals.5. Induction of structural chromosome aberrations and sister chromatid exchanges (SCEs) after treatment of blastocysts.6. Further development of the treated embryos after transfer of them into the uterine horns of foster mothers (Day 16.5).Mercuric chloride (MC), methylmercuric chloride (MMC), and 4‐Nitroquinoline 1‐oxide (4 NQO) were used for the experiment as model agents. The susceptibility of embryos to toxic effects of MMC changed as developmental stage progressed. The toxic effects of MC differed in manifestation from that of MMC. MMC was about 200 times as toxic to post‐implantation development as MC. These results were chiefly due to the difference between the compounds as regards the penetration of cell membrane and the distribution in living embryonic cells. As for the effects of 4NQO, structural chromosome aberrations and SCEs were induced at the concentration lower than the threshold value for the inhibition of morphological development. 4 NQO treated embryos which were transferred to the uterine horns of recipient mothers were implanted lower rate than control embryos. The embryos could not be implanted at all when treated with 10‐8M. The fetuses originated from the treated (10‐10M and 10‐9M 4NQO for 24 hr) blastocysts showed a remarkable decrease in their body weights without signs of external malformations.
A Review of Unilateral Cleft Lip and Palate Surgery*
Authors: FUKUDA Osamu 
Published: May 2008

ABSTRACT  Operative techniques for unilateral cleft lip and palate have undergone continuous development, with improvement and modification, during the last three decades. The author's operation began with Tennison's method and gradually changed into a narrower and long triangular flap method. The edge of the orbicularis oris muscle on the cleft side is tucked under the center of the philtral dimple to obtain muscles linkage and a philtral ridge on the affected side. The longitudinal line is sutured with meticulous subcuticular stitches using 6–0 Nylon, resulting in a neat scar.Relationship between vertical height of lip and width of triangular flap was examined in follow‐up studies. Flap width increased rapidly for one year after surgery and then slowed down to a pace proportionate with lip height. Although ratio of flap width to height increased from 27% to 40%, the balance of both sides of the lip did not, as had been thought might be possible, change. Correction of the cleft lip nose by the triangular flap method is rather difficult. It is considered natural for many surgeons to prefer a combination of the rotation‐advancement flap and small triangular flap.Much remains to be discussed regarding cleft palate treatment. Author prefers closure of the hard palate using a vomer flap in the primary cleft lip operation because the most effective push‐back of the palate, without fistulae, is achieved. Underdevelopment of lip and maxilla should be evaluated from many aspects, and with a long‐term view.
Hyperadeninuria in a Patient with Congenital Deficiency of Adenine Phosphoribosyltransferase
Authors: NORO Tadao , KAMIKAWA Akira , SAMORI Tomoji 
Published: May 2008

Abstract The authors have previously reported on the possibility of using the detection of crystalluria of 2, 8‐dihydroxyadenine as a screening test for the early discovery of congenital adenine phosphoribosytransferase deficiency.Since the amount of adenine in urine was determined by high performance liquid chromatography and hyperadeninuria in a girl patient with this disease was definitely recognized, it is concluded that the detection of crystalluria of 2,8‐dihydroxyadenine as a primary screening test and the demonstration of hyperadeninuria as a secondary screening are helpful in an early detection of this disease.The authors would like to propose this disease be designated a “Adenine‐body Urine Disease,” since adenine bodies such as adenine and 2,8‐dihydroxyadenine are excreted into the urine in large volumes.
Variation within Species in Response to Caffeine Teratologic Effects*
Authors: SULLIVAN F. M. , SMITH S. E. , McELHATTON P. R. 
Published: May 2008

