bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the Effects of Paternal Drug/Chemical Exposure on the Offspring
Authors: ADAMS Perrie M.
Published: May 2008

Abstract A number of different approaches to the study of the effects of male‐mediated drug or chemical insult on the subsequent offspring have been used. Typically a modified dominant lethal protocol has been used with the offspring allowed to go to term and the functional development assessed at specific postnatal ages. The present review examines the importance of the mating times for identification of the stages of spermatogenesis most sensitive to insult and the possible mechanisms involved in male‐mediated transmission of the effect of toxic exposure to the offspring.

The functional assessments demonstrating a paternal‐mediation of drug and/or chemical exposure have included motor coordination, reflexive behavior, locomotor activity and associative learning. The importance of the mating sequence, assessment methods and interpretation alternatives must be considered in designing studies to identify the extent of the risk to the male genome of drug/chemical exposure as reflected in functional deficits to the subsequent offspring.
Methods in Behavioral Teratology Screening: Current Status and New Developments
Authors: VORHEES Charles V.
Published: May 2008

Abstract In 1975 our laboratory began developing a behavioral teratology screening test battery suitable for use in preclinical safety assessment experiments with rats. The battery involved assessment of physical milestones of development, sensorimotor reflex ontogeny, pre‐ and postweaning locomotor activity, motor coordination, and tests of learning and memory. Although some of the specific procedures were new, the tests themselves were drawn from the experimental animal psychology, undernutrition, psychopharmacology, and developmental X‐ray literatures. The features which distinguished this approach from the past were not to be found in the tests employed, but rather from (1) the effort to objectify and standardize the tests to make them better suited as screening instruments and (2) the evaluation of them collectively and individually for reliability and validity. Reliability was ascertained by replication and validity by evaluation of positive and presumptively negative control test agents. The present paper reviews the rationale for the test battery and some of the positive effects that have been detected with the individual tests. New tests added to and old tests modified in the battery are discussed in the light of the recommendations which have come from the recently completed U.S. Collaborative Behavioral Teratology Study. Particular emphasis is placed on a discussion of the Biel water maze as a test that has been perhaps the most successful instrument for identifying behavioral teratogens to come out of the Cincinnati research effort.
The Evaluation of Behavioral Teratogenic Effects*
Authors: KIMMEL Carole A.
Published: May 2008

Abstract The evaluation of behavioral teratogenic effects in animal studies will be discussed in light of the results of the Collaborative Behavioral Teratology Study (CBTS) (Buelke‐Sam et al., 1985) and the U.S. EPA's guidelines for the risk assessment of suspect developmental toxicants (U.S. EPA, 1986a). Although behavioral teratology testing is not routinely required by the U.S. regulatory agencies, data on existing chemicals are reviewed and evaluated in the risk assessment process. Such data can be of value in at least three ways: 1) data from postnatal studies may be useful in elucidating the consequences of perinatal findings; 2) behavioral data may help to further define the lower end of the dose response curve; and 3) for chemicals where human exposure is likely, behavioral studies may help to focus on types of effects which may be important to monitor in the exposed human population. Recent efforts in methods development and validation, including the CBTS, have provided guidance for the development of regulatory testing requirements in specific cases. For example, the U.S. EPA has recently published a proposed test rule which includes developmental neurotoxicity testing for the triethylene glycol ethers (U.S. EPA, 1986b). Generic guidelines for such testing may be developed which can then be applied on a case by case basis.
A Sterile 21, X Chinese Hamster
Authors: SONTA Shin‐ichi , SEMBA Reiji
Published: May 2008

Abstract A Chinese hamster with a single X chromosome was found in 23 off‐spring from crosses between a male heterozygous for T(1;3)8Idr translocation and karyologically normal females. All karyotypes of cells from various tissues of this animal were 21, X. The animal had an external genitalia generally characteristic to the female but no typical proestrous and estrous figure was found in the vaginal smear, and the animal showed no indication of pregnancy by any crosses. On autopsy, two gonads were found. Microscopically, there were some large fluid‐filled cysts and many follicle‐like bodies in the cortex of both gonads, but no mature follicle containing an oocyte was observed. The XO conditions in the Chinese hamster are compared with those of other mammals.
Effect of Copper on Cultured Fibroblasts from Macular Mouse as a Model of Menkes Kinky Hair Disease
Authors: KATSURA Tadahiko , YAMANO Tsunekazu , SHIMADA Morimi
Published: May 2008

Abstract When the fibroblast from a patient with Menkes kinky hair disease (MKHD) was cultured in a copper‐enriched medium, the rounded, detached and floating cells increased in number. Cell proliferation was also inhibited considerably in the fibroblast from MKHD as compared to that from the normal control. The fibroblast from hemizygote of the macular mouse showed a similar sensitivity for copper in culture medium. Copper content was significantly increased in the cultured fibroblasts from the patient with MKHD and the hemizygote of the macular mouse in a copper‐enriched medium compared to that in the fibroblast from the respective control. These results were well identical to those in literatures concerning MKHD and indicate that the fibroblast from the hemizygote of the macular mouse biochemically show a close similarity to those from MKHD and that the macular mouse serves cellbiologically as a model of MKHD.
Histogenetic Causes of Mental Retardation: Current State and Future Implications1,2
Authors: SCHMITT Horst P.
Published: May 2008

