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IN Nature1 and elsewhere2,3, A. N. Studitsky has recently made statements to the effect that “studies of the interrelationship of the endocrine glands in the causation of experimental chondrodystrophy, taking into account the influence of the vitamin D balance, prove almost certainly the hypothesis of the humoral nature of this disease”. More specifically it may, according to Studitsky, be concluded “that the achondroplasia of the chick embryo is a hyper-parathyroid dystrophy of the skeleton, developing against the background of avitaminosis D”, and the author continues that “it does not seem improbable that our hypothesis as to the nature of faetal achondroplasia can also be extended to the analogous affection in man”. It is the purpose of this note to point out very briefly that one of the few conclusions which available evidence permits one to draw concerning the causation of chondrodystrophy is that humoral agencies play no part in the origin of this skeletal abnormality.

THE only information concerning the primary sox ratio of birds, based on acceptable criteria, is to be found in a publication by Hays which relates to Rhode Island Red fowl1. Hays's results give the sexes in the progenies of 39 hens which in the course of a ten-year period had shown 100 per cent fertility and 100 per cent hatchability of their eggs during the two-months hatching season of one of these years. The 39 hens in question had a total of 931 offspring : 61 chicks were lost before the sex could be ascertained; among the remaining 870 chicks, 432 were males and 438 were females. These results clearly pointed to equality of the sexes as determined at fertilization. Yet, Hays suggested (see below), that significant differences may have existed between individual hens in the sex ratios of their offspring.

IT has been shown that treatment of chicken embryos with insulin will produce malformations of quite different kinds according to the developmental stage at which the hormone is administered. During the earliest period of incubation rumplessness is the typical insulin-induced defect, that is, a partial or complete suppression of the tail skeleton and its related soft tissues1–3. When, however, insulin is injected after 4 or 5 days of incubation the tail structures remain intact, but the embryos are likely (incidence and severity always depending on dosage) to have disproportionately short legs (micromelia) and abnormalities of the facial skeleton, most commonly expressed as a shortening of the upper beak4. During the second period of response embryos can be effectively protected against the teratogenic activity of insulin by supplying them with supplementary nicotinamide, whereas during early stages only a limited lowering of the teratogenic activity of insulin is achieved by nicotinamide supplementation5,6.

IT is well known that the effectiveness of teratogens, measured either in incidence or in severity of resulting malformations, is frequently modified, in a plus or minus direction, by unrelated external conditions. The mechanisms by which these modifying agencies operate are largely unknown. A little, if not a great deal more, is known about the role of drug interaction in teratogenesis. There are, for example, the facts of interference with essential metabolites, such as deprivation of available vitamins by competing analogues1 or by blockage of their utilization in co-enzyme systems2. Then there are the potentiating effects of lowering the available sources of utilizable carbohydrates3 or of uncoupling oxidative phosphorylation4. Among the latter sources of synergism we found compounds, for example, 2-deoxy-D-glucose and chlorpromazine, which when administered alone were nonteratogenic and which even in larger (and highly toxic) amounts did not produce malformations. Other compounds of this type, however, are themselves teratogenic, in dosages higher than those required for synergism, but the range of their interference with development may be more restricted than their synergistic activity.

THE fact that cortisone has an inhibitory effect on growth of chicken embryos was first noted in 19471. A detailed study of this phenomenon was afterwards undertaken by Karnofsky, Ridgway and Patterson2 and their observations were confirmed by Yamada3 and by Siegel, Smith and Gerstl4. Cavallero, di Marco, Fuoco and Sala5 secured evidence indicating that the growth-inhibiting effect of cortisone is brought about by an interference with protein synthesis, and an excess of hydroxyproline found by Roberts, Karnofsky and Frankel6 after cortisone treatment presumably points to the same conclusion. In experiments with weanling rats, Tuchmann-Duplessis and Mercier-Parot7 failed to counteract the growth-inhibitory action of cortisone by concurrent treatment with somatotropic pituitary hormone, glucosamine or the polysaccharide fraction of human placenta. In chicken embryos, on the other hand, Sobel8 observed that the deleterious effects of cortisone on growth and survival were partially counteracted by simultaneous administration of somatotropic pituitary hormone.

TREATMENT with insulin has well-established teratogenic effects in chick development. When administered during the earliest stages of incubation (first 2 days), it is responsible for the occurrence of rumplessness (chiefly absence of the tail vertebrae), whereas somewhat later (4th or 5th) day) it leads to a syndrome of micromelia and abnormalities of the beak (namely, a shortened upper beak or parrot beak). During these later stages, but not in the early ones, the teratogenic activity of insulin is strikingly exaggerated by the simultaneous administration of chlorpromazine1. The amounts of chlorpromazine which produce this effect were non-teratogenic and only moderately toxic if given alone.

Recently we have reported on linkage tests between the genes for single comb and for the creeper traits in fowl1. Afterwards, the back-cross matings of heterozygous rose-combed Creeper hens to Leghorn cocks were continued through the third laying year of the hens. During this period we obtained a total of 781 offspring (hatched chicks and classifiable dead embryos), distributed as follows: There was 0.38 per cent of crossing-over. These data added to our earlier ones bring the total off-spring of matings between heterozygous Creeper females and normal males to 4,313 individuals with 0.56 per cent of crossing-over, and the total offspring of all back-crosses to 7,408 chicks with 0.39 per cent crossing-over.