Abstract The most recent work from our own laboratory and also the. very large studies carried out by the FDA have clearly shown that caffeine has teratogenic effects in animals only when given in very high single daily doses. The doses necessary to produce teratogenic effects are of the order of one‐third the oral LD50 and usually produce other signs of severe maternal toxicity. Much larger daily doses if administered in divided doses or spread throughout the day in the drinking water, do not produce teratogenic effects. The teratogenic activity is dependent on the production of high peak blood levels probably around 60μg/ml or greater. Since such levels are never approached in humans even with high caffeine intakes, and on the basis of the available epidemiological evidence it would not appear that caffeine presents a teratogenic hazard for humans.The available animal evidence suggests that high concentrations of caffeine in the embryo may cause haemorrhages which could be the mechanism of action whereby it causes the palatal and digital defects which have been observed.Other actions of caffeine which have been observed in animal experiments have been reduction in fetal weight and associated retardation of ossification. These effects are seen with lower doses of caffeine than those causing teratogenic effects. The significance of these observations for humans is uncertain and is currently under investigation.
Prenatal Diagnosis of Fetal Chromosomes: Evaluation of Mi dtri mester Amniocetesis and Chorionic Villus Sampling in Early Pregnancy*
Authors: SUZUMORI Kaoru 
Published: May 2008

Abstract The congenital anomaly resulting from chromosomal aberrations is serious and well‐known. The incidence in newborn infants is estimated to be 0.5‐1% (WHO). In many cases the mechanism causing a chromosomal aberration is unknown. There appear to be the protective procedures. The procedure that fetal cells obtained by midtrimester amniocentesis could be grown in culture and karyotyped has opened a new area to genetic counseling for chromosomal aberrations. In the past 15 years, 949 pregnant women have undergone amniocentesis in our hospital. Most institutes now employ ultrasonography for examinations of the fetal position and the localization of placenta prior to amniocentesis. The use of this device remarkably reduced the incidence of fetal loss, and the amniocentesis appears to be safe and efficient. A discrepancy has been noted between the rates of chromosomal aberration by diagnosed at amniocentesis and the rates that would be expected from observation in live births. Multiple regression analysis was performed based on the personal informations of mother, providing what may be the risk factors for the recurrence of sibling with a non‐inhetrited chromosomal aberration.Recently, the technique to obtain chorionic villus in early pregnancy for the prenatal diagnosis of fetal defects, now being tested in the United States and Europe, may replace midtrimester amniocentesis within the next few years. The main advantage is that it can reduce the psychologic impact because emotional and physical stresses of a midtrimester abortion are serious problems. There are many possible approaches to obtain chorionic villus sample. Our experience has shown that biopsy forceps inserted via the cervix is most successful. The possibility was discussed that this may be developed in the future for clinical use as an alternative to amniocentesis.
Prenatal Diagnosis of the Hemoglobin Disorders by DNA Analysis*
Authors: FUKUMAKI Yasuyuki 
Published: May 2008

Abstract Three types of approach to prenatal diagnosis by DNA analysis were described with drawing on examples from sickle cell anemia and thalassemias. The first approach is to detect the change of the restriction pattern of fetal DNA due to the mutation. One type of 6|3‐thalassemia mutation was detected by Southern blotting analysis of genomic DNA when probed with a radiolabeled globin gene because of a large deletion in the β‐globin gene cluster. Since the sickle mutation altered the recognition site of MstII in the β‐globin gene, Southern blot of MstII digest of DNA from a homozygote hybridized with a 1.15 kb MstII 0‐globin gene sequence yielded autoradiograms with a 1.35 kb fragment instead of a normal 1.15 kb fragment.The second approach is based upon the feasibility of using synthetic oligonucleotide probes to detect single base mismatches. Two synthetic 19 nucleotide long oilgonucleotide probes, one complementary to the normal human 0‐globin gene sequence and one complementary to a β‐thalassemia gene sequence (a C‐T substitution at position 654 of IVS2) were used to distinguish between the normal and thalassemia genes in BamHI digests of genomic DNAs.Linkage analysis using restriction fragment length polymorphisms (RFLPs) in the β‐globin gene cluster provides the third approach to prenatal diagnosis by DNA analysis. Allele‐linked RFLPs are only available for detection of the sickle mutation and one type of nonsense mutation of β‐thalassemia in limited populations. Familial‐linked RFLPs have been used for prenatal diagnosis of β‐thalassemias because 17 polymorphic restriction enzyme cleavage sites were identified in the β‐globin gene cluster. This approach is also applicable to prenatal diagnosis of genetic disorders in which the gene products responsible for pathogenesis have not been identified. However, a possibility of diagnosis by this approach depends on RFLPs of parents. Further technical development to simplify the DNA analysis will facilitate clinical use of DNA analysis in prenatal diagnosis.
Clinical Delineation of Multiple Congenital Anomalies*
Authors: KUROKI Yoshikazu , YASUDA Mineo 
Published: May 2008

