ABSTRACT The diameter distribution was compared between centronucleated and non-centronucleated myofibers on a cross-sectional specimen of the hindleg rectus femoris muscle from muscular dystrophic (dyldy) mice aged from 17 to 120 days. At any age examined, it was very similar in centronucleated and non-centro- nucleated myofibers, and the proportion in number of the former to the latter was so high as about 1/3 to 1 in spite that it was determined on a single cross section of 5 pm thick for each muscle. The histochemical study showed that central nuclei were observable apparently in any type of myofibers stained densely, palely or intermediately with NADH dehydrogenase or PAS. In addition, it was found that a considerable number of centronucleated myofibers had also peripheral nuclei and that the central nuclei tended to migrate neither toward the center nor toward the periphery in the myofiber with age or growth. These findings are inconsistent with the widely-accepted view that the centronucleated myofibers in dystrophic muscles are the regenerated ones which are abortive. The pathological implication of the central nucleation was discussed with refer- ence to the bone-muscle imbalance hypothesis previously postulated by the present author as the pathogenesis of mouse muscular dystrophy.
ABSTRACT The genetic effects of the H-2 histocompatibility gene complex on the frequencies of urethan and ethylnitrosourea (ENU)-induced malformations in pre- natal fetuses of mice were examined, and a new functional gene linked to the H-2 complex on chromosome 17 was mapped. The H-2 congenic pair strains of mouse, BIO.A and C57BL/10 (BlO), were test- ed for susceptibility to urethan-induced external malformations in fetuses. The BIO.A strain expressing the H-20 haplotype characteristically showed a high suscep- tibility to urethan-induced polydactyly and kinky tail. However, the B10 strain expressing the H-2b haplotype was resistant to urethan-induced malformation. The same tendency was observed for ENU-induced malformations. Thus, susceptibili- ties to urethan and ENU-induced external malformation must be affected by a gene linked to the H-2 complex. In a mapping study using BIO.A recombinant mouse strains, B1O.A (5R) was sensitive, while BIO.A (2K) and BIO.A (4R) were resistant to urethan-induced external malformations. Variations in the susceptibility to teratogenicity of ure- than in BIO.A recombinant strains indicated that a new functional gene located between the H-2 S region and the Upg-1 locus on chromosome 17 was involved in regulation of susceptibility
ABSTRACT Malformed rat newborns showing severe subcutaneous edema were frequently found dead in our Wistar-Imamichi rat colony. Their family record suggested that this malformation would be an inherited disorder. Experimental crosses of the phenotypically normal litter-mates revealed that this malformation was a new lethal mutant of the rat, following a single autosomal recessive inheri- tance. External features and skeletal anomalies of the mutant were carefully check- ed and compared to those of the phenotypically normal litter-mates. The com- parison revealed that (1) this mutant has a characteristic external appearance that includes shortening of the head, trunk, tail and extremities, systemic subcutaneous edema, protruding of the tongue and cleft palate, (2) the axial bones and appen- dices are shortened and deformed severely and (3) ossification status of the new- born is delayed in digital bones and advanced in the vertebral centra and arches, sternebrae, choracoid process and talus. Observation of the parturition showed that this mutant is born alive but die shortly after birth because of breathing in- sufficiency. Based on these observations, this mutant was diagnosed as congenital osteochondrodysplasia with systemic subcutaneous edema (ocd for the gene symbol). The mode of inheritance and the similarities to some genetical disorders of other species, including human, are discussed.
ABSTRACT True incidence of this malformation is probably greater than that re- ported since the definitive diagnosis has been made at autopsy in most cases. Vari- ous hypotheses on the pathogenesis of tracheal agenesis have been proposed but they are still controversial. In this report, we present a case of tracheal agenesis with a broncho-esophageal fistula and discuss the formal genesis.
ABSTRACT The Behavioral Teratology Meeting, a satellite meeting to the Annual Meeting of the Japanese Teratology Meeting hold a symposium on behavioral teratology on July 24, 1986 in Tokyo. The invited to this symposium were four American speakers who came to Japan to attend the 4th International Congress of Toxicology. Presentations of these guest speakers appear as review articles in Congenital Anomalies following this communication. In general discussion, many critical and suggestive comments were expressed by the participants on the selected topics of behavioral teratology; 1) species and strains, 2) developmental stage, 3) positive controls, 4) procedures and 5) interpretation, and these were briefly introduced.
