bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Use of Animal Models in Understanding Human Teratogens
Authors: WEBSTER William S. 
Published: May 2008

Abstract The testing of drugs and other chemicals in pregnant animals is required by legislation in a number of countries as a screening procedure for teratogenic potential in the human. The testing procedure involves methodology designed in the 1960s which was based on regimens established in the 1940s for toxicity testing. The requirement that animals are dosed to maternally toxic levels, frequently means that the embryos are exposed to inappropriately high concentrations of the test substance. Positive results in this type of experiment may have no relevence to the human situation where the exposure profile is often quite different, with the human embryo being exposed for prolonged periods to much lower drug concentrations. One way of duplicating the anticipated human exposure is to grow rat embryos in serum containing the drug and/or its metabolites at concentrations determined in the human during early clinical testing. It is proposed that mammalian embryos will respond in a similar manner to a particular concentration of a test substance.In vitro experiments using isotretinoin and its main metabolite 4‐oxo‐isotretinoin showed that the metabolite was teratogenic at concentrations which occurred in the human during normal repetitive dosing and hence the metabolite was the likely human teratogen. Similarly, rat embryo culture studies showed that the anticonvulsant drug, valproic acid, was teratogenic at blood concentrations which occurred during normal dosing in the human. Other in vitro studies showed that cadmium is unlikely to be a human teratogen, despite the fact that it is well established as a teratogen in experimental animals in vivo.It is proposed that embryo culture should be used as an adjunct procedure during teratology testing making use of metabolic and pharmacokinetic data obtained from the human during clinical testing.
Developmental Disturbance of the Cerebral Cortex of Mouse Offspring from Dams Treated with Ochratoxin A during Pregnancy
Authors: HOSHINO Kiyoshi , FUKUI Yoshihiro , HAYASAKA Ikuo , KAMEYAMA Yoshiro 
Published: May 2008

ABSTRACT  This study was designed to elucidate long‐term pathological effects of ochratoxin A, one of the food contaminating mycotoxins, on the developing brain in mice. A single intraperitoneal injection of ochratoxin A at a dose of 2 or 3 mg/kg was given to pregnant mice on day 10 of gestation. They were allowed to give birth and the offspring were examined 6 weeks after birth. Their body weight, brain weight, brain size, thickness and cell packing density of dorsal neo‐cortex in histological sections were examined. Growth of basal dendrites of pyramidal neurons in the layer V of dorsal neocortex was also examined with Golgi‐Cox specimens in terms of number of dendrites directly arising from the perikaryon, number of endings of dendrites, branching index (No. of endings/No. of arisings), mean distance from the perikaryon to the tips of dendrites, and number of intersections of dendrites with the zonal boundaries.Significant changes were found in brain weight, anteroposterior length of cerebrum, mean distance from the perikaryon to the tips of dendrites and number of intersections of dendrites with the zonal boundaries. These parameters can be recommended as sensitive ones in order to estimate rather weak effects of cyto‐toxic chemical agents exposed in utero on the development of cerebral cortex.
Congenital Anomalies of Central Nervous System and Neuronal Plasticity*
Authors: SHIMADA Morimi 
Published: May 2008

Abstract Pathological studies on autopsied brains of mentally and physically handicapped children disclose not infrequently various abnormalities at the histological and cytological levels, such as the abnormal cytoarchitecture, heterotopic neuronal nests, abnormal orientation of neurons and tortuous dendrites. These abnormalities have generally been considered to result from the disorders of neuron production and/or mechanical obstruction of neuronal migration including abnormal radial fibers.Our experimental studies on the microcephalic mouse, which was induced either by prenatal or by postnatal administration of cytosine arabinoside, indicated that the following factors play important roles for above mentioned histological and cytological changes: (1) Disturbance of the neuron production following the destruction of the matrix layer. (2) Regional and incomplete regeneration of the matrix layer and delayed neuron production in the regenerated matrix layer. (3) Unbalanced and plastic synaptogenesis between the remaining neurons which have been produced prior to the destruction of the matrix layer, migrating young neurons produced in the regenerated matrix layer and the afferent fiber terminals which originate from subcortical neurons.
Congenital Amputation of All the Limbs Related with Amniotic Rupture
Authors: SINGH Jay Datta , SINGH Gajendra 
Published: May 2008