Abstract Pathogenetically, mental retardation (MR) may be classified into three basic forms, including MR with grossly evident developmental abnormalities of the CNS, MR with encephaloclastic, sclerotic and atrophic change of central nervous tissue, and MR without evident alterations of the CNS at the routine microscopic level [“poor morphology MR (PMMR)”]. The complicated polyetiologic situation of MR will be summarized in a multigraph in order to provide a synopsis of the manifold interrelations and of the general factors involved in the origin and pathogenesis of MR. PMMR is said to comprise about 40% of the observations of MR. However, with special techniques, such as selected silver impregnations, immunocytochemistry, electron microscopy, autoradiography, and others, morphologic correlates may also be demonstrated in PMMR at the fine structural level. Of great importance in this respect are not only factors interfering with intrauterine development, but also mechanisms acting upon postnatal differentiation in the most critical period of brain plasticity. This fact should deserve more attention in future morphologic research into the fine structural and molecular correlates of MR. The same is true for CNS myelination which has only infrequently been considered in former investigations into MR. Further, not only the quality and quantity of changes in the CNS should be regarded, but also their topographic distribution in MR. The reticular formation and the hippocampus (limbic system) will be emphasized as sites of major importance in this respect. Future implications for research into morphologic correlates of PMMR will be discussed. Special emphasis will be put on the importance to take more advance of the results of basic neurobiologic research into the molecular bases of learning and behavior as a guideline for future research into PMMR.
Cerebellar Abnormalities Induced by Intracisternal Injection of Cytosine Arabinoside in Neonatal Mice
Authors: FUKUI Yoshihiro , HOSHINO Kiyoshi , KAMEYAMA Yoshiro
Published: May 2008

Abstract In order to examine the direct effects of cytosine arabinoside (Ara‐C) on cerebellar development, Slc:ICR mice were treated intracisternally with a single dose of 160 μ Ara‐C on day 0, 1, 2, 4, 5, 7 or 10 after birth. The mice in each group were killed at 30 days of age. Cerebellar weight was heavily reduced, but body and total brain weights were only slightly reduced in all Ara‐C‐treated groups. In mice treated on day 0, 1 or 2, derangement of the layered structure of the vermis was evident in the anterior folia. In the immunohistochemical examinations with GFAP and S‐100 protein, Bergmann glial fibers ran tortuously and not perpendicular to the pia mater in the disarranged area. Bergmann glial cell bodies were scattered in the cerebellar cortex and not always adjacent to Purkinje cells. In the group treated on day 4 or later, the layered structure of the vermis was well preserved.
Histopathological Changes of the Placenta in Diabetes Induced by Maternal Administration of Streptozotocin during Pregnancy in the Rat
Authors: PADMANABHAN R. , AL‐ZUHAIR A. G. H. , ALI Aida Hussein
Published: May 2008

Abstract The objective of this investigation was to find out the histopathological changes of the placenta and to correlate them with fetal malformations and growth retardation in experimental diabetes. Diabetes was induced in Wistar rats at different stages of gestation by intraperitoneal injection of streptozotocin (STZ). The controls were either buffer treated or injected with STZ followed by 2–6 IU insulin until term. All fetuses and placentae were collected on day 20 of gestation. Fetuses of diabetic rats were significantly growth retarded. Maxillary hypoplasia, edema, gastroschisis, exencephaly and septal defects of the heart were the major malformations. Most of the experimental placentae weighed heavier relative to their body mass. Toluidine blue stained sections of the placentae revealed severe histological abnormalities. The unusually large sized placentae had extensive cystic degeneration, often with an increased population of leucocytes. Giant cells were very numerous. Perivascular fibrosis, persistence of fetal mesenchyme, edema, infarcts and vacuolisation were observed in the labyrinths. In the small placentae, the glycogen cells were fewer and the glycogen in them remained unutilized. Reduction of labyrinthine zone, hypovascularity, constriction of vessels, perivascular edema and platelet aggregation characterized these placentae. The placentae of externally malformed fetuses showed cystic degeneration; their labyrinths contained constricted and less extensive vascular network. Phagocytic giant cells, polymorphs and platelet aggregation were also marked. Placentae of externally normal looking fetuses also presented cystic degeneration, reduction in fetal vasculature, dilated maternal sinusoids and giant cell proliferation. Insulin treatment resulted in the preservation of most of the normal histology of the placenta which correlated well with the reduced fetal malformations.
A Case of 4p Trisomy Syndrome Originated from Maternal rcp(4; | 4)(p | 5. |;p ||.|): An Analysis with CBG, Ag‐NORs and Cd Banding Techniques in Prometaphase Cells
Authors: NARITOMI Kenji , IZUMIKAWA Yoshinori , MIYAGI Chuken , HIRAYAMA Kiyotake
Published: May 2008

Abstract A case of 4p trisomy syndrome originated from familial rep (4; 14) is reported. The rearrangement was characterized by a breakpoint at the centromeric region of chromosome 14 and by a reciprocal translocation between chromosomes 4 and 14. The translocation was observed in three generations. As a result of CBG banding analysis in prometaphase cells, the breakpoint of der(14) was considered to be located at 14p11.1, and a part of 14p11.1 was translocated to chromosome 4p. It was unknown whether a part of the centromere was involved in it or not.
Mental Retardation and Neurochemistry
Authors: HIRANO Shusuke
Published: May 2008

