Transplacental exposure to methylene blue initiates teratogenesis in the mouse: Preliminary evidence for a mechanistic implication of cyclic GMP pathway disruption

Background: The vital dye methylene blue (MB) has been shown to be teratoge nic when injected into the amnion in the second trimester. On the other han d, the teratogenic potential of transplacental exposure to MB has not been determined. Methods: MB was administered subcutaneously to ICR (CD-1) mice at 0, 35, 50 , 60, or 70 mg/kg on gestation day 8 (plug day = day 0). Teratological asse ssments were carried out at term gestation, on gestation day 18. Since MB i nhibits soluble guanylate cyclase enzyme activity, zaprinast (ZPN), a selec tive cGMP-phosphodiesterase type V inhibitor, was administered to prevent d evelopmental disorders initiated by MB at 50 mg/kg. Results: There was a dose-dependent increment of embryolethality. MB treatm ent also produced axial skeleton and neural tube defects. Coadministration of ZPN (20 mg/kg per three times) abolished completely MB-induced neural tu be defects and reduced by one-half the incidence of fetuses exhibiting axia l skeletal defects. ZPN did not provide protection against the embryocidal effects of MB. Conclusions: This study showed that transplacental exposure to MB is terato genic in the mouse. Coadministration of ZPN prevented partly MB-induced ter atogenesis, which supports the hypothesis that imbalance of cGMP pathway ac counts, in part, for the teratogenicity of MB. (C) 2001 Wiley-Liss, Inc.