Oral administration of D-penicillamine causes neonatal mortality without morphological defects in CD-1 mice

D-Penicillamine (DPA) causes axial skeletal defects in rats and fetal lethality when given as 0.83% and 1.6% of the diet, but its mechanism of action on the axial skeleton is unknown. We have been using submerged fetal CD-1 mouse limb-bud organ cultures to evaluate the mechanisms of teratogenesis in the developing murine limb. Before attempting to evaluate the in vitro effects of DPA, a dose response morphological teratology study was undertaken using CD-1 mice to determine the effects of DPA on the mouse and determine the potential of using the mouse limb-bud assay to investigate the terata produced by DPA. Groups (n = 8) of nulliparous pregnant mice (vaginal plug = day 0 of gestation) were dosed, via oral gavage, with 0, 250, 500, 1000 and 2000 mg kg-1 DPA for the first 12 days of gestation. Body weights and food consumption were measured daily. On day 18, fetuses were removed by Caesarian section. Two-thirds of the fetal skeletons were stained with alcian blue and alizarin red and then cleared and examined for defects. Soft-tissue defects were examined in the remaining one-third using a modification of the Wilson freehand technique. Maternal body weight gains were not different before day 12 of the experiment, but differed in the interval of day 13-18 (P = 0.004). No group differences were noted in male/female ratios, site of implantation, implantation numbers and number of fetuses. Decreased survivability was seen in the 2000 mg kg-1 group. No treatment-related defects were seen.(ABSTRACT TRUNCATED AT 250 WORDS)