AbstractA female infant born with all the four limbs amputated close to the proximal ends is reported. The parents both Indians, having six normal children with poor socio‐economic background denied family history of any congenital anomalies. The mother neither suffered any illness nor had exposure to any known teratogen to the best of their knowledge during this pregnancy. However the mother had attempted to abort this baby in the week 7 of gestation with help of an indigenous mechanical device, a herbal stick, per vaginam which resulted in gushing out of some fluid (amniotic fluid) only. This unsuccessfully attempted abortion neither affected the mother nor the pregnancy apparently and on full term this baby was born. When examined on postnatal day 33, the baby looked very healthy, alert and responsive weighing 3500 g, with CR length 38 cm and occipito‐frontal circumference 35 cm. No abnormalities were observed except that all the limbs were amputated just distal to their proximal end. The baby could move all the stumps of the amputated limbs actively. This case seems to be first of its kind being reported from India.The etio‐pathogenesis of amputation of limbs was reviewed and evaluated in the light of the available literature. Of the possible etiological factors suggested in the literature the most convincing mode of amputation of all the limbs simultaneously in the present case seems to be the multiple amniotic band formation.
Morphological analysis of neural tube defects: Chlorambucil‐induced exencephaly in mice
Authors: TANAKA Osamu , YOSHIOKA Natsumi , YOSHIOKA Takafumi , NAORA Hiroyuki , HATTA Toshihisa 
Published: May 2008

Abstract: Exencephaly has been induced in mouse embryos by chlorambucil (CA), a cytotoxic agent. To understand the course of development of this malformation, open neural tube defects in CA‐treated mice were examined using light and scanning electron microscopes (SEM). CA was given to the pregnant mice on day 7.4 of gestation. Embryos were removed and fixed on gestational days 9.3–9.4, 9.7–9.8 and 10.4, and compared to control embryos from untreated mice. By gestational day 9.4, all control embryos had closed neural tubes, except for the posterior neuropores, and well developed brain vesicles. By contrast, in the experimental embryos the frequencies of open neural tube were 26/33 (78.8%), 32/ 40 (80.0%) and 23/66 (34.8%) on each day examined, respectively. Open neural tube defects were classified into six patterns according to the location and magnitude of the open area. The patterns of open neural tube on day 9.7–9.8 were diverse; however, in almost all cases on day 10.4 the open neural tube appeared in a region from the caudal forebrain to the rostral hindbrain. It was evident that an unusual pattern of closure of the neural tube was involved in forming the cranial neural tube. The present study shows that failure of closure of the cranial neural tube in the CA‐treated mouse embryos can be defined as a primary neural tube defect (NTD), which can be, in part, repaired by unusual closure of the neural tube.At high magnifications of SEM, the neuroectodermal surfaces of the 9.0‐day affected embryos often had a number of slender processes projecting from the neuroepithelial cells. “Ruffles” and “blebs” at the lateral edges of the neural folds were observed in both control and affected embryos.
Growth Retardation during Organogenesis in Genetically Diabetic Mice, Yellow KK
Authors: OOSHIMA Yojiro 
Published: May 2008

SummaryYellow KK mice with non‐insulin dependent diabetes were mated at 7 (group A) or 13 (group B) weeks of age. On day 13, 16, or 18 of pregnancy, the plasma glucose concentration in dams was determined, and the embryos/fetuses and placentae were weighed and examined.The rate of early embryonic death was high and invariable on all three days. The rate of late death increased with advancing pregnancy in both groups and the incidence in group B was higher than in group A on each of the three days. On day 13 of pregnancy, maternal plasma glucose concentration in group B was significantly higher than in group A (465mg/dl vs 230 mg/dl). Embryonic and placental weights in group B were less than those in group A (84 vs 113 mg and 59 vs 68 mg). In group B, there was an inverse correlation between the maternal plasma glucose concentration and the embryonic weight. A similar inverse correlation existed between the maternal plasma glucose concentration and the placental weight. On days 16 and 18 of pregnancy, fetal weights in group B were less than those in group A, but placental weights did not differ significantly between the two groups.From these results, it appears that in the yellow KK mouse fetal growth retardation has already begun in the organogenesis period and is closely related to maternal hyperglycemia.
Effects of Chlorambucil on the Brain Development in Mice during Post‐neurulation Period
Authors: TANAKA Osamu , YOSHIOKA Natsumi , YOSHIOKA Takafumi , OTANI Hiroki , HATTA Toshihisa , HASHIMOTO Ryuju , ABU‐MUSA Antoine 
Published: May 2008

