Teratogenesis 



715 



While the substances which produce such 

 general effects may alter embryo metab- 

 olism in a specific manner, the visible effects 

 show no specificities in these moribund em- 

 bryos. In determining whether a given effect 

 is specific one must very carefvxlly consider 

 the general toxic effects and use adequate 

 controls. The non-specific symptoms of mori- 

 bimdity must be recognized so that they may 

 not be confused with moi-e specific effects. 



EFFECTS OF DOSE 



In general the greater the dose of a given 

 treatment the greater will be its effect. This 

 may be due to an increase in intensity of 

 action at the time of application or to an 

 increased duration of its action. Both of these 

 points must be borne in mind in any dis- 

 cussion of critical periods. It is possible to 

 subject an embryo to a treatment prior to 

 the critical period for a structure, yet if the 

 effects of the treatment persist long enough, 

 it may include the critical stage for this 

 structure. A more intense treatment may 

 produce anomalies in a stage which does 

 not respond to less intense treatment. Thus 

 Job, Leibold and Fitzmaurice ('35) produced 

 hydrocephalus and defects of the eyes and 

 jaws in rats which had been exposed to 

 x-rays during the ninth, tenth and eleventh 

 days of gestation. Exposure of older embryos 

 to the same dose did not produce any abnor- 

 malities. Warkany and Schraffenberger 

 ('47), on the other hand, obtained some 

 anomalies after irradiating with higher doses 

 as late as the sixteenth dav of gestation. 

 There was a very high incidence as late as 

 the fourteenth day after the intense treat- 

 ment. 



While it is true that many teratogenic 

 agencies are most effective in doses which 

 are toxic to a fairly high percentage of the 

 treated embryos, one must not confuse the 

 toxic effects with the teratogenic ones. There 

 is ample evidence to show that the two are 

 frequently separable. Ancel C45c) has shown 

 that the toxicity of some substances may in- 

 crease without concomitant increase in tera- 

 togenicity. On the other hand Landauer and 

 Bliss ('46) have shown that an increase in 

 dose of insvilin causes a relatively greater 

 increase in the teratogenic effect than in 

 toxicity. If one injects both svilfanilamide 

 and nicotinamide into an egg, there is a 

 much greater mortality than with the former 

 alone (Zwilling and DeBell, '50). However, 

 the micromelic effects of the sulfanilamide 

 are eliminated. 



RECOVERY 



One of the factors involved in differences 

 of response to the same treatment in a rela- 

 tively homogeneous group of embryos is the 

 ability of some of them to recover from the 

 effects of the treatment sufficiently early 

 for the affected structures to resvune some 

 semblance of normality. In some types of 

 experiments recovery phenomena may be 

 demonstrated by removing the embryos from 

 the altered environment and placing them 

 in a normal one. In such cases the degree of 

 recovery is usually related to the duration 

 of the treatment. Under certain conditions 

 some of the effects of treatment may be 

 alleviated by slowing down the metabolic 

 rate of the exposed individuals shortly after 

 the treatment. This was done by Cook ('39), 

 who kept Ascaris eggs at low temperatures 

 following a lethal x-ray treatment. On re- 

 turn to higher temperatures the lethal effects 

 of the irradiation were not noted, although 

 other effects (delayed cleavage) were still 

 present. Child ('41) cites nujnerous instances 

 in which recovery seems to be related to an 

 acclimatization (differential acclimation or 

 tolerance) to a toxic environment. It has 

 been noted (Zwilling, '48) that chick em- 

 bryos may have quite different patterns of 

 hypoglycemia after treatment with the same 

 dose of insulin. Some remain hypoglycemic 

 for as long as 8 days, while others recover 

 normal blood sugar levels at various inter- 

 vals prior to this. The recovery is associated 

 with a decrease in the micromelic effect of 

 the insulin; embryos which recover early 

 are less micromelic. Such differences in tol- 

 erance and ability to recover are probably 

 related to genetic differences between in- 

 dividuals (see above). 



RESUME 



In this chapter an endeavor has been made 

 to show that aberrant development results 

 from a distortion of normal developmental 

 processes; that both genetic and environ- 

 mental factors may be responsible for pro- 

 ducing anomalies; and that the same de- 

 velopmental principles are involved in both. 

 Terata may follow treatment of embryos 

 with highly toxic foreign substances but also 

 may resvxlt from dietary imbalance, blood 

 factor incompatability, irradiations and ac- 

 tion of disease-causing agents. The reaction 

 of the embryo may depend not only on the 

 stage at which it is subjected to the abnormal 

 influence, but on the nature of the tera- 



