High pH prevents retinoic acid-induced teratogenesis.

Exogenously applied retinoic acid is known to cause teratogenic effects in a variety of animal systems. We examined whether the formation of teratogenic effects may be influenced by the electrical charge of retinoic acid. The pKa of retinoic acid ranges from 6 to 8, indicating that it is electrically neutral in a pH5 medium and is negatively charged in a pH9 medium. With this idea in mind, embryos of the pond snail Lymnaea stagnalis were pulse-treated with retinoic acid and cultured in media of different pH. The percentage of embryos with retinoic acid-induced eye defects was 6-fold lower in the pH9 medium as compared to the pH5 medium. In contrast, the apical plate defects induced by retinoic acid were not pH-dependent. The observation that high pH prevents eye defects but not apical plate defects can be explained by taking into account an electrophoretic redistribution of retinoic acid resulting from the voltage gradients that are generated by the Lymnaea embryo.