Despite remarkable advances in teratology over the past decade, there are many problems which should be elucidated. This report reviews the recent progress of teratology in human congential anomalies from the standpoint of physicians dealing with the fetus and new-born infant. We mention about the prevention, early diagnosis and treatment of congenital anomalies from the standpoint of clinical medicine. This paper discusses elucidation of congenital anomalies (infectious diseases, food additives, soft drinks, luxury goods, ultrasonic pulse waves, fast-cure for diseases of pregnant women); problems for definition and classification of congenital anomalies (definition and classification of malformations, definition and classificaition of disorders in differentiation, development and growth of the brain, and inborn error of immunology); difficulties for detection and diagnosis of congenital anomalies (early detection of human brain damage, diagnosis of carriers of recessive inheritance, detection of autosomal abnormalities, especially mosaic; and problems of the prevention and its application for congential anomalies (education for physicians, the screening for inheritable chromosomal abnormalities, pregnancy of advanced maternal age, and artficial abortion for fetuses with congenital anomalies) .

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Mass screening for inborn errors of metabolism is a unique means for prevention of handicapped children. A nation-wide screening pro-gram for 5 inborn metabolic diseases, namely PKU, maple syrup urine disease, homocystinuria, histidinemia and galactosemia, started in October 1977 in Japan, and at the end of 1979 fiscal year, approximately 90% of all Japanese newborn infants were examined. Total number of newborn infants so far examined reached 3,356,388 and 547 patients were detected, including 56 PKU, 5 MSUD, 415 histidinemia and 24 galactosemia. At least one hypermethioninemic patient was biochemically proved to be homocystinuric. Among 56 patients with PKU, benign hyperphenylalaninemics and at least one patient with aberrant biopterin metabolism were found after careful follow up and examination. The incidence of PKU is roughly one in 60,000, which means 1/5 that of white population. Screening method for histidinemia has much improved by introduction of thin layer chromatography detecting urocanic acid in the dried blood specimen in addition to the usual Guthrie test. Treatment of histidinemia still remains controversial. Increasing number of screening centers have in recent years been adopting Paigen-phage test in addition to the routine Beutler test. This will improve the efficiency of galactosemia detection in the near future. A new screening program for congenital hypothyroidism just started in 1980. Provisional surveys so far carried out promise fruitful results.

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The authors touched upon some current problems on behavioral teratology which weighed on our mind as neuroanatomist or teratologist.

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Veterinary teratology has developed originally with the object of protecting livestock and companion animals from congenital anomalies. Studies of animals with congenital anomalies, however, are now expected to contribute to medical knowledge of the analogous human disorders. The present review schemes out an outline of the more important congenital anomalies of domestic animals. Fetal damages caused by viral teratogens are emphasized, because enormous losses result from several viral infections such as Akabane disease (arthrogryposis and hydranencephaly syndrome) of cattle and sheep in Japan and Australia. Congenital metabolic diseases, such as mannosidosis of Angus cattle in Australia and New Zealand, are also described with emphasis, because they might be useful models of human diseases. As genetic, structural, functional and ecological features in domestic animals are quite different from those of men and rodent laboratory animals, some characteristics of veterinary teratology are suggested. It seems that studies on congenital anomalies in domestic animals represent a significant support for researches in human teratology.

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Artificial insemination (AI) has been widely applied in farm animals, especially cattle, for the efficient use of superior genes from male animals. The use of frozen semen for AI in cattle has been widespread. Although a relationship between the occurrence of congenital malformations and the use of frozen spermatozoa has not been demonstrated, it has been reported that aging of gametes, which would occur with the practice of AI, induces embryonic abnormalities which lead to early embryonic death. Successful fertilization in vitro has been reported for 14 mammalian species; newborn young have been obtained in the rabbit, rat, mouse and man after transfer of eggs fertilized in vitro into host females. In many species a high incidence of polyspermy is found during in vitro fertilization, inducing chromosomal abnormalities and leading to early embryonic loss after transfer. In one study, nearly half of the young derived from rat eggs fertilized in vitro showed some degree of microphthalmia. However, there was no clear evidence that the abnormality was directly caused by in vitro fertilization. We have observed no congenital malformation in three generations of rats derived from eggs fertilized in vitro; others have reported similar results in the second generation of mice after in vitro fertilization. We have reported the successful fertilization in vitro of cattle and pig oocytes, but transfer and in vivo development have not been investigated in these species.

