The effect of oxygen concentration on the teratogenicity of salicylate, niridazole, cyclophosphamide, and phosphoramide mustard in rat embryos in vitro.

Comparisons were made of rat embryos cultured at 5% or 20% oxygen in the presence of salicylate (SAL), cyclophosphamide (CP), niridazole (NDZ), or phosphoramide mustard (PM). Multiple regression analyses were used to compare the effects of drug concentration, oxygen concentration, and the product of drug times oxygen concentration on malformation incidence, viability, and protein content of embryos cultured for 24 hours. Drug concentration significantly affected malformation incidence or severity and protein content (P less than 0.001) for the four drugs tested. Oxygen concentration significantly affected protein content for the four compounds (P less than 0.001) but affected malformation incidence only with NDZ. Furthermore, the interaction of oxygen concentration and drug concentration significantly affected the malformation incidence in the presence of NDZ (P less than 0.001), and protein content (P less than 0.001) and viability (P less than 0.001) in the presence of CP. The pattern of significant effects of the independent variables (drug concentration, oxygen concentration, and drug times oxygen concentration) is consistent with the hypotheses of oxygen-dependent metabolism (or lack of metabolism) of the drugs in question. NDZ, which is thought to be converted to reactive intermediates by an oxygen-inhibited nitroreductase, was more toxic at reduced oxygen tension. CP, which is activated by an oxygen-dependent P-450 system, was more toxic with increased oxygen tension. Significant effects of the independent variables on embryos exposed to SAL or PM were consistent with the effects on control embryos, notably, increased protein content with increased oxygen.