328 TERATOGENESIS

337. Antimitotie activity of thalidomide

In order to ascertain whether thalidomide (I) interferes with mitosis, I was administered to chick embryos before and 24 hr after incubation. A depression of mitotic activity of blood cells occurred which could be related to the time of administration since mitotic activity was unaffected if I was administered a few days after incubation. Villa, L. & Eridani, S. (1963). Cytological effects of thalidomide. Lancet i, 725.

338. Teratogenesis in fish

The developing fish embryo is very sensitive to the action of several physical and chemical agents such as temperature, ultraviolet radiation and changes in the concentration and ionic contents of the surrounding medium. The azo colouring, Trypan Blue, is teratogenic in the developing Zebra fish (Battle & Laale, Anat. Rec. 1960, 138, 333) but was unable to produce malformations in embryos of the freshwater fish, Medaka. The antidiabetic drug, tolbuta- mide (N-p-toluenesulphonyl N'-n-butylurea) (I) gave positive results.

Embryos of Medaka in 4 development stages, 2-4 cell, 8-16 cell, blastulae and 1-day-old embryos were exposed to 0.25-1 ~o solutions of I for 1-4 days. At all concentrations of I a high percentage of malformations occurred, particularly when given in the early embryonic stages. All the malformed embryos showed major cardiovascular defects and about 50 ~ had eye defects and abnormal curvature of the trunk and tail. The addition of glucose to the medium containing the drug increased the incidence of malformations. By adding [22Na] sodium chloride to the medium it was possible to induce changes in the normal turnover of 22Na. The author suggests that I produces a change in the permeability of the cellular mem- brane which indirectly results in abnormal development; or alternatively I acts directly on a metabolic process vital to normal development. Smithberg, M. (1962). Teratogenic effects of tolbutamide on the early development of the fish, Oryzias latipes. Amer. J. Anat. 111, 205.

339. Chlorpromazine potentiates teratogenic activity

The action of insulin (I) on chick embryos produces a variety of malformations according to the stage of development at which I is administered. In the early stages of embryonic development there is a partial suppression of the tail skeleton and its related soft tissues (rumplessness) but if the administration of I is delayed until 4-5 days of incubation the most common abnormalities produced are shortening of the legs and upper beak. The protection afforded by nicotinamide to 4-5-day-old embryos but not to younger embryos against damage by I, suggested to the authors that malformations might arise from disturbance of oxidative phosphorylation. The authors therefore selected chlorpromazine (II), an agent known to uncouple oxidative phosphorylation, in order to study its effect on the terato- genie activity of I.

Injection of 2-5 mg II, with 2 or 4 units of I into the yolk sac of 5-day incubated eggs approximately doubled the incidence of leg and beak defects ss well as increasing the mor- tality rate. II itself had little immediate toxic effect and caused no abnormalities. When administered to embryos after only one day's incubation, one unit of I" with 2-5 mg II caused no significant change in the incidence of rumplessness. This is to be expected if un- coupling of oxidative phosphorylation by I is aggravated by II. In contrast, compounds with a wider spectrum of metabolic competition such as 2-deoxy-I>glucose potentiated the effect of I at both periods of incubation. Landauer, W. & Clark, Ellen M. (1963). Interaction of insulin and chlorpromazine in tera- togenesis. Nature, Lond. 198, 215.