702 



Teratogenesis 



3. It has been shown that blood factor 

 incompatibilities between a mother and a 

 fetus may result in abnormal development. 

 The best known case is that involving Rh 

 factors [see Levine ('48) for review of the 

 literature] ; in this situation Rh positive 

 blood from a fetus may produce antibodies 

 in an Rh negative mother which may in turn 

 have a deleterious effect on the fetus. In 

 practice it is found that subsequent fetuses 

 are more severely affected and have more 

 severe symptoms of erythroblastosis. (Note 

 that when several such cases occur in one 

 family the records may resemble those for 

 direct inheritance, yet these conditions arise 

 only indirectly through the blood factor in- 

 compatibilities.) 



4. Considerable evidence has been pre- 

 sented (Gregg, '41; Erickson, '44) which in- 

 dicates that various congenital anomalies 

 (cataract, microcephaly, heart disease, den- 

 tal defects, etc.) occur after women contract 

 rubella (German measles) during the early 

 months of pregnancy. It has been assumed 

 by most people that the virus crosses the 

 placenta and attacks the fetal tissues directly. 

 Hamburger and Habel ('47) have shown 

 that some viruses may produce teratological 

 effects when applied directly to a chick em- 

 bryo. Gillman et al. ('48) have produced a 

 number of congenital anomalies (hydroceph- 

 alus, cleft palate, eye and tail defects, etc.) 

 by injecting trypan blue into rats during 

 pregnancy or prior to conception. The dye 

 itself does not reach the embryo; instead, ac- 

 cording to these authors, it produces meta- 

 bolic disturbances in the mother which in 

 turn affect the developing embryos. These 

 authors believe that it is not necessary for 

 viruses or other disease-causing organisms to 

 act directly on the fetus. They may produce 

 their effects indirectly, through an accumula- 

 tion in the blood of products of disturbed 

 maternal metabolism. This concept has far 

 reaching implications for further studies on 

 the etiology of human congenital malforma- 

 tions. 



Two generalizations from these studies of 

 environmental effects should be emphasized 

 at this time. (1) Essentially the same effects 

 may be produced by a variety of seemingly 

 unrelated treatments. (2) In many instances 

 the morphological consequences of environ- 

 mental interventions are essentially the same 

 as those caused by genetic factors. 



Phenocopies. When experimental treatment 

 of a genetically normal embryo modifies its 

 development so that its final appearance du- 

 plicates that of a mutant of the same species 



it is called a phenocopy (Goldschmidt, '38). 

 Goldschmidt was the first to recognize that 

 phenocopies could be of great value in elu- 

 cidating gene action. His comparison of the 

 effects of temperature variation on wing de- 

 velopment with mutant wing conditions in 

 Drosophila is now classic. A high incidence 

 of a particular type of wing defect was ob- 

 tained when the larvae were subjected to 

 the proper temperature at the proper time 

 (i.e., phenocritical period). It was reasoned 

 that the temperature alteration modified the 

 rate of processes important for wing develop- 

 ment, that these were probably the same 

 processes disturbed by mutant genes which 

 produced wing defects, and that the pheno- 

 critical period for a given condition was the 

 same as the period when the gene producing 

 a similar condition was operative. 



This reasoning is very suggestive, but one 

 must, in order to have valid conclusions of 

 this sort, verify each step. Even in Drosophila 

 Henke, Fink and Ma ('41) have shown that 

 phenocopies may be produced by treating 

 larvae at periods other than the critical one 

 for the mutant copied. An example from 

 vertebrate material may be used to illustrate 

 some of the problems in studies of pheno- 

 copies. Tail reduction occurs in different 

 ways in the two rumpless mutations of chick- 

 ens. Presumptive tail tissue degenerates 

 (Zwilling, '42), in dominant rvimpless em- 

 bryos, prior to its incorporation into the tail 

 (i.e., during the second and third days). The 

 degree of tail reduction is correlated with the 

 amount of degenerate tissue. In recessive 

 rumpless embryos (Zwilling, '45a) degen- 

 eration does not occur until after rather ab- 

 normal tail structures have formed. Abnor- 

 mal tail morphogenesis may occur at any 

 stage between the third and sixth days and 

 the degree of tail reduction is correlated with 

 the time when the abnormalities appear. 

 Structures proximal to the involved regions 

 continue to develop normally.* Phenocopies 



* Several mutations in mice cause taillessness of 

 one degree or another. Chesley ('35) and Glueck- 

 sohn-Schoenheimer C49b) have described the devel- 

 opmental events leading to tail defects in a number 

 of them. In one case (Brachyury heterozygotes) 

 the tail may develop normally at first and then de- 

 generate distal to a given point. In other genetic 

 combinations ("T/t", T/f-) the tail may. at first, 

 form normally except that the notochord is missing. 

 After a while the tail in these degenerates com- 

 pletely. Here we see at least two more genetic 

 mechanisms which result in tail loss. At least two 

 groups (Hamburgh, '52; Waddington and Carter, 

 '52) are studying tail defects (phenocopies) which 

 follow injection of trypan blue into pregnant mice. 



