ABSTRACT Intrauterine infections of various microorganisms have the potential to induce brain abnormalities in the fetus and newborn infant. Among the infectious pathogens, cytomegalovirus (CMV) is the most significant infectious cause of brain abnormalities, with variations from fatal cytomegalic inclusion disease to functional brain disorders, such as mental retardation or epilepsy. Here, we present three autopsy cases of congenital CMV infection, and we review the features of the brain abnormalities of congenital CMV infection. A ventriculofugal spread of infection seems to be characteristics of congenital CMV-infected brains and is suggested to be the cause of neuronal migration disorders, resulting in brain malformations, such as microcephaly, lissencephaly and polymicrogyria. We also present an experimental animal model for congenital CMV infection. With the model we showed that murine cytomegalovirus (MCMV) infection in the developing mouse brain caused a disturbance of neuronal migration and neuronal cell loss, detected with morphometric measurements by labeling the neuronal precursor cells with BrdU. As shown by immunohistochemical double staining of BrdU and viral-antigen, infected neuronal cells constituted only a part of the disordered neuronal cells, suggesting that an indirect effect of vital infection on neuronal cells also contributes the migration disorders presumably mediated by cytokines or the induction of apoptosis. Neuronal migration dis- orders caused by MCMV infection are also discussed with reference to those caused by X-irradiation.
ABSTRACT Maldevelopment of the brain in offspring whose mothers smoked during pregnancy is being evaluated and reviewed using our Japanese data. In addition to the criteria for the fetal tobacco syndrome (FTS), I proposed the term, “fetal tobacco effects (FTE)”, when the gestational age is <37 weeks. Maternal factors during pregnancy including coffee drinking or polydrug use, and malconditions, such as premature rupturing of the membranes or placental abnormalities, were present at higher frequencies in FTE than FTS, although the factors of smoking and light drinking during pregnancy did not differ between them. As an indicator of maldevelopment of the brain, CNS involvement was more frequent and severer in FTE than in FTS. These findings suggest that factors in addition to smoking causing reduction in the gestation period may contribute to CNS involvement. As to the concomitant effects of ethanol and tobacco on maldevelopment of the brain, CNS involvement was highest in the offspring of women who both smoked and drank heavily. In conclusion, based on the concept of FTE in addition to FTS, a causal relationship between prenatal smoking and maldevelopment of the brains of offspring has to be investigated, especially as to factors modifying the effects of tobacco during pregnancy.
ABSTRACT Treatment of mouse preimplantation embryos with adriamycin (ADM), methyl methanesulfonate (MMS) and all-trans retinoic acid (RA) on their later develop- ment including implantation, growth and organogenesis were investigated. ICR mice were treated intraperitoneally with ADM or MMS on day 3 of gestation, or with RA on day 4 of gestation. The uterine contents were examined on day 18 of gestation. The viable fetuses were inspected for external and skeletal malformations. Irrespective of the kind of chemical agents tested, frequencies of total malformed fetuses were significantly increased, whereas the frequencies were considerably lower than those of malformations in fetuses of dams treated with ADM, MMS or RA during the period of organogenesis. In the fetuses of ADM-treated mice, the most common abnormality was umbilical hernia, followed by cleft palate. In the MMS-treated fetuses, the most common abnormality was cleft palate. Among the malformations observed in this study, duplication of hindlimb (5/193 fetuses) induced by the treatment with RA at the preimplantation stage was a quite unique abnormality. This type of malformation has never before been found in our historical control embryos and in embryos treated with various kind of teratogens. Based on these results and other data, it is concluded that embryos at the preimplantation stage are susceptible to environmental chemical-induced congenital malformations.
SUMMARY This study was designed to examine whether defects of the meningeal anlage and intracranial hydrodynamic overload are involved in the pathogenesis of secondary cranioschisis after the neural tube closure. Chlorambucil (CA) 3.0-4.0 mg/kg administered to pregnant mice on day 7.5 of gestation (E7.5) caused abnormal blebs at the occipital region of embryos on E13.5 in a dose-dependent fashion compared with control. At blebs, the mesencephalic ventricle was dilated, particularly on the dorsal midline and posterior to the pineal invagination. Histology showed fewer mesenchymal cells and vessels, as well as thinner neuroepithelial tissue than in controls. Transmission electron microscopy re- vealed that the cytoplasm of mesenchymal cells in the bleb region contained abnormal electron-dense deposits, whereas deposits or other subcellular abnormalities were not evi- dent in either the neuroepithelium or the surface ectoderm of the affected region. We administered 3.5 mgkg of CA on E7.5 and studied the embryonic development. Mesoder- mal hypoplasia appeared on E11.5, whereas blebs were initially recognized on E13.5. On E15.5 and E18.5, the meninges and calvaria were hypoplastic, although no apparent cra- nioschisis was evident. TO examine whether increased intracranial hydrodynamic pressure plus defects in the anlage of the meninges and cranium induces secondary cranioschisis, we injected kaolin into the cerebral ventricle on E13.5 to induce hydrocephaly. These embryos developed exo utero and we examined the morphology on E18.5. Hydrocephaly was induced and the defects were more severe in the meninges and cranium than in embryos exposed to CA alone, although cranioschisis was not histologically confirmed. These results suggested that hypoplasia in the mesoderm during early organogenesis un- derlies later abnormalities of the meninges and cranium, which may be involved in the pathogenesis of certain types of cranioschisis
ABSTRACT The Non-Clinical Evaluation Subcommittee of the Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA) collected historical control data from developmental and reproductive toxicity studies, which were conducted by the member companies and associated contract laboratories between 1986 and 1993. The data include spontaneous incidences of fetal morphological alterations and other observations made at terminal cesarean sections in rats, rabbits and mice. In addition, mating and natural delivery data in rats are also provided. There were strain differences as well as inter-laboratory variations in the incidences of fetal visceral and skeletal alterations for both rats and rabbits. These inter-laboratory variations were attributed to differences in the selection of observation parameters, observation criteria and classification of the findings