During the past 30 years, the noteworthy progress in teratology was attained ; identification of a number of chromosomally determined birth defects, increased detection of single gene defects and discovery of several new human teratogens as well as hundreds embryopathogens in laboratory animals. Gained knowledge led to realization of such preventive practices as the exchange blood transfusion, amniocentesis, massscreening of the overall newborns for detection of several curable inborn metabolic errors and administration of the attenuated rubella vaccines to prepubertal girls. However, teratology to-day seems not towards complete because there remain a number of obstacles to the attainment of prevention of overall birth defects. What follows are some of the unsolved problems in teratology : 1 . Occurrence of the most commonly found spontaneous defects of multi-factorial origin is practically uncontrollable at present. Some clue to the solution of this problem hopefully will be found by promoting such studies as : hormone administration and other environmental modification to pregnant mice of A/J origin are selectively lethal to the embryos with the spontaneously occurring cleft lip (Kalter, 1975; Juriloff and Fraser, 1977) . Another study on the reported relationship between a specific maternal HL-A type and occurrence of a certain birth defects in the progeny seems to be promising in this respect (Pietrzyk, 1977 ; Slavkin, 1979) . 2 . Although the practice of clinical screening of defective embryos in all pregnant women during the first trimester is eagerly desired, their diagnosis has not been successful by the current methods. High hopes are set for technical improvement of the sonar method, which allows detailed visualization of such early conceptuses. Acquisition of the embryonic tissues to be subjected to cytogenetic analysis from all women in early pregnancy will also be desired. 3. Generally, the results obtained by testing of drugs and other agents for developmental toxicity have relatively low predictive reliability regarding the human risk. Although enhancement of the predictive value is expected by proper planning of the experiment, precise and detailed examinations and careful scrutinization of the results, teratological information in laboratory animals can not step over the realm of assumption. This causes often unsettled controversy.

抄録全体を表示

Behavioral teratology, or neurobehavioral teratology as more recently proposed, is the science for the study of abnormal functional development. Since the development of the central nervous system is immature at birth especially in experimental animals, studies on the effects of postnatally administered agents should be included. Thus, behavioral teratogens, environmental agents that induce abnormal behavioral development, may be more properly called as behavioral developmental toxogens. Significance of studying abnormal development of behavior includes possibility of repeated observations without sacrificing offspring and lower threshold as compared to morphological teratogenic dose. Hearing loss by streptomycin had been established several years before the episode of thalidomide tragedy and a quite few behavioral developmental distrubances have been reported in humans due to many environmental agents such as progestogens, obstetric analgesics, narcotics, heavy metals, alcohol and smoking. Animal experiments to detect behavioral teratogens and ellucidate modes of action have been rapidly in progress. The extent of behavioral teratogens has been found as large as that of classic morphological teratogens. Goals of the experimental behavioral teratology are establishment of screening methods and introduction of general principles for the extrapolation of animal data to humans. The Japanese Government issued the regulation in 1975 to include the investigation on the behavior of offspring in the reproduction test of drugs to be newly marketed. Several proposals were introduced for the screening methods of abnormal behavioral development. However, no official guideline has been agreed so far. Recently, the Behavioral Teratology Society has been founded in U.S.A. in close collaboration with the Teratology Society. The Japanese Teratology Society had a group discussion on behavioral teratology in the 20th Annual Meeting and it is expected to have a permanent organization. It is to be emphasized that multidisciplinary approaches from various fields including clinical medicine are important for the brilliant progress of the behavioral teratology.

