700 



Teratogenesis 



in the details of development and the mode 

 of nuti'ition found in placental embryos. We 

 feel, therefore, that until more controlled 

 and reliable data on human material are 

 forthcoming one must accept the generali- 

 zations derived from studies of other forms. 

 What, then, are the major problems in 

 teratology? Briefly they may be separated 

 into two classes: (1) What are the causal 

 agents? and (2) How do these agents produce 

 their effects? 



THE CAUSAL AGENTS 



In their quest for information about the 

 etiology of congenital malformations many 

 of the teratologists of the past have become 

 strong proponents of either environmental or 

 hereditary factors as the exclusive cause of 

 the abnormalities. Mall ('08), one of the 

 most influential American teratologists of 

 his time, emphasized that all anomalies were 

 the result of external influences on normal 

 ova. These abnormal influences were caused 

 by faulty nutrition, the consequence of poor 

 implantation. Streeter ('30, '31), on the other 

 hand, has placed extreme emphasis on the 

 importance of genetic factors not only for 

 the embryonic phases of development but 

 for all subsequent stages of life; everything 

 depended on one's being a "good egg" to 

 start with. Observations of the past few 

 decades indicate quite strongly that a com- 

 promise between the two is more represen- 

 tative of the facts — that not only may 

 anomalies be mediated by both hereditary 

 and environmental factors, but similar kinds 

 of anomalies may be produced by either. 



Hereditary Factors. A wide variety of con- 

 genital anomalies, in many kinds of animals, 

 has been found to be transmitted from gen- 

 eration to generation in a regular mendelian 

 fashion. There is no doubt about the genetic 

 basis for these conditions [the reader is re- 

 ferred to Griineberg ('52), Gruenwald ('47), 

 and Landauer ('51) for bibliographies on this 

 subject]. The mode of inheritance is varied. 

 Characters may be transmitted as simple re- 

 cessives, i.e., the condition is not expressed 

 unless the individual receives a mutant gene 

 for the character from each parent. Other 

 characters may be transmitted as dominants. 

 In this situation a single factor, from one 

 parent, will produce the anomaly. The actual 

 expression of either type of inheritance may 

 vary from relatively minor to severe and 

 often lethal maldevelopment. 



Many of the dominant mutations are pe- 



culiar in that the presence of two mutant 

 genes (homozygotes) produces effects which 

 are more severe than found in heterozygotes. 

 Heterozygotes of the Creeper mutation in 

 fowl (Dunn and Landauer, '26; Landauer 

 and Dunn, '30; Landauer, '32) produce a 

 characteristic chondrodystrophy. The long 

 bones, especially of the legs, are dispropor- 

 tionately shortened. However, most of the 

 heterozygotes are quite viable. Homozygotes, 

 on the other hand, never survive to hatching. 

 Most of them are retarded and die during 

 the third or fourth day of development. 

 Some survive to later stages and show a typi- 

 cal phokomelic condition — extremely short 

 legs, deformed beaks and eyes and a general 

 dwarfing. 



Another example of this sort is the muta- 

 tion Kinky in the mouse (Caspari and David, 

 '40). In the heterozygotes the only expression 

 is an absence or fusion of tail vertebrae. 

 Gluecksohn-Schoenheimer ('49a) has shown 

 that the homozygotes are, for the most part, 

 lethal and evince, before death, a wide 

 variety of duplication and twinning. That 

 this may be a more severe and possibly early 

 expression of a similar tendency in hetero- 

 zygotes is indicated by forking of the distal 

 part of the tail and occasional occurrence of 

 duplication of the vagina in the latter. 



Lethal effects, however, are not invariable 

 consequences of homozygosity in dominant 

 mutations. In many cases the heterozygous 

 and homozygous conditions are distinguish- 

 able only by breeding tests. On the other 

 hand there are mutations like Yellow (Rob- 

 ertson, '42) and the spotting genes in mice 

 (Russell and Fondal, '51) in which there are 

 relatively minor effects on pigment or color 

 pattern in heterozygotes but in which the 

 homozygovis condition leads to severe and 

 frequently lethal defects. 



Essentially the same syndrome of effects 

 may be produced in a given species by en- 

 tirely independent recessive or dominant mu- 

 tations. The type of inheritance cannot be 

 determined from the appearance of the in- 

 dividual animals. Conditions similar to the 

 chondrodystrophy produced by the Creeper 

 factor have been caused by at least five dis- 

 tinct recessive lethals in fowl (Landauer, '35; 

 Asmundson, '39, '42; Landauer, '41; Lamor- 

 eux, '42; Hays, '44). Likewise rumplessness 

 may result, in fowl, from the action of two 

 independent mutations — one dominant 

 (Dunn, '25), the other recessive (Landauer, 

 '45a). While the recessive rumpless chickens 

 may have other associated anomalies (acces- 



