D-Penicillamine toxicity in mice. III. Pathological study of offspring of penicillamine-fed pregnant and lactating mice

Abstract

Mice were divided into six experimental diet groups during pregnancy and lactation: (1) C + C, control diet; (2) P(2) + (2), 2 g of d-penicillamine/kg of diet; (3) P(4) + P(4), 4 g of d-penicillamine/kg of diet (these groups received diets throughout pregnancy and lactation); (4) P(4) + P(4)Cu, the test diet was fed during pregnancy, and 5 × 10 −3, m copper sulfate solution was added to replace drinking water after delivery; (5) C + P(4), the test diet was given only during lactation; (6) P(4) + C, the test diet was given only during pregnancy. Highest mortality, most severe and variegated neurological abnormalities, and rupture of aortic aneurysms were observed in the P(4) + P(4) offspring. Supplementation with copper (P(4) + P(4)Cu) resulted in no abnormalities. In C + P(4), mortality was higher and abnormalities were more variegated than in P(4) + C or P(2) + P(2). No abnormality was detected in C + C. The aortas in P(4) + P(4) showed dissecting aneurysms and breaks in the elastic lamellae; neuronal degeneration was noted in the cerebral cortex, thalamic nuclei, and spinal ganglion on the 14th and 21st postnatal days, but not on the 1st or 7th postnatal days. No neuronal degeneration was observed in the copper-supplemented group. In C + P(4), there were a few abnormal neurons in the cerebral cortex on the 21st postnatal day. No neuronal degeneration was detected in C + C, P(2) + P(2), or P(4) + C. These observations suggest that abnormal signs and gross lesions are related to copper deficiency induced by the metal-chelating action of d-penicillamine especially postnatally through two basic mechanisms: maturation defect in fibrous protein and neuronal degeneration in the brain and spinal ganglia.