Abstract The teratogenic effect of chlorambucil (CA), given during proliferation of matrix cells of the brain following the closure of the neural tube, on the development of central nervous system in mouse embryos was investigated histologically. CA (4, 8 or 15 mg/kg) was given orally to pregnant mice on day 9, 10, 11 or 12 of gestation by single shot, and the fetuses were examined on day 18 of gestation.Significant decrease in the brain size and microcephaly occurred in fetuses treated with CA regardless of the gestational age studied. The microcephalic brains were characterized by the severe reduction of the cerebral hemispheres in a rostrocaudal direction rather than in the lateral directions. The fetal brains from mice given a low dosage of 4 mg/kg CA maintained normal cerebral cortex, but higher dosages (8 or 15 mg/kg) showed severe dysplasia of all the cerebral histological structures. In the groups treated with 8 or 15 mg/kg CA on day 10 or 11 of gestation, severe cranial malformations, identified as cranioschisis or encephalocele, were often observed. The malformed brains with cranioschisis showed an extensive necrosis of the brain tissue around the lesions. The present study shows that the microcephaly induced by cytotoxic teratogens such as CA, given during the proliferative period of matrix cells after closure of the neural tube, is different from that induced during the migratory period of the neuroblasts, and suggests that the degeneration of the brain tissue by the cytotoxic agent may induce the partial anencephaly in mice.
Behavioral Testing in the Context of Reproductive and Developmental Toxicity Screening in the West*
Authors: SCHARDEIN J. L. , YORK R. G. , WEISENBURGER W. P. 
Published: May 2008

Abstract Methods for assessing animal neurobehavior following prenatal/perinatal exposures have been in use for almost 20 years and screening tests incorporating them are regulated in three settings: in Japanese Segment II and III studies on drugs, European (EEC/UK) Segment I studies on drugs, and American neurotoxicity studies on chemicals.The methods used in the West for assessing behavior in these contexts at present are described in detail. The evolution of the methods over time, the concepts of apical tests and functional domains, the use of positive control agents, what the U.S. Collaborative Study has shown us, and justification for assessing animal behavior in predicting outcome from human exposures are discussed.
Mouse Embryo Culture for Chromosome Analysis*
Authors: TATEWAKI Reiko , TANAKA Osamu 
Published: May 2008

Abstract Mouse embryo culture has been established and applied in the study of the causal mechanisms of abnormal development. Mouse embryo culture can be used as an experimental system to examine the influence of teratogen on early development, together with investigations using developmental engineering such as chimera, transgenic mice and nuclear transfer. We combined mouse embryo culture with embryo transfer and chromosome analysis, and studied the relationship between environmental factors (including maternal factors) and genetic predisposition in developmental abnormalities in the embryos of diabetic mice.In mouse embryo culture from one‐cell to the blastocyst stage, fertilized eggs were incubated in modified Whitten's medium and mixed gas (5% O2, 5% CO2 and 90% N2) at 37°C for three days. β‐Mercaptoethanol 20 μM and EDTA‐2Na 100 μM were added in order to overcome “two‐cell block’ in which two‐cell stage embryos could not develop further. Under theses conditions, from 55 to 100% of the cultured one‐cell stage embryos developed into blastocysts depending on the strain.For chromosome preparation, Mikamo and Hamaguchi's method (1975) was modified. This method can be applied from one‐cell to pre‐implantation stage embryos, and allows a higher rate of success (63% of prepared embryos) in preparing chromosome slides than that reported in the literature. Using improved methods of embryo culture, embryo transfer and chromosome analysis, we have obtained evidence that both environmental and genetic factors are the causes of malformation during diabetic pregnancy in mice. Mouse embryo culture associated with chromosome analysis is a useful procedure, and offers important data for the clarification of the causal mechanisms in developmental abnormalities.
Stage Differences in Developmental Disorders in ICR Mouse Embryos Irradiated with Gamma‐Rays
Authors: KUSAMA Tomoko , HASEGAWA Yasunari 
Published: May 2008

