The study sought to establish an animal model of chromosome anomalies in man. Based on knowledge of reproductive performance in aged mice, an attempt was made to reveal the underlying mechanism of chromosome anomalies. Epidemiologic discipline of this kind may be used to define environmental factors which are responsible to non-disjunction in relation to ageing of the mother. Experimental findings are summarized as follows: 1. A decline of the reproductive performance in aged mice (10 to 16 months-old) was demonstrated. The rate of ovulation was slightly decreased after 10 months of age, but no tendency to decrease was noted in relation to ageing of the mother. An initial reduction in litter-size in aged mice, therefore, was probably due to the embryonic death after 70 M. Yamamoto ovulation. Another finding suggested that the major cause of embryonic loss in aged mice occurred before or during implantation rather than after implantation or during the early organogenesis up to the 10. 5th day of gestation. 2. With advancing age of the female, increased incidence of chromosome aneuploidies was observed among fetuses born to aged mothers. On the other hand, the triploid formations, where a different mechanism was cytologically responsible, was not related to the maternal ageing. Among 12 fetuses with aneuploidies, 8 were mosaics, and 5 out of 12 were litter mates. It is considered that these aneuploid ova were shed together and developed to mosaicism under an unfavourable "milieu interieur" In aged mice. A possible interpretation was proposed for the occurrence of these chromosome anomalies in reference to recent hypotheses for the etiology of chromosome non-disjunction. The author wishes to express his appreciation to Dr. Gen- ichi Watanabe for his advice.

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Pregnant rats received consecutive daily oral doses of salicylic acid and aspirin at dose levels of 75, 150 and 300 mg/kg from the 8 th to 14 th day of gestation, and their teratogenic effects were examined. In 300 mg/kg groups of both agents, the body weight gains were inhibited with the toxic symptoms such as salivation, piloerection, and some animals died within a few days after the beginning of the administration, and high fetal mortality prevailed. Various kinds of anomalies were observed with high incidence in the descendants of 150 mg/kg groups, especially in the salicylic acid group. It is concluded that these agents act teratogenically in the rats, and the teratogenic effect of salicylic acid may be considered as possibly due to direct action of the agent on the fetus, since a relative distribution of the agent was found in the fetus through the placental barrier.

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To elucidate the mechanism of sulfonamide-induced malformations in mice, the effects of PABA, folic acid, tetrahydrofolic acid, nicotinamide, pyridoxine, 1-acorbic acid and riboflavin on the teratogenic action of sulfadimethoxine, manifested mainly as cleft palate, were studied. Tetrahydrofolic acid, an active form of the folic acid, was found to block teratogenicity completely. Nicotinamide, pyridoxine or 1-ascorbic acid reduced induction of the malformed embryos, while PABA, folic acid and riboflavin had no effect. As for the process through which such inhibiting effects are achieved, it isconsidered that co-factor-related or metabolism-promoting factors such as tetrahydrofolic acid, nicotinamide, pyridoxine or 1-ascorbic acid activate the metabolism around the tetrahydrofolic acid in a folate metabolism. It may be concluded that the teratogenic effect of sulfadimethoxine is not caused by the deficiency of folic acid due to its competitive antagonism with PABA which is known as the substantial step of its antibacterial action. Rather, it is the interference with the folate metabolism around the tetrahydrofolic acid in early embryos characterized by vigorous protein synthesis which is suggested to be the cause.

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Single oral doses ranging from 20 to 960 mg/kg of procarbazine were given to pregnant SD-JCL rats on any one day between day 3 and day 14 of gestation (sperm day = day 0). The rats were sacrificed at term and their fetuses examined for external, visceral and skeletal anomalies. The results were summarized as follows. 1. In general, susceptibility of embryos to the lethal action of procarbazine decreased as development proceeded. However, fetal mortality in rats treated on day 7 was higher than that on day 6. 2. Term fetuses exhibited gross external malformations such as microcephaly, micrognathia, cleft palate, anal atresia, shortening or curvature of the tail, hypoplastic digits, reduction deformities of the limb and generalized edema. The microcephaly was complicated with hydrocephaly and produced by treatment on day 8 to day 14. Micrognathia, cleft palate, shortening or curvature of the tail and hypoplastic digits were detected in fetuses treated on day 10 or later. The critical period for reduction deformities of the limb was between day 11 and day 14. 3. Visceral examination revealed enlargement and deformation of the brain ventricles, anophthalmos and microphthalmos, and lower position of the ovary or higher position of the testis. Eye anomalies were observed in fetuses treated before day 9. The critical period for the enlargement of the lateral ventricles extended over all days of administration. After day 10 of gestation, the treatment induced enlargement of the lateral ventricles complicated with enlargement of the third ventricle or atrophy in a posterior part of the cerebrum. 4. Skeletal I malformations were observed in the skull and facial bones, vertebrae, ribs, clavicle, scapula, ossa coxae and limb bones. The vertebral anomalies, which were detected in the cervical and thoracic segments at lower doses, involved all vertebral segments at higher doses. Deformities in the clavicle, scapula and ossa coxae, together with malformed limb bones, were found in fetuses treated after day 10. Hindlirnb bones, especially the fibula, were more susceptible to procarbazine than forelimb bones.

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