708 



Teratogenesis 



"shaker-short" mutation of mice, Bonnevie 

 ('34) has traced such an inherited situation 

 back to its apparent origin. Shaker-short mice 

 are characterized by a number of abnormali- 

 ties, the most striking of which are their 

 erratic wahzing movements. These aberra- 

 tions of movement, and a deafness, have been 

 linked to abnormal development of the ears. 

 An embryological study revealed that the 

 inner ears in these mice are normal until the 

 ninth day of gestation. The various append- 

 ages which should be formed in subsequent 

 stages are not elaborated despite the fact that 

 differentiation of the epithelium of the vesi- 

 cle is normal and variovis regional character- 

 istics are present in approximately the usual 

 location in the distorted ears. The onset of 

 these deviations is correlated with a failure 

 of the myelencephalon to expand as it does 

 normally. Largely as a result of lack of pres- 

 sure on the ear vesicle, according to Bon- 

 nevie, the aural appendages are inhibited. 

 Thus, despite the capacity for normal cellu- 

 lar differentiation the abnormal mechanical 

 conditions interfere with normal form devel- 

 opment to such an extent that severe anom- 

 alies and aberrant fvmctioning result. 



ABNORMALITY OF BOTH INITIAL 

 STIMULUS AND RESPONDING TISSUE 



In theory it is possible that both the in- 

 ductive stimulus and the reacting tissue may 

 be defective in some respect. This may be 

 the situation in many of the experiments in 

 which the entire embryo is subjected to the 

 influence of an abnormal chemical or phys- 

 ical milieu for protracted intervals. It is also 

 probably true in many cases of gene-medi- 

 ated anomalies. Too frequently investigators 

 are prone to implicate an inductor without 

 considering that the reacting tissue may also 

 be involved. Recently, just this situation has 

 been illustrated by the experiments of Moore 

 ('46, '47, '48). In hybrids of R. pipiens o y^ 

 R. sylvatica $ development proceeds nor- 

 mally to the initial stages of gastrulation. 

 The majority of the embryos cease their de- 

 velopment at this point and continvie as 

 "blocked" gastrulae for several days before 

 they cytolize. Moore has tested both the com- 

 petence of the ectoderm and the inductive 

 capacity of the dorsal lips of such gastrulae. 

 This was accomplished by heteroplastic and 

 xenoplastic transplants in which the ecto- 

 derm was placed in specified regions of the 

 host and the dorsal lip in the blastocoele of 

 another host. Similar transplants of normal 

 R. pipiens gastrular tissue were used as con- 



trol. By comparing both the number and the 

 size of the induced structures in the two 

 situations Moore has concluded that both the 

 competence of the ectoderm and the inductive 

 capacity of the dorsal lip are defective in 

 hybrids. It is of interest that Barth ('46) and 

 Barth and Jaeger ('47) have shown that 

 respiration, lactic acid production and apy- 

 rase activity are interfered with in these 

 hybrid gastrulae, while Brachet ('47b) has 

 demonstrated that there is an inhibition of 

 ribonucleic acid synthesis in similar blocked 

 hybrids. Sze ('53) has shown that respiration 

 is depressed in all regions of the ectoderm of 

 the hybrids. 



ABNORMAL DIFFERENTIATION OF 

 COMPONENT TISSUES 



There are a number of anomalous situa- 

 tions in which the tissues either do not differ- 

 entiate normally or differentiate in another 

 direction than expected. These might be con- 

 sidered cases of abnormal response of react- 

 ing tissues, although the exact circumstances 

 involved in these cases are, for the most 

 part, imknown. 



One of the best known examples of a tissue 

 differentiating atypically is found in Leh- 

 mann's ('38) lithium-treated Triton embryos, 

 in which the presumptive chorda material 

 becomes continuous with and differentiates 

 as mesoderm. [Cohen ('38) believes that it 

 becomes entoderm in his experiments.] An- 

 other instance is that of an inherited anomaly 

 in mice (Hovelacque and Noel, '23) in which 

 the distal end of the precartilaginous con- 

 densation of the tibia differentiates into 

 fibrous ligaments instead of cartilage. 



In the case of Griineberg's ('38) grey 

 lethal mvitation in rats the cartilage cells, 

 especially of the ribs and trachea, are larger 

 than normal and form thick, enlarged cap- 

 sules; in addition the perichondrium is ab- 

 normally thickened and active. The result is 

 a hyperplasia of the tracheal and costal car- 

 tilages which is instrumental in causing an 

 emphysema of the lungs. This eventually 

 leads to the death of the animal. Hyperac- 

 tivity of the cartilage continues even when 

 it is transplanted to a normal host but does 

 not do so when grown in tissue culture (Fell 

 and Griineberg, '39). Normal cartilage does 

 not become abnormal in a lethal host. These 

 experiments led the authors to the conclusion 

 that the abnormal condition is intrinsic to 

 the cells which bear the lethal genes. 



While the phenomenon is rare, embryonic 

 tissue may be involved in tumor formation. 