ABSTRACTThis study was designed to determine precisely the radiosensitive period in the development of ICR mouse embryos during which external malformations and growth retardation tend to occur. Female and male mice were placed together for only three hours to allow fairly precise identification of the time of conception. The pregnant mice were divided into 31 groups, which were irradiated in turn with 1.5 Gy gamma radiation at 6‐hour intervals during the period of organogenesis. They were then observed on day 18 of gestation. Items recorded were intrauterine death, external malformations, sex ratio and fetal body weight. Death of the embryo/fetus, especially death in the early period of organogenesis, was most frequent in mice irradiated between days 6.75 and 8.25 of gestation, but there was no statistically significant difference in the frequency of early‐ and late‐period deaths between irradiated and control groups. The types and frequencies of external malformations observed differed according to the exposure period. The most highly sensitive period for each malformation lasted no more than 12 hours. Reduction of fetal body weight was a good indicator of radiation effects, and was observed mostly in the groups irradiated between days 9.75 and 11.00 of gestation. The sex ratio was not affected by the period in which irradiation was performed.
The Pathogenesis of Anorectal Malformation Induced by All‐Trans Retinoic Acid in Mice
Authors: HASHIMOTO Ryozo , ODA Sen‐ichi , INOUYE Minoru , YAMAMURA Hideki 
Published: May 2008

ABSTRACTThe pathogenesis of anorectal malformations has been discussed for more than 100 years, however, much remains to be elucidated. We studied the pathogenesis of high‐type anorectal malformations induced by all‐trans retinoic acid (all‐trans RA) in mice. Pregnant females were injected intraperitoneally once with all‐trans RA, suspended in corn oil (5 mg/ml), at a dose of 100 mg/kg on day 9 of pregnancy. The all‐trans RA‐treated females were killed on one of days 10 to 18 of pregnancy. All fetuses examined on day 18 of pregnancy following in utero exposure to all‐trans RA had anorectal malformations. In the affected male fetuses, the rectum was positioned away from the retroperitoneum toward the ventral side leading to the opening of the urethra just underneath the urinary bladder. Deficiency of the cloacal plate at the dorsal part was also observed in the affected embryos during days 10–11 of pregnancy. The cloacal plate is considered to bring the cloacal cavity to the anus, and thus the deficiency of the dorsal part may be the major cause of the hightype anorectal malformations.
Craniofacial Dysmorphia of Frontal Proboscis in Holoprosencephaly
Authors: LEE Suk Keun , SUH Yeon‐Lim , CHI Je G. 
Published: May 2008

ABSTRACTWe have examined eleven cases of holoprosencephaly with special emphasis on the frontal proboscis. Although the nostril appears blind ended grossly, the proboscis has a single slender midline nostril lined with squamous mucosa containing numerous sebaceous glands. It is actually connected to a poorly formed but definite nasal cavity microscopically. The inner portion of the nostril tunnel is lined by olfactory mucosa containing numerous subjacent secretary glands. Despite the absence of olfactory bulbs and tracts the cartilaginous nasal capsule is identified along with abnormal nasal cavity. However, the nasal capsule is hypoplastic, and has an aberrant nasal septum and no concha. In severe form of holoprosencephaly, i.e., cyclopia, the nasal capsule is noted above the level of the ethmoid plate, in which case the nasal cavity dose not communicate with nasopharynx because it is too distant from the hypoplastic maxilla. Therefore, choanal atresia is resulted. Although unique maxillary bone comprises the whole upper jaw, the failure of fusion between vomeronasal septum and palatal processes in holoprosencephaly results in abnormal maxillary bone which is characterized by a narrow palate without palatal arch form. Nevertheless, through serial microscopic sections we could find a space between the posterior maxilla and the sphenoid bone, which is composed of adipose tissue and is similar in shape to the nasal capsule. This space is thought to be made for the nasal capsule during early developmental period. The present study suggests that the frontal proboscis in holoprosencephaly is an undescended nose. In most cases it is connected to the aberrant nasal cavity which is located beneath the proboscis. The level of proboscis descends gradually toward normal nose position as the severity of holoprosencephaly decreased from cyclopia, ethmocephaly, cebocephaly, to premaxillary agenesis. Key words: frontal proboscis, holoprosencephaly, craniofacial dysmorphia
Behavioral Characteristics of the Mentally Retarded with Arithmetic Tasks: From a Special Educational Point of View*
Authors: SUZUMURA Kinya 
Published: May 2008

