ABSTRACT Autism is a behaviorally defined disorder associated with characteristic impairments in social interactions and communication, as well as restricted and repetitive behaviors and interest. Its prevalence was once thought to be 2/10 000, but recently several large autism prevalence reviews revealed that the rate of occurrence was roughly 30/10 000. While it has been considered a developmental disorder, little is certain about its etiology. Neuroanatomical studies at the histological level in the brains of autistic patients provide many arguments in the etiology of autism. Results from postmortem and imaging studies have implicated many major structures of the brain including the limbic system, cerebellum, corpus callosum, basal ganglia and brainstem. There is no single biological or clinical marker for autism. While several promising candidate genes have been presented, the critical loci are yet unknown. Environmental influences such as rubella virus, valproic acid, and thalidomide exposure during pregnancy are also considered important, as concordance in monozygotic twins is less than 100% and the phenotypic expression of the disorder varies widely. It is thus hypothesized that non-genetic mechanisms contribute to the onset of autistic syndrome. In light of these ambiguities, hope is held that an animal model of autism may help elucidate matters. In this article, we overview most of the currently available animal models for autism, and propose the rat with mild and transient neonatal hypothyroidism as a novel model for autism.
ABSTRACT Reconstructed micro computed tomography (Micro-CT, µ-CT) images have revealed the detailed three-dimensional structure of the cranium of human fetal congenital anomalies for the first time. The objects were a head and a cervix of female autosite and a parasite consisting of only a head conjoined to the scapular region of the autosite of an asymmetric double malformation (asymmetric conjoined twins, heteropagus twinning) at a gestational age of 8 months. The cranium of the autosite was normal, but that of the parasite was characterized by otocephaly (agnathia, synotia, and monorhina) and almost all the cranial bones were of an abnormal shape. It is suggested that a part of occipital bone (the basioccipital and exoccipital bones), the vomer and cribriform plate were absent and this resulted in the fusion and overlapping of bilateral temporal and craniofacial bones that should have been adjacent to them. This resulted in a reformation and relocation of most of the cranial bones. Micro-CT is a useful tool to visualize the detailed bone structure which has not been clarified by the conventional dissection methods and other imaging technologies and is a powerful instrument for studying congenital anomalies.
ABSTRACT Leptin is an obese gene product, and leptin-deficient ob/ob mice develop hyperphagia and reduced locomotor activity. Leptin is thought to be related to brain development, because leptin receptors are widely expressed in the brain, and because brain weight as well as brain protein and DNA contents were reduced in adult ob/ob mice. In this study, we investigated the effect of leptin on the fetal cingulate cortex, since the leptin receptor is expressed in the neurons of the cingulate cortex, which is involved in emotion as well as in sensory, motor, and cognitive processes. The ob/ob fetuses had more pycnotic cells than wild-type fetuses in the cingulate cortex at embryonic day (E) 18. Many pycnotic cells were observed in the intermediate zone of the cingulate cortex. Most cells observed in this area were neuronal lineage cells, while few undifferentiated cells and oligodendrocyte precursor cells were found. At E18 there was no significant difference in the rostrocaudal length of the corpus callosum, which contains the neuronal projection from the cingulate cortex, between ob/ob and wild-type fetuses. We also showed that the length of the cerebrum was greater and the width of the cerebrum and cerebellum were lesser in ob/ob fetuses than in wild-type at E16. These results suggest an increased cell death in neuronal lineage cells in the intermediate zone of the cingulate cortex in leptin-deficient ob/ob mice. Leptin deficiency may also alter the gross morphology of the brain in development, but not the formation of the corpus callosum.
ABSTRACT It is well-known that TCDD (2,3,7,8, tetrachloridedibenzo-p-dioxin) induces cleft palates (CPs) in pregnant C57BL mice. However, it is unclear if TCDD is a possible teratogen for cleft lip. We examined maxillofacial malformations including cleft lip in three animal strains: A/J mice, C57BL/6J mice and ICR mice. The A/J mouse develops cleft lip and palate spontaneously at a 5–10% rate. TCDD was administered in olive oil on gestation day (GD) 12.5 with gastric tubes at 10 µg/kg, 20 µg/kg, or 40 µg/kg to examine the dose–response, and on a single day from GD 8.5–14.5 to examine the timing effects of TCDD administration on lip and palate formation. Furthermore, the palatal shelf movements during GD 8.5–14.5 were observed with a stereoscopic microscope. All embryos had cleft palates when the TCDD was administered just before palatogenesis (GD11.5-GD12.5). With respect to the TCDD effects, there were large differences among the strains. In the A/J mice, the difference between a lethal dose and a dose that could induce a cleft palate was close. Cleft lips were not induced, even when the TCDD was given just before labiogenesis. Morphologically, both palatal shelves contacted perfectly along their lengths, but separated and formed cleft palates. In conclusion, TCDD is a strong inducer of cleft palates, and interferes with the fusion phase of the secondary palate, but has no effect on the lip.
