Meso-2,3-dimercaptosuccinic acid (DMSA) affects maternal and fetal copper metabolism in Swiss mice

Meso-2,3-dimercaptosuccinic acid (DMSA) is a chelating agent used to treat heavy metal intoxication. DMSA has been reported to be teratogenic in the mouse, and it has been suggested that this teratogenicity may be secondary to DMSA-induced alterations in Zn metabolism. In the present study, 0, 400 or 800 mg DMSA/kg body weight were administered on gestation days 6-15 to pregnant Swiss mice by gavage (PO) or subcutaneous injection (SC). Mice were fed a diet containing 14 μg Cu, 10 μg Cu, 120 μg Fe, 1175 μg Mg and 6.8 mg Ca/g diet. A sub-grioup of mice inthe 800 mg DSMA/kg Sc group was fed a diet containing 250 μg Zn/g. DMSA administration did not result in overt maternal toxicity. There was no effect of the drug on fetal or placental weight, or on crown-rump length. However, some fetuses from DMSA-treated dams were characterized by skeletal abnormalities including supernumerary ribs, unossified anterior phalanges and malformed sternebrae. Drug exposure was not associated with consistent changes in tissue Zn, Fe, Ca or Mg levels. Supplemental Zn had no marked effects on the fetus. Fetal liver Cu concentrations exhibited dose-dependent decreases with increasing DSMA dose. This finding suggests that the developmental toxicity of DMSA may be mediated through disturbed maternal/fetal copper metabolism.