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The teratogenicity of D-penicillamine was studied using the Sprague-Dawley rat. Fetuses from rats fed diets containing 0.83% D-penicillamine during pregnancy had a high incidence of malformations. Maternal and fetal tissue copper levels were significantly lower in the D-penicillamine group than in controls, suggesting that the teratogenicity of the drug may be due in part to the induction of copper deficiency by its chelating properties.

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.

The teratogenicity of D-penicillamine (DP) (dimethyl cysteine) was studied using the Sprague-Dawley rat. D-Penicillamine was fed during pregnancy at a level of 0 (control), 0.17, 0.83, or 1.66% of the diet. The frequency of resorptions, and the frequency and severity of malformations, increased with increasing levels of the drug. Maternal and fetal tissue copper levels were significantly lower in the DP groups than in controls, with the levels decreasing in a dose-related manner. Maternal and fetal zinc levels were lower in the 1.6% DP group than in controls. Maternal liver iron concentration was higher in the drug-fed rats than in controls, increasing in a dose-related manner. Fetal iron concentration was not consistently affected by the drug. Maternal and fetal manganese, calcium, and magnesium concentrations were similar among all groups. These results suggest that the teratogenicity of D-penicillamine may be due in part to induction of copper deficiency and, at high dose levels, zinc deficiency, caused by its chelating properties.