Abstract Neurochemical aspect of mental retardation is described, with special reference to phenylketonuria (PKU) as a cause of the inhibition of brain development. Biochemical and behavioral findings are outlined in S few animal models of PKU, including that of “maternal PKU” in which genetically normal offspring of rats with experimental PKU show significantly lowered discrimination learning ability. Possible roles of disordered amino acid metabolism and defective myelination in the inhibited brain development are briefly discussed.
Cell‐to‐cell Interactions during Development of the Neocortex, with Special Reference to Neuronal Migration*
Authors: FUSHIKI Shinji
Published: May 2008

Abstract Neuronal migration plays a key role in forming a characteristic laminar cytoarchitecture of the neocortex. In this review, the localization of cell‐surface molecules in developing murine neocortex including that of the reeler mutant were described in association with their functional significance. L1 antigen appeared solely on neurons which were placed in the intermediate zone, the cortical plate and the marginal zone. In the cortical plate the surface of neuronal cell body was positively stained until embryonic day 17. Later on, the cell body became negative whereas cell processes in the intermediate and the marginal zones remained positive. Migrating neurons in the intermediate zone were L1 positive. N‐CAM, on the contrary, were detectable on both matrix cells and neurons. The L2/HNK‐1 epitope was present on endfeet of matrix cells, in addition to on the neuronal surface. In vitro perturbation assays using embryonic neocortical explants showed that the antibody for L1 could modify the rate of neuronal migration to some degree. These results suggest the functional roles of the L1 molecule in neuronal migration. However, L1 was present in the reeler mouse that is supposed to have a genetic defect in neuronal migration resulting in a disorganized cytoarchitecture. The scanning electron microscope (SEM) fractographic studies revealed a defective formation of the bundles of matrix cell processes in the developing reeler neocortex. Our observations indicate deranged cellular interactions among matrix cells in the reeler, although no molecular abnormalities have so far been demonstrable. The significance of cell‐to‐cell interactions in neocortical histogenesis was discussed.
Developmental Toxicity of Aspirin Prenatally Given to Rats: Assessment in Sic: Wistar‐KY Rats
Authors: OKAMOTO Masaharu , KIHARA Takahide , TANIMURA Takashi
Published: May 2008

Abstract Slc:Wistar‐KY rats were administered orally with 62.5, 125, 187.5 or 250 mg/kg aspirin suspended with 0.5 % CMC‐Na on days 9–11 of gestation (plug += day 0). Suppression of maternal weight gain and food consumption during treatment was observed at and over 187.5 mg/kg. At term, the fetal mortality increased at and over 187.5 mg/kg and the fetal weight was lowered at and over 125 mg/kg. Among 15 live fetuses at 250 mg/kg, 4 had external malformations. In the skeletal examination (double staining), skeletal anomalies increased at and over 187.5 mg/kg. The skeletal variations such as vertebral anomalies, fused costal cartilages and increased presacral vertebrae were often encountered and delayed ossification was also found at and over 125 mg/kg. The internal anomalies tended to increase at and over 187.5 mg/kg. The live birth rate was significantly lower at 187.5 mg/kg than that in controls, and all pups, except for 3 from a dam, died before weaning. At 125 mg/kg, the pivoting locomotion on day 7 post partum was poorer as compared with controls. The physical and functional development at 62.5 mg/kg was not changed. There were no significant effects on male offspring in the open‐field, rotarod, under‐water T‐maze and avoidance learning tests. However, in the Biel T‐maze test (9–10 weeks of age), the aspirin‐treated groups showed more errors and the increased elapsed time on the 1st trial day than controls. These results indicate that aspirin may induce a slight learning defect on rat offspring even at the non‐teratogenic dose and the Biel T‐maze test is more sensitive than any other learning tests given in this study.
Effects of Folic Acid and Folinic Acid on Pyrimethamine Teratogenesis in Rats
Authors: KUDO Gen , KOKUE Eiichi , HAYAMA Toyoaki
Published: May 2008

ABSTRACT  The effects of folic acid (FA) and folinic acid (FNA) on the tera‐togenicity of the antifolate drug pyrimethamine (PYR) were examined in rats. PYR and FA were orally administered with mashed feed. FNA was intraperitoneal‐ly injected. The drugs were administered for 5 days of day 11–15 of gestation. Six groups were made; G‐I PYR 1.6 (mg/kg/day), G‐II PYR 3.6, G‐HI PYR 1.6 + FA 50, G‐IV PYR 3.6 + FNA 12, G‐V FA 50, G‐VI control. No malformations were found in G‐I, IV, V and VI. All fetuses in G‐II and HI had malformations. Main malformations in G‐II and III were cleft palate and brachygnathia. Accordingly it might be demonstrated that the teratogenicity of PYR was potentiated by concurrent FA in rats.
Chromosome Analysis in Preimplantation Stage Embryos of Non‐Obese Diabetic (NOD) Mice
Authors: TATEWAKI Reiko , OTANI Hiroki , TANAKA Osamu , KITADA Jin‐ichi
Published: May 2008

Abstract Congenital malformations such as exencephaly occur at a high incidence in non‐obese diabetic (NOD) mouse embryos (Otani et al., 1987a). Using in vitro culture and embryo transfer, genetic predispositions as well as environmental factors were suggested to be the causes (Tatewaki et al., 1987).