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This study was undertaken in an effort to elucidate the postnatal development and prognosis of experimentally-induced microcephalic mice. Microcephalic mice were produced by injecting cytosine arabinoside to the pregnant mice as described previously. In the treated mice, the postnatal development such as the bodyweight gain, weaning and reflex development and behavioral organization, and the prognosis such as deformities of the vertebral column and natural death were examined. Body-weight of the treated mice was significantly lower than that of the control through the entire period tested. The microcephalic youngsters weaned several days later than the control. The primitive reflexes such as cross extensor reflex, pivoting and rooting reflex were either accelerated, lasted longer or rather weak in the treated mice. Righting reflex, hindlimb grasp reflex and bar holding ability were poor and completions of these reflexes were delayed. The deformities of the vertebral column were examined rentogenographically as they matured. Kyphosis appeared by 30 to 60 days of life and gradually progressed. During 250 days of observation, about one half of treated mice were dead, whereas only I was dead in the control, thus indicating shorter survival in the microcephalic mice.

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A 26-year-old epileptic primipara treated with high doses of various anticonvulsants throughout her pregnancy, produced at term a girl with multiple malformations of skeletal system, extremities, and central nervous system. Autopsy on the sixth postnatal day revealed secondary changes of purulent bronchopneumonia, meningitis at the site of the lumbar myelomeningocele, and hematomyelia. The main dysplasia in the CNS consisted of craniolacunia with lumbar myelomeningocele, unithalamus, hypoplasia of cerebellar vermis with localized meningeal angiomatosis, and unilateral aplasia of anterior pyramidal tract. The possible teratogenic effect of anticonvulsants on the fetal CNS was discussed.

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The process of embryonic death induced by the treatment with 1 mg/kg vinblastine of the pregnant rats on day 9.5 of gestation (the neurulation-stage) was examined by light and electron microscopy. At 4 hours after treatment, numerous metaphase-arrested cells were observed in all the germ layers of the embryo. Electron microscopic observation revealed that these metaphase-arrested cells frequently exhibited dilation and vesiculation of the endoplasmic reticulum, and the spindle microtubules were shorter than in the normal 9.5-day embryo. At 6 hours, most of the cells in the embryo became metaphase-arrested, but sporadic interphase cells were found among them. In addition to dilation and vesiculation of the endoplasmic reticulum, conspicuous surface blebbings occurred in the metaphase-arrested cells of all the germ layers, and the resulting free spherules were numerous in the extracellular space. The interphase cells in all the germ layers of the embryo frequently exhibited extreme dilation of endoplasmic reticulum and nuclear membrane, and their nucleoli were broken into ring-shaped fragments. At 1 2 hours, numerous metaphase-arrested cells were detached not only from the neuroectoderm into the amniotic cavity but also from the embryonic and yolk sac endoderms into the yolk sac cavity, and the histoarchitectural organization of the embryo was variously disorganized. Necrotic cells containing pyknotic nuclei were numerous throughout the embryo. At 24 hours, the embryo was highly disorganized, but the intercellular connection of amnion, embryonic endoderm and yolk sac endoderm still remained. The metaphase-arrested cells decreased in number all over the embryo, while the interphase cells increased, suggesting possible recovery from the arrest of cell division by vinblastine. It was considered that the main factor of embryonic death by vinblastine may be attributed to the disorganization of histoarchitecture of the embryo brought about by the loss of the inter-cellular connection of the metaphase-arrested cells.

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C57BL/6 female mice were mated with C57BL/6, DBA/2 or BDF_1 male mice (B-Groups), and DBA/2 female mice were mated with DBA/2, C57BL/6 or BDF_1 males (D-Groups). C57BL/6 mice are Ah responsive (aromatic hydro-carbon responsive) and DBA/2 mice are Ah nonresponsive. On day 8 of pregnancy, mice of each group were injected ip with benzo [a] pyrene (BP) in corn oil at a dose of 150 or 300 mg/kg. Untreated and vehicle treated pregnant mice served as controls. Pregnant mice were killed on day 18 and the fetuses were examined for mortality, growth, external and skeletal abnormalities. Fetal mortality increased with the dose of BP in all the experimental groups except the mating group of DBA/2 × DBA/2. The decrease of fetal body weight was dose dependent in all groups, and was more prominent in D-Groups than in B-Groups. The incidence of cervical ribs increased with the dose of BP in D-Groups but not in B-Groups. These results suggest that fetuses with Ah responsive genotype were more susceptible to BP in terms of fetal mortality and the fetuses from the mothers with Ah nonresponsive genotype were more susceptible in terms of the decrease in fetal body weight and the increase in the incidence of cervical ribs.

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