CONGENITAL MALFORMATIONS INDUCED BY RIBOFLAVIN DEFICIENCY IN STRAINS OF INBRED MICE
Authors: Kalter Harold 
Published: December 2021

Acute maternal deprivation of riboflavin at the end of the middle-third of pregnancy of inbred mice has thus been shown to induce a great many malformations in the offspring. Among these were malformations of the skeleton that resembled those produced in rats by chronic riboflavin deficiency, and defects of the esophagus and brain. In the experiments of Warkany and Nelson with rats, malformations of soft tissue occurred only rarely after chronic riboflavin deficiency; Nelson et al., however, by means of galactoflavin, caused abnormalities of viscera and brains of rats. The more extensive spectrum of malformations resulting from treatment with the antagonist, than through deficiency due to long-term deprivation, is without doubt the outcome of a greater intensity of riboflavin deficiency.
The individual abnormalities merit cursory discussion. To the author's knowledge, this is the first report of the experimental production of absent and abnormal esophagus. The fact that such a condition can be produced at will in large numbers of experimental animals is of importance, as understanding such a situation is facilitated by ability to create it and to observe its ontogenetic steps. Although fistulous communication with the trachea is not involved in the induced anomaly, a study of it may lead to some clarification of the deviation that leads to the more common abnormality of tracheo-esophageal fistula; and in addition will probably contribute to unravelling the problem of hydramnios in esophageal atresia.
The hydrocephalus induced by riboflavin deficiency is remarkably similar to cystic fourth ventricle as encountered in man, and to a hereditary hydrocephalus recently described in mice. Again, patient investigation of the developmental sequence of the induced malformation will surely be rewarding.
It is especially interesting to note the frequencies of particular malformations produced by different teratogens. Cleft palate, for instance, has been a quite common malformation in experimental teratology, yet little or nothing has been done by way of comparing how frequently it occurs after different treatments.
This may be discussed for two teratogens, in several inbred strains of mice, as an indication of the usefulness for elucidating some theoretic points to which it can be put. After pregnant mice are injected with cortisone, a proportion of their young have cleft palate. The proportion of affected young depends, among other things, on the strain treated. Strain-A offspring are nearly all affected; DBA-mice, about 75% affected; and C57BL-mice, about 20% affected. The strain-A offspring also show an incidence of about 5 to 10% of spontaneous occurence of cleft lip with or without cleft palate. Some experimenters believe that teratogens operate by increasing the frequency of spontaneous, genetically influenced, malformations. Apparent examples of this phenomenon are common.
According to this belief, cortisone-induced cleft palate occurs with such great frequency in strain-A mice because this strain shows a similar malformation spontaneously. The doubtfulness of this line of reasoning can be indicated in several ways. First, it does not explain why cortisone regularly induces cleft palate in DBA-and C57BL-mice, which never have cleft lip and only extremely rarely have cleft palate, spontaneously. Secondly, one should strictly distinguish between the complex of cleft lip, with or without cleft palate, and cleft palate alone, as they are dissimilar in morphology, genetics and embryology. The cleft-lip complex is not produced by cortisone. And, thirdly, the comparative susceptibility of A-, DBA-, and C57BL-mice to cleft palate induced by cortisone is very different from that for galactoflavin; the offspring of pregnant strain-A females fed galactoflavin only rarely have cleft palate, whereas offspring of treated DBA- and C57BL-females have moderately low to moderately high incidences of this anomaly.
If lack of riboflavin has such variable and widespread consequences in the four strains studied, the presumption can be made that the range of possible teratogenic effects of riboflavin deficiency in other strains of mice may be vastly greater than this. And the variabilities and differences here described for mice can be only a crude approximation of the complexity of the response to a similar situation that is potential in a species so unimaginably heterogeneous genetically as man.