Chromosomes of preimplantation embryos, cultured to transfer mutually between non‐obese diabetic (NOD) and ICR mice, were analyzed as a clue to elucidate the cause of developmental anomalies. Among these preimplantation embryos, aneuploidy, mixoploidy and structural anomalies were found, but in incidence of chromosomal anomalies there was no significant difference, statistically, between preimplantation embryos from diabetic mothers and those from non‐diabetic mothers. These findings are considered to show that no increase in developmental abnormality in chromosomes occurs during the preimplantation stage.
Fetal Heart Malformations in Experimental Hyperphenylalaninemia in Pregnant Rats
Authors: SUYAMA Itsujin , TANI Mayumi , MATSUMURA Masahiro , ISSHIKI Gen , OKANO Yoshiyuki , OURA Toshiaki , NISHI‐MURA Kouichi
Published: May 2008

Abstract Sprague‐Dawley rats were given L‐phenylalanine intraperitoneally from the 8th to 11th day of pregnancy. The hearts of the fetuses were examined on the 21st day of pregnancy. We found that the group given the higher doses of L‐phenylalanine had significantly more heart defects than the group given the lower dose and the controls. Ventricular septal defect was found in 80 % of the fetuses with congenital deformities of the heart. [14C] Leucine uptake by the embryos was significantly lower in the group loaded with L‐phenylalanine than in the controls.

The activity of thymidine kinase, one of the rate‐limiting enzymes in DNA synthesis, was significantly lower in the brain and heart tissues of the young rats loaded with L‐phenylalanine than in the controls.

Thus, when blood levels of phenylalanine are high in early pregnancy, an amino acid imbalance in the embryo occurs during fetal organogenesis. Also, thymidine kinase decreases, which may hinder DNA synthesis. Both of these mechanisms seem to be involved in the higher incidence of fetal heart malformations in maternal phenylketonuria.
Effect of Prenatal Methylazoxymethanol Acetate Exposure on the Motor Behavior of the Rat Offspring
Authors: YAMAMOTO Yoshitame , TANIMURA Takashi
Published: May 2008

Abstract Crj:CD (Sprague‐Dawley) rats were treated intraperitoneally with methylazoxymethanol acetate (MAM) at 0 and 30 mg/kg on day 13 of gestation and were allowed to deliver. On day 4 postpartum, the litter size was adjusted to 8 with an equal sex distribution. Two males and females from each litter were tested between 3 and 5 weeks of age for open field activity and rotorod performance. At week 7 postpartum, all offspring were sacrificed and examined for brain anomalies.

The open field activity of MAM treated offspring tended to increase; number of ambulations and rearings were significantly increased at 3 weeks of age in male offspring treated with MAM when compared to those of male controls. At 3 weeks of age, the male offspring in the MAM treated group showed significantly reduced rotorod performance when compared to that in the control. Severe reductions of the cerebral hemispheres were observed at 7 weeks of age in the male and female offspring treated with MAM.

These results indicate that the motor behavior of offspring is significantly impaired at weaning when they were exposed to MAM prenatally. The effects were more severe for males than females.
Study on Cause of Death in Rat Neonates with Congenital Osteochondrodysplasia (ocd/ocd) I. Morphological Abnormalities in Lung and Respiratory Tract
Authors: KIKUKAWA Keiichiro , KAMEI Takayuki , SUZUKI Katsushi
Published: May 2008

Abstract The rat with congenital osteochondrodysplasia with systemic subcutaneous edema (ocd/ocd) dies shortly after parturition. The cause of death has not been fully understood in the similar lethal disorders in other species. The present study describes the morphological abnormalities in the respiratory tract in relation to the cause of death in ocd/ocd. Mid saggital section of the respiratory tract of the ocd/ocd neonate revealed that the air flow from nose to lung is disturbed by occlusion of the pharynx and larynx area with the cleft palate and relatively large tongue. Smaller thoracic volume was also noted in the ocd/ocd neonate. Of intra‐thoracic organs, only the lung showed significantly smaller weight in the ocd/ocd neonate than that of phenotypically normal (+/quest;). Histology of the fetal and neonatal lung showed atelectasis and many small alveolar cavities with abundant lung surfactants in the ocd/ocd. Disarrangement of the cells composing the alveolar wall was also revealed in the ocd/ocd. Electron microscopy of the fetal lung demonstrates the lamella bodies in the alveolar cavities and the pneumocyte type II cells in both genotypes. Insufficiency of the surfactant was excluded for the cause of death in the ocd/ocd.
Study on Cause of Death in Rat Neonates with Congenital Osteochondrodysplasia(ocd/ocd) II. Functional Abnormalities in Central Nervous System and Respiratory Muscle
Authors: KIKUKAWA Keiichiro , KAMEI Takayuki , SUZUKI Katsushi
Published: May 2008

Abstract The rat with congenital osteochondrodysplasia with systemic subcutaneous edema (ocd/ocd) dies shortly after birth. It has been considered that the cause of death would be disturbed air flow from nose to lung by morphological abnormalities in respiratory tract. Respiratory rhythm was studied in the isolated and perfused preparation of brain stem‐spinal cord‐thorax in the ocd/ocd and phenotypically normal (+/?). The response of the isolated and perfused preparation of thorax and diaphragm to the electrical stimulation was also studied. The spontaneous depolarizations of cervical ventral root C4 or C5 in the brain stem‐spinal cord‐thorax preparation were very low and infrequent in the ocd/ocd. The both tensions of the thorax and diaphragm preparations to the electrical stimulation were lower in the ocd/ocd than those in the +/?.

