Neonatal deaths and pulmonary dysplasia due to D-penicillamine in the rat



D-penicillamine, added to a low copper diet fed through pregnancy or given by gavage to pregnant rats which were on a copper-deficient or a normal diet produced fetal resorptions and malformations. Doses of 300 to 400 mg per day for 6 days (days 9–14 of gestation) with a diet normal for copper prevented maternal weight gain and at 350 or 400 mg/day caused fetal death on day 16 or 17. Forty percent of offspring had tracheobronchomegaly and 42% had cystic lungs. Associated abnormalities included pleural hemorrhages, dilated esophagi, and unaerated lungs. The lungs had large, poorly formed, thick-walled acini without partitioning and a thick rim of connective tissue around vessels and bronchi. At the higher doses, all members of one of 12 litters had angulation of the spine and half the members of another litter had cleft palates. A postulated mechanism for these alterations in pulmonary connective tissue productive of malformations which model human tracheobronchomegaly and cystic lungs, is interference with lysyl oxidase, a copper-requiring enzyme, which cross-links elastin.