抄録全体を表示

Considerable interest has developed in recent years with respect to the postnatal functional evaluations as an integral part of neurobehavioral teratology screening programs. It is now clear that, in addition to morphological abnormalities present at birth, long-term postnatal assessments of functional alterations should be carried out for any suspected teratogenic agent such as chemicals and numerous enviornmental pollutants. Certain basic requirements for the validity and sensitivity of tests for behavioral assessments are one of the prime essentials to develop properly a standard testing system. We must establish a more control for factors operating between conception and weaning which can influence later behavior of the offspring. In order to separate prenatal from postnatal influences on subsequent maturation and develpment, fostering method should be employed. If not so, we must investigate the extent to which maternal behavior in the presence of newborns is affected by a teratogenic agent. Using haphazardly breeding animals, we may be so difficult to interpret their behavioral characteristics especially in the learning process because of the trouble of the extreme variability in a heterogeneous population. Further discussion will be given on pleiotropy and genetic correlation. Building from simple task to a well-chosen battery of tests is a logical approach of the behavioral assessments and is taken as the direction of a behavioral teratology. A more detailed analysis of functional disturbances will be involved an integrated approach with co-operation of a number of investigators from varying discipline.

抄録全体を表示

This paper considers the evidences to indicate the role of mother-pup relationship in determining the effects of teratogenic agents on animal behaviors. The maternal behavior in rodents, especially in rats and mice, includes licking the pup (L), retrieving the pup to nest (R), and nursing position(NP) . The sequential order of maternal response to the pups is various and the time needed to be fully maternal varies with the species. Most evidence from experimental researches on infantile stimulation, the pups' separation from the mother, and large litter-size suggests that some abnormalities in the treated pups result from the direct effects of the treatment on the pups, but that some are due to changes in the behavior of the mother toward the pups. These abnormalities are attributable either to the interaction between mother and pups or to the changes in maternal responsiveness to the treated pups. Therefore, if a teratogenic action occurs in the pups' behavior during the preweaning or postweaning period, adequate consideration should be given as to whether the behavioral abnormalities observed are produced by the changes in the maternal behavior towards the postnatal pups. In order to estimate the effectiveness of the mother, cross fostering with a split-litter procedure must be used in the researches into teratogenic effects on behavioral development and learning performance. As one of experimental variables maternal variable must be systematically accounted for before any assumption can be made about the effects of teratogenic agent.

抄録全体を表示

According to our investigations, when chlorpromazine (0.5-2.0mg/kg/day), prochlorperazine (0.8-1.6mg//kg/day) and phenobarbital (20-40 mg/kg/day) were temporarilly given to male newborn rats for 7 days, various kinds of behavioral abnormalities, especially learning impairment which could be detected by discriminated lever-press avoidance, tended to be observed after maturation. However, postnatal treatments with haloperidol (0.1 mg/kg/day) and diazepam (4mg/kg/day) did not produce such behavioral changes. The properties of behavioral abnormalities were varied depending upon drug species and administration schedules. It was speculated that a hyperirritability to emvironmental stimuli may be induced by postnatal pretreatments with phenothiazine derivatives, while a hypoirritability by phenobarbital. In addition, the acute inhibitory effect of chlorpromazine on conditioned avoidance response was exhibited more strongly in phenothiazine-and phenobarbital-pretreated animals than in haloperidol-, diazepam- and saline-pretreated ones. Considering these experimental results, significant roles of operant conditioning in behavioral teratology were emphasized, and mechanisms concerning the behavioral abnormalities were discussed. In the present situation in Japan, there is a lack of experts who major in behavioral teratology. Systematic education and training for behavioral research is strongly required. Suitable and economic standardization of the methods and equipments to detect behavioral abnormalities based on behavioral teratology are needed. Interdisciplinary co-operation in particular has to be important for this purpose.

抄録全体を表示

Bredinin had teratogenic and embryo-lethal actions in mice and rats. These actions were reduced by the administration of guanosine to pregnant rats. In vitro, bredinin inhibited the proliferation of mouse embryo cells at a concentration of more than 10^<-7>M. The inhibitory effect was diminished by the addition of guanosine 5'-monophosphate (GMP) or guanosine to the culture medium. These results suggest that the teratogenic actions of bredinin are induced from a cytotoxic effect which is possibly due to bredinin competition with guanosine in fetal cells.