ABSTRACT Newborn rat studies were conducted with oral administration of 3-ethylphenol (3EP) and 4-ethylphenol (4EP) on postnatal days (PND) 4–21 to allow comparison of no observed adverse effect level (NOAEL) and unequivocally toxic level (UETL) with those from 28-day studies of young rats starting at 5–6 weeks of age. In the newborn rat studies, slightly lowered body weight was observed after 3EP treatment, and deaths, hypoactivity, Straub tail, deep respiration and delayed righting reflex were clearly observed after 4EP treatment. In the young rat studies, salivation, staggering gait, changes in the liver including high values of liver weight and alanine aminotransferase or total cholesterol and the lesions in the forestomach were clearly observed after 3EP and 4EP treatments. NOAELs of 3EP and 4EP in the newborn rat studies appeared to be almost 3 times lower than those in the young rat studies. As a clear toxicity of 3EP was not observed in newborn rats, UETLs were not established for 3EP. Regarding 4EP, UETL of young rats was 4–5 times higher than that of newborn rats. In conclusion, newborn rats were 3–5 times more susceptible to 3EP and 4EP than young rats.
ABSTRACT We examined embryotoxicity using the embryonic stem cell test (EST) protocol. Tests were conducted using standard reagents for the atomic absorption measurement of 11 metal ions, silver, cobalt, chromium, copper, mercury, nickel, palladium, antimony, tin, vanadium, and zinc from among metals comprising dental alloys. In addition, for four metals like silver, cobalt, chromium, and nickel, the tests were also conducted using a test solution extracted from powder in the cell culture medium. The embryotoxic potential was obtained from a biostatistics-based prediction model, which was calculated from three endpoints, the ID50, IC50ES and IC503T3. Data with the standard reagents showed that chromium and mercury ions corresponded to class 3, that is, having a strong embryotoxicity, while antimony, tin, and vanadium ions exhibited a weak embryotoxicity. The other metal ions demonstrated no embryotoxicity. On the other hand, when extracts of metal powder in cell culture solutions were used, silver exhibited a weak embryotoxicity while all other metals exhibited no embryotoxicity. In the future, it will be important to clarify the embryotoxicity of the many dental materials that are in use today. In addition, it is necessary to develop substances to ensure they have no toxicity before use in dental applications.
ABSTRACT The objective of the study was to check the effect of oxoline acid, a bactericidal drug for the treatment of urinary tract infection during pregnancy, on congenital abnormalities of informative offspring and fetal development. Human data of oxoline acid use during pregnancy have not been reported, but the use of this quinolone derivative is not recommended during pregnancy by the US Food and Drug Administration. The teratogenic and fetotoxic potential of oxoline acid was evaluated in the population-based large data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities between 1980 and 1996. Observed and expected numbers of congenital abnormalities were compared in the newborn infants and fetus of case mothers with oxoline acid treatment. In addition, gestational age and birthweight were evaluated in control newborn infants born to mothers with or without oxoline acid treatment. Of 38 151 newborn infants without any congenital abnormalities (control group), 13 (0.03%) had mothers who were treated with oxoline acid, while of 22 843 cases with congenital abnormalities, five (0.02%) had mothers who were treated with oxoline acid during pregnancy (POR with 95% CI: 0.6, 0.2–1.8). The comparison of observed and expected number of different congenital abnormalities did not show the teratogenic potential of oxoline acid. There was a 0.9 weak shorter gestational age without a smaller birthweight in the newborn infants born to mothers with oxoline acid treatment. Our data did not indicate teratogenic and fetotoxic effect of oxoline acid, however, the number of cases and controls was limited.
ABSTRACT The present study was designed to explore whether maternal uninephrectomy affects development of the collecting ducts in fetal kidney. Localization of DNA fragmented cells in the kidney of fetal rats from uninephrectomized mothers were examined by the terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP-biotin nick end labeling (TUNEL) method. Immunohistochemistry was used to examine the localizations of bcl-2 gene products. The gene expressions for bcl-2, p53, and WT1 mRNAs were examined by using the semi-quantitative reverse transcript-polymerase chain reaction. TUNEL positive cells were more numerous in the medullary collecting ducts of the fetuses from uninephrectomized mothers than in those of the fetuses from sham-operated ones. The expressions of bcl-2, p53, and WT1 mRNAs were lower in the fetuses from uninephrectomized mothers than in the fetuses from sham-operated ones. Cells in the medullary collecting ducts showed positive reactions to anti-bcl-2 gene products antibody with the reactions being weaker in the fetuses from uninephrectomized mothers. These results showed that maternal uninephrectomy accelerated the development of fetal rat kidney and it was associated with the lowered the expression of bcl-2 in fetal rat kidney.