The epidemiology of congenital malformations in Japan was reviewed based on National Vital Statistics. A six-fold increase was noted in the frequency of malformations as cause of fetal death attended by physician from 538 out of 151,338 (0.36%) in 1952 to 2,476 out of 122,273 (2.02%) in 1972. The increase in the ratio of malformations was noted as statistically significant both in spontaneous and artificial fetal deaths as well as in both middle and late fetal deaths. Anencephalus was noted as a major malformation responsible for such increase in fetal death: 88 or 0.33% in 1952 and 837 or 3.42% in 1972. The increase in musculo-skeletal malformations and malformations due to chromosomal abnormality was noted as statistically significant in malformations in early neonatal infant deaths and infant deaths respectively. Possible cause for the increase of anencephalus were discussed by reviewing relevant literature, and a need for systematic epidemiological study in this country was emphasized.

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1. ICR-JCL mice were treated with an intraperitoneal injection of 600,000 IU/kg of vitamin A palmitate on day 10 of pregnancy. 2. The limb buds were dissected out 2, 4, 12, and 24 hours after injection of vitamin A and were submitted to electron microscopic observations. 2-a. The first sign of the effects of hypervitaminosis A on the limb buds was found 4 hours after injection of vitamin A as an appearance of the degenerating cells associated with membrane swelling. 2-b. Twelve hours after administration of vitamin A, the degenerating cells associated with membrane swelling increased in number and many mesenchymal cells were shrunken and intercellular spaces were large. 2-c. Twenty-four hours after administration of vitamin A, pyknotic cells were increased, and some parts of the mesenchyme seemed to have recovered from its effects. 3. It may be concluded that mesenchyme was affected by vitamin A and that abnormal limbs were formed because of the paucity of mesenchymal cells together with the retardation of the mesenchymal differentiation.

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1. The embryos of MC mice were examined histologically for the early morphogenesis of genetic microphthalmia, especially for maldevelopment of the lens. 2. A blockage of proper contact of the lens vesicle with the head ectoderm resulted in antero-superior dislocation and reduction in size of the optic vesicle. The blockage was probably due to interposed mesodermal tissue of the maxillary process. 3. This finding suggested a significant role of the head mesoderm in the manifestation of lens maldevelopment in MC mice.

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Pregnant mice were treated with a single intraperitoneal injection of 10,000 I.U. vitamin A on day 8, 9, 10, 11 and 12 of pregnancy respectively. Offsprings were examined on day 18. In the results, cleft palate, malformations of the digit and pathologic changes in the tooth were the notable malformations observed. The author of the present paper especially paid attention to pathologic changes in teeth and their morphogenetic study was planned. Among various kinds of pathological changes observed in the tooth germs, the most remarkable one was hemorrhage in the dental papilla and the enamel organ. No differences were seen between the germs of the incisor and molar. Severe hemorrhagic changes were more prevalent in the fetus treated in the early stage of development than in the later stage. Disordered arrangement and partial necrosis due to hemorrhage were observed not only in the odontoblast layer but also in the layers of inner or outer dental epethelium. In severe cases, a wavy pattern was present in the predentine, and said pattern was caused by disarrangement of odontoblasts and ameloblasts. Such disarrangement seemed to be due to massive hemorrhage extending from the dental papilla into the enamel organ. The findings observed in the present study would suggest that the hypoplastic dental development in these experimental cases may originate from the above pathological changes in the odontoblast and ameloblast layer. Further, it may be concluded that the disturbed morphogenesis of teeth was due to hemorrhage in the tooth germ of the mouse fetus, and such hemorrhage was caused by hypervitaminosis A from day 8 to 12 of pregnancy.

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Linear alkylbenzene sulfonate (LAS) was administered subcutaneously to pregnant mice during the critical period of the organogenesis in the fetuses, and its embryotoxic and teratogenic effects were examined. LAS was given once daily at doses of 0.4, 2, 10 and 50 mg/kg for 7 days from day 7 to 13 of gestation. The results obtained were as follows. 1. No suppression of body weight gain of pregnant mice was seen in all groups, and the pregnancy was well maintained. Some weight changes in a few organs of dams were observed, but these changes were not dose-dependent, and also no significant pathological changes of the organs were found in any group. 2. Neither fetal mortality nor growth inhibition of live fetuses were noticed, and also no significant differences between the treated and control groups were found in external and internal anomalies of fetuses. In the examination for skeletal system of fetuses, a significant retarded ossification of calcaneus or talus in 10 mg/kg group and of talus in 2 mg/kg group were noticed. The groups given 0.4, 2 and 10 mg/kg LAS showed a higher incidence of fetuses with 14th rib than the control group, but no significant differences between the highest dose and the control groups were found. No skeletal anomalies were found in all groups. 3. In the postnatal observation, the mean litter size was lower in 0.4, 2 and 10 mg/kg groups than in the control, but the body weight gain of newborn after delivery in these groups was greater than in control. Among other groups except 0.4 mg/kg group, no marked differences in weaning rate at 3 weeks after birth were observed. No deleterious effects on postnatal differentiation and motor or sensory activities of newborn were observed in any group, and neither were there any fetuses found with external, internal or skeletal anomalies.

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