714 



Teratogenesis 



cleavage stage is also most sensitive to centri- 

 fugation (Forsthoefel, '51). There may, thus, 

 be a considerable delay before visible effects 

 of some treatments are evident. 



Ancel ('45a) concluded that the micro- 

 melic effect of sulfanilamide resulted from 

 its interference with pre-cartilaginous mes- 

 enchyme. He applied the drug at 48 hours. 

 The writer's earlier discussion of the differ- 

 ences in susceptible periods to various 

 micromelia-inducing chemicals (p. 705) in- 

 dicates that stages of active chondrification 

 are also affected. In addition, the application 

 of sulfanilamide at 120 hours (Zwilling and 

 DeBell, '50) will also produce micromelia. 

 Moreover, if sulfanilamide is injected at 

 48 hours and nicotinamide at 120 hours 

 (exposing the limb to the drug during the 

 pre-cartilage stage) the micromelic effects 

 are entirely abolished. All of this indicates 

 that sulfanilamide acts over a considerable 

 period of time. This probably is true of other 

 teratogenic agents. It is likely that some of 

 them may have relatively little effect until 

 development of a particular structiure has 

 proceeded sufficiently for it to reach its 

 sensitive stage. Experiments must be care- 

 fully planned for accurate determination of 

 sensitive periods and not based solely on the 

 results of treating one stage. In like manner, 

 in view of the fact that indistinguishable 

 end results may be mediated through more 

 than one developmental pathway (i.e., limb- 

 lessness or taillessness, either by degeneration 

 of normally formed structure or failure of 

 the structure to be elaborated), only the 

 most limited conclusions about sensitive pe- 

 riods can be obtained from the appearance 

 alone of a fully developed organism. 



NATURE OF TERATOGENIC AGENCY 



Instances where the same terata have been 

 produced by a variety of treatments have 

 led to the emphasis on stage of treatment 

 and neglect of specific action of the agent 

 (vide supra). However, there is evidence 

 which indicates that the specific nature of 

 the substance used is of considerable impor- 

 tance. Most impressive, in recent years, has 

 been the research of Ancel ('45a, '45b, '50) 

 and his collaborators. These investigators 

 have applied some 90 or more substances to 

 chick embryos of the same age in the same 

 manner. They have found considerable dif- 

 ferences in regard to the terata produced. 

 For instance, eserine sulfate and a number 

 of sulfa compounds produce micromelia 

 (frequently accompanied by parrot beak and 



occasionally by syndactyly) but no rump- 

 lessness or coelosomy (a condition in which 

 the viscera protrude from and are outside 

 the body cavity). Another group of sub- 

 stances (ricin, trypaflavine, etc.) produced 

 coelosomy but no micromelia or rumpless- 

 ness. Still another group (sodium cacodylate, 

 sodium methyl arsonate, saponin) resulted 

 in rumplessness, which was frequently asso- 

 ciated with coelosomy and ectro- or hemi- 

 melia (a condition in which all or part of 

 a limb is absent), but no micromelia. More- 

 over, these substances retain their specific 

 action even when applied simultaneously 

 (Ancel, '47). Trypaflavine alone resulted in 

 the non-development of the amnion but no 

 rumplessness, while methyl arsonate pro- 

 duced rumplessness and no abnormalities of 

 the amnion. Together they produced, in addi- 

 tion to embryos with either of the two 

 anomalies, some embryos which were both 

 rumpless and anamniotic. Ancel and his group 

 have not overlooked or minimized the im- 

 portance of the stage when these substances 

 are applied. They have demonstrated that 

 the same substance may have different effects 

 on different stages. All specific effects must, 

 therefore, be defined in terms of both the 

 stage treated (or affected) and the nature 

 of the agent. 



The investigations of Hamburger and 

 Habel ('47) offer additional evidence for 

 specific action. These authors have shown 

 that two different viruses (influenza-A and 

 mumps), both of which penetrate embryonic 

 tissues and multiply therein, may have dif- 

 ferent teratological effects. Both of the 

 viruses, applied to 48-hour embryos, were 

 toxic but only the influenza-A was terato- 

 genic. It caused a specific syndrome: micro- 

 cephaly, micrencephaly, twisting of the axis 

 and impairment of growth of the amnion. 

 It must be concluded that these differences 

 in effect are due to specific differences in 

 the action of the two viruses. 



Along with the specific action of many 

 svibstances one frequently finds "general 

 toxic effects" or "non-specific mortality." As 

 implied, these effects are noted in those in- 

 dividuals which succumb to the treatment 

 at a relatively early stage and usually show 

 a imiformity regardless of the nature of the 

 treatment. The more specific effects are found 

 in the survivors. In early chick embryos, for 

 example, one encounters a typical syndrome 

 preceding death due to a variety of causes: 

 the extraembryonic blood vessels break 

 down and the entire embryo is retarded, with 

 the head especially showing the retardation. 