Those results show that the cause of death in the ocd/ocd is not only morphological abnormalities but also functional defects in the respiratory system including the central nervous system and muscles.
Effect of Streptozotocin Induced Maternal Diabetes on Fetal Skeletal Development in the Rat
Authors: PADMANABHAN R. , AL‐ZUHAIR A. G. H.
Published: May 2008

Abstract Alizarin red‐S stained skeletons of the fetuses of the streptozotocin induced (on days 2, 6 and 8 of gestation) diabetic and insulin and buffer treated control rats were examined on day 20 of gestation for malformations and hypoplasia. Hypoplasia of both the neurocranial and viscerocranial bones was significant in all 3 diabetic groups. Insulin treatment had a remarkable rescue effect on fetuses of the day 8 group; a moderately similar response was found in others. Inhibition of ossification of the scapula, humerus, radius and ulna was relatively less remarkable when compared to that of the homologous bones of the hind‐limbs. However the metacarpals were affected more than the metatarsals. Day 6 of gestation was particularly susceptible for retardation of sternal ossification. Agenesis, hemi‐ and double hemivertebrae were also observed in a few cases. Reduction in caudal sacral and coccygeal vertebral development was remarkable. Incidence of the 14th rib was highest in the day 6 group and insulin administration significantly reduced this abnormality. Meticulous metabolic control had beneficial effect over the growth retarding effects of maternal diabetes but did not completely prevent the malformations.
Prenatal Exposure to Atomic Radiation and Brain Damage*
Authors: OTAKE Masanori , YOSHIMARU Hiroshi , SCHULL William J.
Published: May 2008

Abstract Evaluation of data on the frequency of severe mental retardation among prenatally exposed survivors of the atomic bombing of Hiroshima and Nagasaki, and the performance of such survivors on intelligence tests and in school has shown the most striking effects on the developing brain of exposure to ionizing radiation to occur among those individuals exposed in the 8th through the 15th, and the 16th through the 25th week after fertilization. This is true under the earlier T65DR and the newer DS86 systems of dosimetry. Seizure data have also revealed a significant effect of radiation in the 8‐15 week period after fertilization.

Although the observed frequency of severe mental retardation in the 8‐15 week period can be satisfactorily described by a linear no‐threshold model with both dosimetries, there is some suggestion of a threshold in the low dose region with the DS86 uterine absorbed doses but not with the T65DR fetal absorbed doses. However, the location and even the existence of a threshold in these weeks after fertilization is difficult to demonstrate statistically with the DS86 uterine absorbed doses. If the threshold is estimated using all 19 cases of mental retardation within these weeks, the lower bound of the confidence interval of the estimate includes zero, and thus a threshold cannot be convincingly established. However, when we exclude two probable nonradiation‐related cases of Down's syndrome, the results suggest a threshold with a lower bound in the 0.10‐0.20 Gy region.

Both dosimetries indicate a threshold in the dose‐response function for mental retardation in the 16‐25 week period, probably in the 0.23‐0.70 Gy interval.

The seizure data provide no persuasive evidence of a threshold in the 8‐15 week period after fertilization; the 95% lower bound of the estimate of the threshold includes zero. Finally, although the mean IQ scores, and the mean school performances in the low dose region are similar to the values in the control group, particularly so with doses under 0.10 Gy, evidence for a threshold is not compelling.
Transgenic Mouse as Tools for the Study of Congenital Anomalies*
Authors: YAMAMURA Ken‐ichi , WAKASUGI Shoji
Published: May 2008

Abstract The molecular events that guide pattern formation during embryonic development have been difficult to characterize in mammals, partly because of the difficulty in drawing a molecular connection between the phenotype of a dysmorphic mutation and the specific gene in which that mutation occurs. However, recent advances for recombinant DNA technique have made it possible to approach and clone the genes involved in the developmental process. The experimental insertion of retroviral or molecularly cloned DNA into mouse embryos to produce transgenic mice is one such approach that has led to information on phenotypes of dysmorphic mutation at the molecular level. During a series of transgenic experiment weobtained a developmental mutant that showed an autosomal dominant trait characterized by a short snout. The primary couse of this dys‐morphism was a developmental defect in the first branchial arch. The transgene was integrated into the chromosome 13. One fragment flanking the insertion site was highly conserved in mammals.
Lung Hypoplasia in Developing Mice and Rats Induced by Maternal Exposure to Nitrofen
Authors: UEKI Reiko , NAKAO Yoshitaka , NISHIDA Takuji , NAKAO Yasuko , WAKABAYASHI Takashi
Published: May 2008

Abstract: The effects of maternal exposure to 2, 4‐dichlorophenyl‐p‐nitrophenyl ether (nitrofen) on prenatal lung growth were examined by dietary administration (2,000 ppm in ICR mice and 500 ppm in CD rats). Embryos and/or fetuses (conceptuses) were removed from dams on days 12 to 18 of gestation in mice and on days 14 to 20 of gestation in rats. Body and lung weights of the conceptuses were measured. General growth retardation was noted especially in the later period of intrauterine life in both mice and rats. Bilateral retardation of lung development of the nitrofen exposed conceptuses was noticed throughout intrauterine life including the periods before the closure of pleuroperitoneal canals in both species indicating that nitrofen induced primary lung hypoplasia. In mice, the left lung was more hypoplastic than the right one, while it was opposite in rats. The species specificity in side prevalence of the developmental retardation of the lung was observed even before completion of the embryonic diaphragm and it was well in accord with the side on which posterolateral diaphragmatic hernia (Bochdalek's diaphragmatic hernia, BDH) took place later. We conclude that nitrofen induces primary lung hypoplasia regardless of the presence or absence of BDH.
Intrauterine Repair of Cleft Lip in Mouse Fetuses
Authors: IGAWA Hiroharu H. , OHURA Takehiko , IWAO Fumiya , YAMAMOTO Yuuhei , FUJIOKA Hirotaka
Published: May 2008

Since most fetuses with drug‐induced cleft lip have concurrent cleft palate, they die shortly after birth as a result of difficulty in suckling. We devised an experimental model, in which cleft lip unaccompanied by cleft palate was produced artificially, in order to permit long‐term follow‐up of intrauterine cleft lip repair surgery.