Abstract The evaluation of multiple congenital anomalies requires several points.1. Definite diagnostic criteria of each malformation and its precise description are of importance in the diagnosis of malformation syndromes.2. Complete family studies improve the accuracy of diagnosis and provide us with valuable information in genetic counselling.3. The use of good reference books and computer‐aided diagnosing systems are effective measures.4. It is of great importance to circulate case documents, and to exchange information on the diagnosis, among clinical dysmorphologists.5. It is crucial to combine the alert clinician's eye and the epidemiologic approach for seeking etiologic associations.6. Animal models of human malformation syndromes contribute much toward deep understanding of deviated morphogenesis.
Effects of Mitomycin C Treatment before Implantation on Development of Mouse Embryo
Authors: NAGAO Tetsuji , ISHIZUKA Yasuo , MIZUTANI Masahiro 
Published: May 2008

Abstract ICR mice were treated intraperitoneally with mitomycin C (MMC) at a single dose of l‐5mg/kg on day 0, 1, 2 or 3 of pregnancy (vaginal plug = day G). Embryotoxicity and teratogenicity were examined at term.A dose‐dependent increase in fetal mortality and decrease in the number of implants, fetal weight or number of ossified sacral and caudal vertebrae were observed. The incidence of external malformation, umbilical hernia, significantly increased among the fetuses of dams treated with MMC at 5mg/kg on day 1, 2 or 3. Skeletal malformation failed to show significant increase though some fetuses from MMC‐treated mice were attended with multiple defects such as fusion of ribs or axial skeleton.Maternal contribution to and the direct action of MMC on embryonic development were investigated by embryo transfer. In regard to malformation inducement and decrease in implants, the maternal environment was found to have more significant effect than the direct action of this drug but both these factors are significantly responsible for increased fetal mortality and growth retardation.
A Clinical Case of Persistent Stapedial Artery
Authors: MASUDA Yu , WATANABE Shuichi , OMICHI Takuya , OGURA Yoshio 
Published: May 2008

Abstract A case of persistent stapedial artery is presented.The patient was a 49‐year‐old man who had suffered from tinnitus in the left ear and bilateral hearing impairment for 20 years. The preoperative audiological examinations showed considerable combined hearing loss, suggesting middle ear anomalies or otosclerosis. An exploratory tympanotomy on the left ear was performed, and complete fixation of the stapedial footplate and a small vessel running vertically on the footplate were observed. By reconstructive surgery using a prosthesis, postoperative hearing improved. The histological examination of the removed portion of the stapes showed an otosclerotic lesion. Cases of persistent stapedial artery found in the literature were discussed from the clinical and embryological viewpoint.
Developmental Abnormalities of Dendrites of the Cerebral Cortical Neurons in Mental Retardation*
Authors: TAKASHIMA Sachio , MITO Takashi , HASHIMOTO Kimio 
Published: May 2008

Abstract This paper of Golgi studies describes abnormal dendritic structure and development assessed by camera lucida representation, quantitation of dendritic spines, and dendritic branch measurement in metabolic and chromosomal diseases with mental retardation, reviewing the literatures of Golgi study.Neuronal lipid storage diseases with progressive mental and motor deterioration show characteristic meganeurites between the soma and origin of the axon, and all dendrites have fewer number of branches, shorter total basal dendritic length and marked reduction of spines. Phenylketonuria and Lesch‐Nyhan syndrome also present decreased number of spines.On the other hand, children and adults with Down's syndrome show poor dendritic spine density and dendritic branchings as well as structural irregularity of spines. This poor' development of dendrites suggesting postnatal poor synaptogenesis may be related to mental retardation in children. These postnatal dendritic abnormalities may be based on genetic factors such as diminished number of cortical granular cells and extrinsic factors which include poor perception of external stimuli as noted in sensory deprivation.Thus, dendritic spine abnormalities may be correlated with mental retardation. However, we need better staining method and more sytemic study.