ABSTRACT A number of different approaches to the study of the effects of male- mediated drug or chemical insult on the subsequent offspring have been used. Typically a modified dominant lethal protocol has been used with the offspring allowed to go to term and the functional development assessed at specific post- natal ages. The present review examines the importance of the mating times for identification of the stages of spermatogenesis most sensitive to insult and the possible mechanisms involved in male-mediated transmission of the effect of toxic exposure to the offspring. The functional assessments demonstrating a paternal-mediation of drug and/or chemical exposure have included motor coordination, reflexive behavior, locomotor activity and associative learning. The importance of the mating sequence, assess- ment methods and interpretation alternatives must be considered in designing studies to identify the extent of the risk to the male genome of drug/chemical ex- posure as reflected in functional deficits to the subsequent offspring.
ABSTRACT In 1975 our laboratory began developing a behavioral teratology screening test battery suitable for use in preclinical safety assessment experiments with rats. The battery involved assessment of physical milestones of development, sensorimotor reflex ontogeny, pre- and postweaning locomotor activity, motor coordination, and tests of learning and memory. Although some of the specific procedures were new, the tests themselves were drawn from the experimental animal psychology, undernutrition, psychopharmacology, and developmental X-ray literatures. The features which distinguished this approach from the past were not to be found in the tests employed, but rather from (1) the effort to objectify and standardize the tests to make them better suited as screening instruments and (2) the evaluation of them collectively and individually for reliability and validity. Reliability was ascertained by replication and validity by evaluation of positive and presumptively negative control test agents. The present paper reviews the rationale for the test battery and some of the positive effects that have been detected with the individual tests. New tests added to and old tests modified in the battery are discussed in the light of the recommendations which have come from the recently completed U.S. Collaborative Behavioral Teratology Study. Particular emphasis is placed on a discussion of the Biel water maze as a test that has been perhaps the most successful instrument for identifying behavioral teratogens to come out of the Cincinnati research effort.
ABSTRACT Behavioral measures used in the CBTS were negative geotaxis, olfac- tory discrimination, auditory startle habituation, 1 -hr and 23-hr activity, an operant discrete trial discrimination task, and activity following amphetamine challenge. Body weights and certain physical landmarks of development also were monitored in two separate studies, one using prenatal treatment with 0, 0.5 or 2.0 mg/kg d- amphetamine sulfate sc on gestation days 12-15, the other using 0, 2.0 or 6.0 mg/kg methylmercuric chloride by gavage on gestational days 6-9. An untreated control group also was included in each study. The CBTS design allowed evaluation of re- producibility and detection sensitivity of these methods, as well as the impact of early testing experience on later assessments, offspring sex differences in response levels and variability, and the contribution of litter-to-litter variation to behavioral measures used in this standardized protocol. Results obtained at the six participat- ing laboratories are discussed in relation to each of these factors and to the degree of overt toxicity obtained with each compound. Behavioral data were reproduc- ible, and detection sensitivities of the tests were very good, requiring no more than 525% change from control values for either sex. Early testing experience was not found to be a major factor in determining later behavioral levels, but litter was found to contribute considerable variability to all physical and behavioral data.
ABSTRACT The evaluation of behavioral teratogenic effects in animal studies will be discussed in light of the results of the Collaborative Behavioral Teratology Study (CBTS) (Buelke-Sam et al., 1985) and the US. EPA's guidelines for the risk assess- ment of suspect developmental toxicants (U.S. EPA, 1986a). Although behavioral teratology testing is not routinely required by the U.S. regulatory agencies, data on existing chemicals are reviewed and evaluated in the risk assessment process. Such data can be of value in at least three ways: 1) data from postnatal studies may be useful in elucidating the consequences of perinatal findings; 2) behavioral data may help to further define the lower end of the dose response curve; and 3) for chemicals where human exposure is likely, behavioral studies may help to focus on types of effects which may be important to monitor in the exposed human popula- tion. Recent efforts in methods development and validation, including the CBTS, have provided guidance for the development of regulatory testing requirements in specific cases. For example, the U.S. EPA has recently published a proposed test rule which includes developmental neurotoxicity testing for the triethylene glycol ethers (U.S. EPA, 1986b). Generic guidelines for such testing may be developed which can the,n be applied on a case by case basis.