5.4 Retinoic acid
The retinoic acid story is both distressing and illuminating. It is distressing because with hindsight it is possible to see how the suffering of many people could have been averted. It is illuminating because we now understand much about how retinoic acid works.
Retinoic acid is a natural product of vitamin A. It had been known since the 1930s that a lack of vitamin A, a vitamin A deficiency, led to fetal abnormalities. Subsequent studies in animals showed that an excess of vitamin A also led to fetal abnormalities. Unfortunately that did not prevent a drug that contained retinoic acid coming on to the market and being available to pregnant women. The drug was Accutane® and it was introduced in the 1980s as an effective treatment for intractable acne. Of the children that survived the exposure to this drug in the womb, many were born with defects of the nervous system, in particular of the brain, which was often grossly malformed.
Since the 1980s, the mechanism by which retinoic acid exerts its devastating effect has been uncovered. Two crucial pieces of information have revealed how both a lack and an excess of retinoic acid could be harmful. The first piece of evidence came from studies on the South African clawed toad, Xenopus laevis. Having noticed that the natural concentration of retinoic acid was ten times higher at the posterior end of the embryo than at the anterior end, Durston et al. (1989) exposed Xenopus tadpoles to different concentrations of retinoic acid. Their results are shown in Figure 12.
Xenopus embryos exposed to increasing concentrations of retinoic acid fail to develop more anterior body structures, i.e. the brain.
The initial discovery that there is a higher concentration of retinoic acid at the posterior end of the Xenopus embryo than at the anterior end led Simeone et al. (1991) to surmise that cells responded differently to different concentrations of retinoic acid. To test his idea, he took cultures of human embryonic stem cells and exposed them to either high or low concentrations of retinoic acid.
What Simeone found was that those stem cells exposed to low concentrations of retinoic acid produced proteins normally associated with the anterior part of the embryo. Those stem cells exposed to high concentrations of retinoic acid produced proteins normally associated with posterior parts of the embryo.
What do these results tell you about the action of retinoic acid?
High concentrations of retinoic acid are needed to switch on those genes required for posterior structures, whereas low concentrations of retinoic acid are needed to switch on those genes needed for anterior structures.
Embryos exposed to high levels of retinoic acid because their mothers took Accutane®, had the development of their anterior nervous system inhibited. It turns out that retinoic acid is an intercellular signal, like testosterone, which also passes straight through the cell membrane. Inside the cell, retinoic acid binds to specific receptors (retinoic acid receptors) and the receptor-retinoic acid combination transfers to the nucleus where it acts as a transcription factor (Figure 13). That part of the DNA to which the transcription factor attaches is called a response element, in this case the retinoic acid response element (RARE).
This example illustrates one very important way in which an environmental factor (a drug in this case) can have a direct effect on the early stages of development, by altering the balance of proteins produced in cells. The importance of this balance of cellular proteins is further illustrated in Section 6.