Fifteen Jcl:ICR mice each on days 15, 16, 17 and 18 of gestation (the day when a vaginal plug was found = day 0 of gestation) were used. Each mouse was laparotomized by midline incision of the lower abdomen, and the fetus at the distal end or the fetus adjacent to the fetus at the distal end of the uterine horn was subjected to surgery. Using a surgical microscope, the uterine wall was incised, and the amnion and chorion were pierced to expose the snout of the fetus. After unilateral complete cleft lip was created, the wound was repaired with 10–0 nylon sutures. The snout was then replaced within the uterus, and the surgical wound in the uterine wall was closed. The uterine horn was then placed back into the peritoneal cavity, and the abdominal wound was closed. The dams were then returned to their individual cages, and the fetuses were delivered spontaneously.

The live birth rate for surgically treated fetuses was 60% in animals treated on day 15 of gestation, 73% among those treated on day 16, 80% among those treated on day 17, and 60% among those treated on day 18. The offspring underwent the normal course of postnatal growth, with good jaw development and no cicatrization at the site of upper lip surgery either grossly or histologically.
Experimental Hydrocephalus in Suckling Hamster Induced by Myxovirus Infection
Authors: TAKANO Tomoyuki , OHNO Masaki , YAMANO Tsunekazu , SHIMADA Morimi
Published: May 2008

Abstract This study was undertaken to elucidate the pathogenesis of the hydrocephalus and aqueductal stenosis induced by intracerebral mumps virus inoculation in suckling hamsters.

Mild ventricular dilatation became apparent after 5 days of inoculation. Focal denuding of the ependymal layer and subsequent aqueductal stenosis were observed by 14 days after inoculation. The virus antigen was detected not only in the ependymal cells and choroid plexus, but also in some neurons in the cerebral cortex, hippocampus, midbrain and cerebellum. In the cerebral aqueduct, the orderly arrangement of the cilialy clusters was destroyed on the 5th day after inoculation. After 10 days, proliferation of GFAP positive cells was noticed around the cerebral aqueduct and subsequently caused aqueductal stenosis. In the advanced state of hydrocephalus, the cerebellum was displaced downward and showed an elongated, atrophic and sleevelike structure similar to the Arnold‐Chiari malformation. It was suggested that the extensive damage of the ependymal cilia may account for early ventricular dilatation, and subsequent aqueductal stenosis with glial proliferation is the main cause of the advanced hydrocephalus. It has not yet been determined whether the mumps virus can pass through the human placenta or not. If it can, however, our results strongly suggest that mumps virus infection in the human fetus will cause congenital hydrocephalus.
Experimental Hydrocephalus in Suckling Hamster Induced by Myxovirus Infection
Authors: TAKANO Tomoyuki , OHNO Masaki , YAMANO Tsunekazu , SHIMADA Morimi
Published: May 2008

Abstract Intraperitoneal inoculation of suckling hamsters with parainfluenza virus type 3 (PIV‐3) caused hydrocephalus in about 17% of animals thus treated. In the inoculated hamsters, the PIV‐3 antigen was found to be located in the choroid plexus and ependymal cells of the ventricular system. This finding suggests that the PIV‐3 inoculated intraperitoneally transferred to the choroid plexus from the blood stream and invades this tissue first, and then gradually affects the ependymal cells of the ventricular system. The pathologic findings obtained in this experiment showed a close similarity with those obtained in our previous experiment on mumps virus induced hydrocephalus. It was conjectured that PIV‐3 induced hydrocephalus was caused by the same pathogenesis with the hydrocephalus by mumps virus infection. Our results strongly suggest that the PIV is a probable candidate for human congenital hydrocephalus of unknown origin, since PIV is the most common myxovirus.
Development of Rabbit Whole Embryo Culture during Organogenesis
Authors: NAYA Masato , KITO Yoshie , ETO Kazuhiro , DEGUCHI Takashi
Published: May 2008

Abstract The rodent embryo culture has widely been spread as a technique in teratogenicity studies. However, the whole embryo culture of rabbits has not been developed. Pregnant rabbits are usually used in a teratogenicity test as a non‐rodent animal to examine the species specificity. Rabbit embryos of the Japanese White strain on day 10 of gestation (the time of copulation = day 0) were cultured at 38°C for 48 hours in 100% rabbit serum. The 35 ml bottles with 5 ml serum were gassed with 95% 02 and 5%70 CO2 continuously. The yolk sac and amniotic sac were opened 24 hours after the beginning of the culture. At the end of the culture, embryos were examined for somite number, as well as protein content and crown‐rump length. Embryos cultured for 48 hours from day 10 seemed to be well developed as well as in vivo embryos. These results showed that rabbit embryo culture became a useful system for the study of reproductive and developmental toxicology, teratology and developmental biology.
Reduced Fertility in Female Homozygotes for hgn (Male Hypogonadism) Selected by hgn‐Associated Hypoplastic Kidney
Authors: SUZUKI Hiroetsu , HAKAMATA Yoji , KAMEI Takayuki , KIKUKAWA Keiichiro , SUZUKI Katsushi
Published: May 2008

