240 PHYSIOLOGIC GENETICS 



if it were, doubling the dose would not reduce the frequency of defect. At other 

 stages, and for other types of malformation, a double dose of nicotinamide two hours 

 after the standard dose of 6-AN does not produce any fewer malformations than the 

 single dose, showing that in such a case a single dose of nicotinamide is enough to 

 correct the inactivation produced by the analog. 1008 Thus the nicotinamide, or DPN 

 requirements of the maternal-fetal system, appear to vary from stage to stage of embryo- 

 genesis, and this approach provides an opportunity to study these variations in a 

 roughly quantitative way. 



Further information might be obtained by comparing the arrays of malformations 

 produced by several DPN inhibitors. It is known that 6-AN forms an analog of 

 DPN which is inactive in a variety of DPN-dependent enzymatic reactions but not in all 

 of them. 277 Presumably malformations caused by treatment with 6-AN result from 

 inhibition of one or more of the DPN-dependent reactions, but it is not possible to say 

 which reaction, when inhibited, leads to which malformation. If other DPN analogs 

 that blocked other DPN-dependent reactions were used, presumably a different array 

 of malformations would result. If a given reaction were blocked by both analogs, the 

 same malformation should result from treatment with either one. Thus by using a 

 battery of analogs, and seeing which malformations were produced in common by 

 which analogs, it might be possible to infer which enzymatic system was blocked in 

 order to produce the defect. As the number of analogs increases, and their biochemical 

 effects are better understood, they should provide excellent tools for studying the 

 biochemistry of normal and abnormal morphogenesis. 



The immunologic aspects of development, now being energetically studied by 

 experimental embryologists, 316 provide another promising approach to the biochemistry 

 of morphogenesis that has so far been little exploited by mammalian teratologists. 

 Gluecksohn-Waelsch 441 showed that female mice immunized with extracts of brain 

 produced offspring with an increased frequency of central-nervous-system malforma- 

 tions, whereas extracts of heart were ineffective. Wood 1402 confirmed the report of 

 Guyer and Smith 513 that lenticular antiserum injected into pregnant rabbits produced 

 defects in the eyes of the embryos (though the claim of Guyer and Smith that these 

 changes was heritable has not been confirmed). Further studies of this type are 

 needed, particularly in view of the preliminary report by Blizzard et a/. 110 that con- 

 genital absence of the thyroid in human beings may result from maternal antithyroid 

 antibodies. It would also be interesting to investigate further the suggestion that 

 excessive amounts of specific proteins administered to the embryo would cause specific 

 inhibitions or stimulations of development in mammals as they do in some other 

 organisms. 



4. What are the biochemical effects of teratogens on development? — As previously suggested, 

 it may be possible to infer, from the biochemical nature of some teratogens, the probable 

 metabolic pathways on which they act to produce their developmental effects, although 

 even with specific analogs the picture may not be entirely clear. With other teratogens, 

 such as cortisone, for instance, the biochemical effects may be so varied and widespread 



