Feeblemindedness is caused by diversified origins. There are feeblemindednesses resulting from extrinsic factors which affect intrauterine life, perinatal life and further post natal life. Here, causes that act on intrauterine life and developmental disturbances of the brain resulting from such extrinsic factors will be discussed. Special reference to extrinsic factors which have the possibility to cause feeblemindedness and developmental disturbances will be stated in a little detail. Further, on experimental approaches to study developmental disturbances of the brain due to extrinsic factors will be referred to. I. Intrauterine life is divided into preimplantation period, period of organogenesis and fetal period. Each period is influenced on either common or specific extrinsic factors. A. It is said that during the preimplantation period severe physical and chemical effects kill cells while effects below a certain level do not involve cells in damage. Therefore, extrinsic factors do not, in general, cause malformations. B. Period of organogenesis : In this period, embryos are the most susceptible and various kinds of developmental disturbances with special reference to those of the brain are caused. Following factors are known teratogenic : 1. Ionizing radiations with special reference to medical irradiation and exposure to the atomic bomb. 2. Infections such as rubella, cytomegalic inclusion disease, and toxoplasmosis. 3. Chemical substances such as thalidomide, aminopterine, etc. 4. Hormonal aberrations with special reference to diabetes of the mother, hypo- or hyperthy-roidism, etc. are also conceivable. 5. Other factors such as maternal age, birth ranks, etc. are also suspected. Among them, ionizing radiations and the above infections only involve the brain. C. Fetal period : In human beings, following factors cause birth defects. 1. Ionizing radiations. 2. The same infectious agents indicated in item B. 3. Poisoning of organic mercuric compounds (congenital MINAMATA disease). 4. Masculinization by synthetic gestagens. 5. Possible oxygen deficiency such as caused by unsuccessful attempts at suiside by hanging, fuel gas poisoning, etc. 6. Abnormal immnologic condition in the mother (suspected) . Among the above factors, except for synthetic gestagens, are causes of possible microcephalias or hydrocephalias which are related to feeblemindedness. II. Experimental approach : On external agents which cause developmental disturbances of the brain related to feeblemindedness, such as hydrocephalia, microcephalia are stated. Further, other malformations of the central nervous system which will occure besides those related to feeblemindedness will also be stated. However, microcephalias that manifest themselves in laboratory animals are usually accompanied by enlargement of the brain cavity, i.e., hydromicro-cephalia in microscopic examinations. Involvements are so severe that it is difficult to find similarities in morphologic changes in experimental specimens compared with those seen in man. However, it is verified that fetal stages will be vulnerable to ionizing radiation according to the dosage factor.

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Hypervitaminosis A in gravid mice of the bc (experimental series I and II) and ICR (series III) strains was induced by daily subcutaneous injections of excess amount of vitamin A on 3 successive days during various early periods of gestation in view of causing various kinds of abnormalities, especially exencephaly, in fetuses. Autopsy was made on day 18 of gestation. Series I. Gravid bc strain mice were treated with 8,000-10,000 I.U. or 5,000 I.U. vitamin A once a day on days 8-10 of gestation. The daily dose of 8,000-10,000 I.U. caused fetal resorption and death in extremely high rates. On the other hand, 5,000 I.U. kept many fetuses alive and caused 100% abnormalities in living fetuses ; high incidence of micromelia, cleft palates and abnormal digits such as oligodactylia, syndactylia and abnormal directions were found. Other observed abnormalities were brachygnathia, short tail, open eyelids, microstomia and gastroschisis. In this series, no exencephaly was found. Series II. During various 3-day-periods including that of days 8-10, pregnant bc strain mice were treated with 2,500 or 5,000 I.U. vitamin A once a day. Treatments on days 8-10 caused a high incidence of cleft palates, micromelia and abnormal digits as observed in series I. Treatments on days earlier than these days and later than days 4-6 caused cleft palates in a high incidence and a case of open eyelids. No exencephaly was observed in this series as well. Series III. This series of experiments was conducted in view of strain-difference in the occurrence of exencephaly, an anomaly which was not observed in our colony of the bc strain though such anomaly seemed to appear in mice of the other strains heretofore reported, and in view of a high susceptibility of the ICR strain for exencephaly-causing activity of excess vitamin A (Ezaki 1964). Treatments were made on susceptible days for exencephaly, and resulted in the occurrence of exencephalies. The observed abnormalities were cleft palates, micromelia, oligodactylia, microtia, microcephaly, exencephaly, exophthalmos, open eyelids and short tail. The observed exencephalies reached a maximum incidence of 14% (7 cases) by treatments on days 6-8 with 10,000 I.U. vitamin A once a day. Furthermore, one case of exencephaly was found in a mother treated on days 8-10. The observations show that there exists a mouse strain (bc) which is not susceptible for exencephaly-causing activity of excess vitamin A.

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In embryos of ddN-and CF#1-mouse and Wistar rat, the formation of some organs were observed during a period of organogenesis, namely, from the 7th or 8th day to the 13th day of pregnancy. Young embryos at various ages were taken from several mothers and were fixed in Bouin's fixative, then were sectioned through paraffin and stained with hematoxylin and eosin. In CF#1-mouse, somites in early stages as well as a number of organs derived from a central nervous system developed more rapidly under a difference corresponding to developmental process during 1/2 days in ddN-mouse. Since the 11th day of pregnancy, there was no difference in the number of somites between both strains of mouse. Wistar rat displayed about one day's retardation of development corresponding to proceedings of organogenesis in the mouse. Meanwhile, in spite of a parallel increase of somites in both strains of mouse since 11th day, the formation of some mesodermal organs such as sclerotome and eye-lid was earlier in CF#1 mouse than ddN-mouse. The correlation between an increase of somites and a period of the beginning of organogenesis was not always the same in each strain of mouse. The correlation in the rat was similar to in CF # 1-mouse. Fluctuations in a period of the beginning of organogenesis due to the difference of strain was observed in respective strains used. The fluctuations in normal developmental stages could be called "The strain-difference". Therefore, it would be undesirable that the developmental stages were expressed with only embryonic ages or with only the number of somites. Hitherto, the fluctuation of results in teratological or other experiments have been explained with a simple word, "The strain-difference". But, when fluctuations of developmental stages due to the difference of strain were considered, it would be difficult to distinguish between the divergence based on "The true strain-difference" and the divergence based on difference in proceedings of the normal development. Hereafter further studies to relate to "The strain-difference" in the process of the normal development of experimental animals have to be carried out.

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The ddN and CF#1 mouse and Wistar rat were examined for the time and order of chondrification during their fetal lives. In the present paper the strain- and species-differences were mentioned with special reference to the development of vertebral bones. The fetuses were removed surgically from the mothers at gestational ages of 12 to 18 days in the mouse and 13 to 20 days in the rat at one day intervals. Their skeletons were examined in methylene-blue stained cleared specimens and alizarin red S stained ones. The chondrification at the initial stage of skeletal development in the ddN mouse started a little later than the CF#1 mouse. But the features of skeletons in the late gestational days showed no difference between the strains. The skeletal development in the rat fetuses was generally one day later at the initial stage of chondrification and was two days later in the late gestational days than both in the ddN and CF#1 mouse. The ossification center in the anterior arch of atlas appeared on the 16th day of gestation in the mouse and on the 20th day in the rat. This difference between the species was the most prominent in the skeletal development.

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