The male hypogonadism rat (hgn/hgn) shows a characteristic male sterility as a single autosomal recessive trait. Recently, the female homozygotes for hgn, assumed to be fertile, could be detected by a /jgji‐associated hypoplastic kidney (hpk/hpk). The present study was to investigate a possible influence of the hgn gene on female reproduction. The hgn/hgn females showed a significant growth retardation as compared with the phenotypically normal ones (+/?; +/hgn or +/+). The litter size at birth and number of implantation traces were significantly less in the hgn/hgn than in the +/? females. The hgn/hgn females became anestrous and infertile much earlier than the +/? did. Histologically, there were a few corpora lutea, some atretic follicles at different stages of maturation and abundant abnormal interstitial cells with pyknotic or karyorexic nuclei in the ovaries of hgn/hgn females that have been infertile. The birth rate expressed by per cent litter size at birth against number of implantation traces was comparable between the hgn/hgn and the +/? female, suggesting that the small litter size of hgn/hgn female could not be due to the embryonic death in utero. Nevertheless, the number of the tubal ova at estrous was comparable in the hgn/hgn and +/? females. Therefore, it was suggested that the half of ova or embryos may be lost during the period from the fertilization to the implantation. Histological appearances of the neonatal ovary in the hgn/hgn seemed hypoplastic. The number of cells including oocytes and interstitial cells, enzymatically separated from neonatal ovary, was significantly less in the hgn/hgn than in the +/hgn. These results suggest that the gene product(s) coded by normal allele of hgn gene(s) involves normal gonadal development in both sexes; the defect may lead testicular dysmorphology in the male and reduced fertility in the female.
Effects of Maternal Hyperthermia on the Developing Guinea‐pig Eye
Authors: UPFOLD Jeffrey , NELSON Anamari , SMITH Murray , EDWARDS Marshall
Published: May 2008

Abstract Maternal hyperthermia of short duration had significant short and long term effects on the developing guinea‐pig eye at embryonic days 19, 21 and 23. A marked regionalisation of the heat‐induced effects was observed in the developing retinae, but the lens defects were most obvious following heat at E21 and E23. Bilateral anterior pole cataracts, bipolar zonular cataracts and microphthalmia have been produced following maternal heat stress. It is suggested that these are determined by the cellular events initiated in the developing eye following the teratogenic insult.
A Developmental Study of Reflex and Activity in Rats with Microcephaly Induced by Prenatal Methylazoxymethanol Acetate (MAM) Treatment
Authors: SUGIOKA Kozo , YAMADORI Takashi
Published: May 2008

Pregnant Wistar rats were given a single i. p. injection of 30 mg/kg methylazoxymethanol (MAM) acetate or saline on day 13 of pregnancy (vaginal plug = day 0). All offspring were subjected to reflex tests during the preweaning period (surface righting reflex, from 3 to 12 days of age; negative geotaxis reflex, from 5 to 12 days of age), and then selected male rats were subjected to open‐field test during the postweaning period (from 21 to 35 days of age). The MAM‐treated rats showed significantly longer latencies in the both reflex tests, and also significant hyperactivity in the open‐field test. These behavioral alterations were analyzed in relation to the large size reduction in the cerebral cortex and the morphological abnormalities of the hippocampus in the MAM‐treated rats.
Atrioventricular Septal Defect in Rat Fetuses Induced by Administration of Bisdiamine
Authors: TASAKA Hiroyasu , OKAMOTO Naomasa , TAKENAKA Hitoshi , KOGA Yasunori , HAMADA Minoru
Published: May 2008

ABSTRACT A high incidence of atrioventricular septal defect was induced in rat fetuses by administration of N, N ‐his (dichloroacetyl)‐1, 8‐octamethylenediamine, bisdiamine, to pregnant Donryu rats. Induction of atrioventricular septal defect was highly dependent on day of bisdiamine administration. When bisdiamine was administered singly on day 9.4 of gestation or consecutively on days 9 and 10 of gestation, the incidence of atrioventricular septal defect in fetuses increased. Survival rate decreased with increase in the amount of bisdiamine administered. Normalized incidence 5 for atrioventricular septal defect, which was calculated as a product of incidence and survival rate, was as high as 54.5% when 175 mg bisdiamine was administered on day 9.4 of gestation. Atrioventricular septal defect thus formed was of the complete type associated with either persistent truncus arteriosus or tetralogy of Fallot, indicating that the conotruncal portion was unexceptionally malformed. The present model is useful for analysis of development and pathogenesis of atrioventricular septal defect and also contributes to clarifying the normal development of atrioventricular valves and septa.
Retardation of Prenatal Brain Growth of Guinea Pigs by Disulfiram1
Authors: HARDING Antony J. , EDWARDS Marshall J.
Published: May 2008

