Stress linked to epigenetics

This abridged article appeared in the April 2010 issue of the Psychiatric Times.

Overly sensitive, aversive reactions to stress seem to run in families. The literature abounds with reports of relatives in these populations predisposed to depression, anxiety, and even suicide. Some family members present with glucocorticoid levels notched abnormally high, and in curiously deregulated concentrations. Behaviorally, they seem to exist at a permanent state of high alert. Attempts to isolate the genetic underpinnings of this obvious hyperaroused stress sensitivity have met with mixed success.

People carrying certain mutations in the serotonin transporter gene seem particularly vulnerable to the normal stresses and strains in life, although there have been difficulties in replicating all the findings. Plenty of people exist who are just as vulnerable to stress but who do not carry this mutation—or any other suspect genetic anomaly—that could explain the behavior. It is now possible to characterize some of this seeming heritability—and accompanying statistical turbulence—without invoking heritability at all. This is the world of epigenetic transfer, the ability to pass on a trait without having to stop at a meiotic border.

A recent study has demonstrated how a powerful environmental stressor can exert molecular effects that last over a long period. The mechanism is epigenetic. It is the first result to characterize a molecular mechanism, induced by early life stressors, that influences behaviors penetrating into adulthood.

For years, we have known that stressed wombs tend to produce stressed babies. Most molecular explanations for this observation invoke the effects of transplacental glucocorticoids on fetal brain development. If mothers become too stressed (so the idea posits), too many stress hormones enter the womb, penetrate the fetal brain, and interfere with its proper development. There is some empirical support for this notion. First, excess levels of maternal glucocorticoids have been shown to cross the placenta, targeting the fetal limbic system and causing it to develop much more slowly than in typical controls. This is thought to result in future behavioral dysfunction, particularly regarding reactions to external stressors.

Social states experienced in early life can directly affect later behavior. Until now, exactly what molecular mechanisms undergird such effects have remained a complete mystery. This embryonic braking system is a coordinated series of responses that normally result in the inhibition of glucocorticoid production after some environmental stress has been successfully negotiated. Without this braking system, the fetal brain is wired to produce excess glucocorticoids in an increasingly unregulated fashion. The baby carries this deregulated system into adulthood. If the adult is female and becomes pregnant, her system, which is already flooded with cortisol, marinates her new baby with glucocorticoid. This once again creates a hyperaroused womb, complete with new fetal damage. The trait is thus passed along, not through the germ line but simply through womb exposure.

The work to be described involved inducing behavioral stress in a cohort of laboratory rodent pups, and then watching the effects of that stress on behavior as the rats matured. For the first time, a molecular change associated with a persistent hyperaroused state in an adult animal was induced by behavioral neglect during the animal’s extreme youth. It is axiomatic from a counseling perspective that social states experienced in early life can directly affect later behavior. Until now, exactly what molecular mechanisms undergird such effects have remained a complete mystery. These data reveal strong epigenetic factors.

The real value lies in what they portend for the future. Uncovering a mechanism induced in childhood that mediates a persistent behavioral experience in adults is a phenomenal achievement. Showing that these associations sometimes have epigenetic underpinnings is an added bonus. These results serve as flashlights, directing where scientists interested in human reactions should spend their next research dollars. Stress responses really do run in families. Showing that some reasons for this may be mostly environmental—with no DNA in sight—is the biggest plus of all.