抄録全体を表示

Following injection of a single dose of 12 mg/kg cyclophosphamide to pregnant mice on day 9 of gestation, the fetuses and placentae were collected on day 18. Fetuses showed various abnormalities and growth retardation. The placentae were lighter. The decidua exhibited hemorrhage, necrosis and infarction. The basal zone contained clumps of glycogen cells and more giant cells than the controls. The labyrinths were hyalinised. The trichorial placental barrier was thicker due to failure of fetal mesenchyme to disappear. The arborization of fetal vasculature was reduced. The necrotic patch at the rim was found to contain acidophilic matrix and giant cells. Such pathological changes and their consequent interference with fetal supply line are suggestive of their probable role in fetal growth retardation and malformations induced by cyclophosphamide.

抄録全体を表示

To devise a staging system for ossification in the supraoccipital bone in preterm rat fetuses, we measured the anterior width (AW), posterior width (PW), longest sagittal length (LSL), median ossified length (MOL), and median nonossified length (MNL) of the bone stained with alizarin red S in fetuses from nontreated preterm (days 19.0 - 21.0) rats, and calculated the median total length (MTL) by adding MNL to MOL. This staging system proved to be useful for examination of retarded ossification in fetuses obtained from teratological tests. Ratios of PW/AW and LSL/AW were nearly constant during the preterm period. However, ratios of MOL/AW, MOL/LSL and MOL/MTL increased as fetal age advanced. These findings indicated that ossification on the median line (MOL) in this bone was most prominent during the preterm period. Therefore, the ossification in this bone in preterm rat fetuses was graded from stage 0 to 5 according to the MOL/MTL ratio (r); stages 0, 1, 2, 3, 4, and 5 corresponded to r = 0, 0 < r ≦ 1/4, 1/4 < r ≦ 1/2, 1/2 < r ≦ 3/4, 3/4 < r < 1, and r = 1, respectively. We utilized this staging to evaluate ossification of the supraoccipital bone in preterm rat fetuses. The peak of distribution of fetuses shifted from stage 1 , through 2 and 3 , to 4 with age. The extent of retarded ossification in the supraoccipital bone in rat fetuses observed in teratological experiments may be simply evaluated by this staging, instead of measuring ossified lengths or areas.

抄録全体を表示

Six patients with melorheostosis were clinically and radiologically followed up in a period from four to six years. An attempt was made to correlate the sclerosing osseous lesions with sclerotomes in the latest radiographs. The sclerotomes appear to provide a good explanation for distribution of sclerosing lesions of melorheostosis which is otherwise inexplicable. As was proposed by Murray and McCredie, melorheostosis might be the late result of a segmental sensory nerve lesion due to a specific insult or injury to a segment or segments of the neural crest during embryogenesis.

抄録全体を表示

The autosomal semi-dominant gene Cts has been considered to manifest a congenital cataract in both heterozygous and homozygous conditions, and microphthalmia only in the homozygous one. The present study was undertaken to confirm the manifestations of microphthalmia even in the heterozygous state of Cts gene and to study the morphological change of the lenses in correlation with the microphthalmia. Measurements of the horizontal diameter of the cornea and weight of the eyeball proved that the eyeballs of heterozygotes were larger than those of homozygotes and smaller than those of unaffected animals. The results of various crosses among three different genotypic mice conformed to those expected for a single autosomal semi-dominant gene. Embryos and fetuses of each genotype at serial stages from day 9 to 20 of pregnancy were examined histologically. Then, swellin of the lens fiber cells was first detected in the homozygotes on day 14 of pregnancy. This change was followed by pyknosis of lens fiber cells and degeneration of fibers. Such changes arose in the later prenatal period and were less extensive in the heterozygous lenses. No faulty closure of embryonic fissure was found histologically in either homozygous or heterozygous eyes. Accordingly, the microphthalmia manifested by Cts gene was considered to be a consequence of developmental disturbance of the cataractous lens.

抄録全体を表示

A fetus with congenital hydrocephalus, probably sex-linked, was diagnosed by ultrasonic echography at the 20th week of gestation. Echograms which demonstrate increased biparietal diameter as well as the dilated lateral ventricles, may facilitate a diagnosis of hydrocephalus early in pregnancy.

抄録全体を表示