Reduction by copper supplementation of teratogenic effects of D-penicillamine.

Previous experiments from this laboratory demonstrated that oral administration of D-penicillamine (DPA) throughout gestation produced significant teratogenic effects and low copper concentrations in both maternal and fetal tissues in a dose-related manner. To test the hypothesis that the teratogenicity of DPA was due to induced copper deficiency, Sprague-Dawley rats were fed throughout gestation complete, purified diets containing 5 (control), 50, or 100 micrograms/g (supplemental) copper. One-half of the rats in each group received DPA at 0.83% of the diet. On day 21 of gestation, fetuses were removed and examined for gross malformations. Selected maternal and fetal tissues were analyzed for copper, zinc, iron and manganese. Animals fed the drug and supplemental copper had a very low incidence of fetal resorption (4%) and malformation (4%) compared to a high frequency of resorption (23%) and malformation (21%) in drug-fed nonsupplemented animals. There were no consistent differences in tissue iron, zinc or manganese levels among the groups. Tissue copper concentrations were lowest in the drug-fed, nonsupplemented group; those of the group fed DPA and supplemental copper were higher, but did not reach control values. Thus, there was a correlation between tissue copper levels and the frequency of malformations, supporting our hypothesis that DPA teratogenicity is due at least in part to induced copper deficiency.