Teratogenesis 



703 



of runiplessness occur sporadically (Landauer 

 and Dunn, '25), may be produced by me- 

 chanical jarring (Landauer and Baumann, 

 '43), by transection of the posterior part of 

 an early embryo's body (Zwilling, '45b), by 

 local irradiation (Wolff, '36) and by topical 

 application of several chemicals (Ancel, '50). 

 After the discovery (Landauer, '45b) that a 

 high incidence of rumplessness is a consistent 

 consequence of injection of insulin into the 

 yolk sac of early embryos (prior to 72 hours) 

 a series of studies was undertaken to estab- 

 lish any relationship between these pheno- 

 copies and the mutants. 



Moseley ('47) made a very careful study 

 of the morphology of insulin-treated embryos 

 at various stages. Roughly 20 per cent of her 

 rumpless embryos resembled the recessive 

 condition. The majority of the rumpless em- 

 bryos (2/3), however, achieved the tailless 

 condition in a manner which was unlike that 

 seen in either of the mutant types. Tail de- 

 fects in this large group followed an abnor- 

 mal deviation of caudal structures which 

 forced them into the cloaca where, after a 

 variable time, they degenerated. Only an 

 embryological study could reveal these facts, 

 since an examination of advanced embryos 

 or hatched chicks merely indicated that there 

 was a marked resemblance to the mutant 

 types. Evidence (Landauer and Rhodes, '52) 

 indicates that insulin rumplessness is medi- 

 ated via an interference with anaerobic gly- 

 colysis. Pyruvic acid, injected somewhat 

 before or simultaneously with insulin, mark- 

 edly decreased the incidence of rumplessness. 

 Mortality was lowered. Similar treatment of 

 embryos of both mutant strains (Landauer, 

 '54) had no effect on incidence of rvimpless- 

 ness in either. Embryological study thus re- 

 veals that the final adult phenocopy condition 

 may be reached by morphogenesis which is 

 unlike that fovmd in mutant forms. The work 

 by Landauer indicates that even the morpho- 

 logical similarity between some of the in- 

 sulin-treated embryos and the recessive 

 mutants is probably preceded by different 

 metabolic disturbances. The extent, there- 

 fore, to which phenocopies can be used in 

 elucidating the action of genetic factors is 

 limited. It mvist be borne in mind that no a 

 priori conclusions can be drawn about gene 

 action from the mere production of a phe- 

 nocopy. One must, without additional evi- 

 dence, be literal and insist that, by defini- 

 tion, only the appearance of a mutant has 

 been duplicated. These points will be 

 stressed again below in our discussion of 

 micromelia. 



HOW AGENTS PRODUCE THEIR 

 EFFECTS 



To say that genetic or environmental fac- 

 tors are the causal agents of anomalies does 

 not, however, explain how these agents pro- 

 duce their effects. In the absence of more 

 specific information rather general hypoth- 

 eses have been advanced to explain the 

 action of agencies which produce terata. One 

 of the oldest of these (Ballantyne credits 

 Harvey's work of 1651 with its foundation) 

 is the concept of arrested development. In- 

 itially this hypothesis was utilized to de- 

 scribe the fact that in many anomalies 

 development seems to have stopped at an 

 early stage in the formation of a structure 

 and that primitive features are retained; for 

 example, a cleft palate results from a failure 

 of the two palatal primordia to fuse and, 

 thereby, an early embryonic condition per- 

 sists. Later authors have extended the im- 

 plications of this concept to include situations 

 in which one does not necessarily find per- 

 sistent embiyonic conditions. In such in- 

 stances the anomaly is supposedly preceded 

 by temporary arrest at some stage and this 

 arrest is the prime contributing factor to the 

 subsequent abnormal development. Follow- 

 ing the St. Hilaires and Dareste, Stockard 

 ('21) was one of the strongest proponents of 

 this concept. He argued that a slowing or 

 virtual stopping of development (by way of 

 low temperature, oxygen lack or various 

 chemical and physical interventions) was 

 the primary result of the treatment and that 

 the type of deformity depended on the time 

 in development when this occurred. E. Wolff 

 ('48) considez's arrests of development of sviffi- 

 cient importance as a first step in production 

 of terata that he postulates this as the first 

 of his laws of teratogenesis. 



Attempts to establish the mechanism of 

 action of teratogenic agents, genetic or other- 

 wise, have been very fruitful on the morpho- 

 logical level. Careful embryological studies 

 have provided considerable information 

 which is basic for causal analyses. In some 

 cases unsuspected relationships have been 

 revealed. Griineberg's ('38) grey lethal mu- 

 tation in rats is a case in point. Skeletal 

 anomalies, excess of erythrocytes and hemo- 

 globin, heart enlargement, lung emphysema, 

 etc., are all related by means of a "pedigree 

 of causes" to an early anomaly of cartilage. 

 However, just as in normal development, 

 there is a deficiency in our knowledge of the 

 metabolic events (and possibly unknown 

 cellular relationships) which cause the visi- 