ABSTRACTVarious types of errors are shown in a mentally retarded boy (CA 12:10, Tanaka‐Binet IQ 45–50) engaging in a standardized arithmetic achievement test for first‐grade pupils. The following issues on behavioral characteristics of the mentally retarded with arithmetic tasks are discussed from a special educational point of view.1. Production of correct solutions depends heavily on self‐regulation, motivation and metacognition levels of the retarded with arithmetic tasks. Therefore, maintaing appropriate levels of these processes is a fundamental principle in encouraging the mentally retarded to do their best.2. How the retarded deal with a task on figures depends on how the figures appear to them. It is a perceptual problem rather than an arithmetic one.3. While the retarded can do well on a task by manipulating the objects in question in his daily life, they cannot solve the same task in an achievement test situation. They attempt to solve a task using a familiar strategy and are difficult to change the one used. They adopt a known strategy with a clue of particular word, phrase or part of story to deal with the tasks.4. Realization of how to use the counting principles develops step by step, but understanding process of every principle on cardinal progression is one thing and that on multiple progression is another.
The Role of Apoptosis in the Manifestation of Polydactyly and Arhinencephaly in Genetic Mutant Mouse Pdn/Pdn*
Authors: NARUSE Ichiro , KEINO Hiromi , TANIGUCHI Masahiko , MASAKI Shigeo 
Published: May 2008

Abstract Pdn/Pdn mouse exhibits preaxial polydactyly and arhinencephaly, including various brain abnormalities such as the absence of corpus callosum and hydrocephaly. We have investigated the mechanism of the manifestation of polydactyly. The abolishment of the deep preaxial mesodermal programmed cell death, foyer primaire préxial (fpp), has been considered to be the starting point of the manifestation of preaxial polydactyly. With this hypothesis, we electrocauterized the fpp region of Pdn/Pdn embryos, because Pdn/Pdn lacks fpp. After surgery, Pdn/Pdn embryos were developed using whole embryo culture system or exo utero method. They exhibited 5 digits in their limbs which received surgery in fpp region.Meanwhile, much more apoptotic degenerations were observed in the brains of Pdn/Pdn newborns and embryos than normals. Anti‐single‐stranded DNA antibody was used to detect the localization of apoptotic cell death in the brains of Pdn/Pdn mice. TRPM‐2 gene has been considered to be an indicator of apoptosis. The brains of Pdn/Pdn newborns and embryos showed higher TRPM‐2 gene expression in Northern blot analysis. From these results, we speculated that abnormal apoptosis in the periventricular zone induced the expansion of the ventricle followed by hydrocephaly.
Species Difference in Developmental Toxicity of an N‐Phenylimide Herbicide between Rats and Rabbits and Sensitive Period of the Toxicity to Rat Embryos
Authors: KAWAMURA Satoshi , KATO Terushige , MATSUO Masatoshi , SASAKI Madoka , KATSUDA Yoko , HOBERMAN Alan M. , YASUDA Mineo 
Published: May 2008

AbstractAn N‐phenylimide herbicide, S‐53482, exhibited developmental toxicity in rats in the absence of maternal toxicity at a dose of 30 mg/kg. The developmental toxicities noted were embryolethality, teratogenicity (mainly ventricular septal defect [VSD] and wavy ribs) and growth retardation. In contrast to rats, the herbicide showed no developmental toxicity in rabbits even at a maternal toxic dose of 3,000 mg/kg. There was a remarkable species difference between rats and rabbits. A single dose of S‐53482 was administered to pregnant rats on one of gestation days 11 through 15 (detection of plug = day 0). Day 12 of gestation was the most sensitive day for embryonic death, VSD, and decreased fetal body weight. It is likely that there is a common mechanism for the three types of developmental toxicity and that S‐53482 does not produce VSD by its direct damage to embryonic heart tissue.