ABSTRACT: Guinea pigs were given disulfiram (125 mg/kg) orally once each morning of days 17–19 or 19–21 of pregnancy. Brain weight was reduced in the offspring whose mother was dosed during days 19–21 of pregnancy. Females of both experimental groups were found to have smaller brains compared with the expected brain weight of similar body weight female controls. Male offspring of both experimental groups did not display any obvious reduction in brain weight.
Micrencephaly in Rats Caused by Maternal Hyperthermia on Days 13 and 14 of Pregnancy1
Authors: HARDING Antony J. , EDWARDS Marshall J.
Published: May 2008

ABSTRACT: Hyperthermia was induced in rats twice at an interval of eight hours on both days 13 and 14 of gestation by partial immersion in a water‐bath. Deep rectal temperature was raised to 42.5°C for five minutes. Body weights of newborn rats were reduced, but by three weeks of age compensatory post‐natal growth had eliminated the defect. In both newborn and 21‐day‐old rats, brain weight was significantly reduced compared with controls of similar body weight. No other anomalies were found.
Neurochemical Correlates of Learning Impairment in Microen‐cephalic Rats Induced by Methylazoxymethanol Acetate*
Authors: TAMARU Masao
Published: May 2008

ABSTRACTNewborn infants with histogenetic brain malformations can be long‐lived with mental retardation, which is considered a major problem in social medicine. Among these infants with mental retardation, many cases are accompanied by microencephaly. Experimentally induced microencephaly in rats presents a useful model for understanding human cerebral disorders. We have studied how neurochemical changes in the brains of microencephalic rats induced by prenatal treatment with methylazoxymethanol acetate (MAM) can affect their learning abilities. We reported that densities of monoaminergic transmitters in the atrophic cerebral hemisphere (CH; consisting of cerebral cortex and hippocampus) of MAM rats was markedly elevated, but that their total quantity per CH unchanged. As for the ability of operant discrimination learning, MAM rats could discriminate tasks. However, excitatory amino acid receptors, in which N‐methyl‐D‐aspartate (NMDA) is well known to be involved in spatial memory, showed decreased total binding in the CH of MAM‐treated rats. Spatial recognition ability evaluated using an 8‐armed radial maze task was impaired. These results suggest that the condensation of monoaminergic terminals in the atrophic CH of MAM rats may compensate for disability in discrimination learning, but the significant reduction of NMDA receptors may impair spatial memory in MAM rats.
Developmental Abnormalities Due to Exposure of Mouse Paternal Germ Cells, Preimplantation Embryos, and Organogenic Embryos to Acrylamide
Authors: NAGAO Tetsuji
Published: May 2008

ABSTRACT The developmental toxicity of acrylamide was investigated after paternal germ cells and preimplantation and organogenic embryos were exposed to the agent. In the first experiment, ICR male mice were injected intraperitoneally with single doses of 62.5 or 125 mg/kg acrylamide or daily doses of 50 mg/kg for 5 days. They were mated with untreated virgin ICR female mice on days 1–21 and 64–80 after the last injection. The sperms involved in fertilization during these two periods were postmeiotic germ cells and spermatogonial stem cells, respectively, at the time of acrylamide treatment. The uterine contents were examined on day 18 of gestation for dominant lethal effects, and the fetuses were examined for external malformation. Acrylamide exposure during the postmeiotic cell or spermatogonial stem cell stage caused no significant increases in the incidence of abnormal fetuses. Dominant lethals, however, were clearly induced when the germ cells had been postmeiotic at the time of acrylamide exposure. In the second experiment, ICR mice were injected intraperitoneally with a single dose of 125 mg/kg acrylamide on day 0, 1, 2, or 3 of gestation. The uterine contents were examined on day 18 of gestation. Acrylamide treatment on day 0 of gestation caused a significant increase in the incidence of malformed fetuses, while treatment on day 1, 2, or 3 of gestation failed to cause an increase in malformation. Polydactyly was the most common type of abnormality. In the third experiment, pregnant mice were treated with three daily doses of 50 or 100 mg/kg acrylamide on days 6–8 or 9–11 of gestation, respectively. There was no significant difference between the incidence of malformed fetuses in the control and acrylamide‐treated groups. These experiments demonstrate the vulnerability of preimplantation embryos to the toxic effects of acrylamide, while paternal germ cells and the organogenic embryos are resistant to the induction of fetal malformations.
Induction of Congenital Malformations in Mice by Paternal Methylnitrosourea Treatment
Authors: WADA Azusa , NAGAO Tetsuji
Published: May 2008

ABSTRACTA single dose of methylnitrosourea (MNU, 25–100 mg/kg) was injected intraperitoneally into ICR strain male mice. The males were mated to untreated females of the same strain on days 1–21 and 64–80 after the treatment. On day 18 of pregnancy, the fetuses were examined for external and skeletal abnormalities. MNU treatment of paternal germ cells caused significant increases in the incidence of abnormal fetuses over the control level. The induction rate per live fetus per unit dose in mg/kg by treating spermatogonial stem cells was estimated to be 3.0 × 10−4, which is quite similar to the rate previously estimated for the same endpoint at the same germ cell stage with the fractionated doses of MNU (daily doses at 5–25 mg/kg for 5 days). Cleft palate and dwarfism were the most frequent external abnormalities in the MNU‐treated and the control series. Malformed ribs was the most frequent skeletal abnormality in the treated series. It was concluded that congenital malformations induced after treating male mice with a single dose of MNU were quantitatively and qualitatively similar to those induced after treating male mice with the fractionated doses of MNU.