How stress echoes down the generations

THE effects of child abuse can last a lifetime. Neglected or abused children have a higher risk of developing all sorts of ailments as adults, including mental illnesses such as depression but also physical ones like cancer and stroke. In fact, the effects may last even longer. Emerging evidence suggests that the consequences of mistreatment in childhood may persist down the generations, affecting a victim’s children or grand-children, even if they have experienced no abuse themselves.

Exactly how this happens is not well understood. Rigorous experiments on human subjects are difficult. Scientists have therefore turned to rats and mice. But now Larry Feig of Tufts University and his colleagues have shown that psychological stress seems to cause similar changes in the sperm of both mice and men. Their study is published this week in Translational Psychiatry.

Biologists know that traits are carried down the generations by genes. Genes encode proteins, and proteins make up organisms. That is still true. But it has recently become clear that it is not the whole story. Organisms regulate the activity of their genes throughout their lives, switching different genes on and off as circumstances require. It is possible that such “epigenetic” phenomena can be passed, along with the genes themselves, to an animal’s descendants. They offer a mechanism by which an animal’s life experiences can have effects on its offspring.

Hunting for signs of this, Dr Feig and his colleagues asked 28 male volunteers to complete a questionnaire assessing the severity of any trauma they had experienced as youngsters. They also asked their volunteers to provide sperm samples. They then looked for evidence for a common epigenetic mechanism involving small molecules called micro-RNAs. Their job is to bind to another molecule called messenger RNA, whose task in turn is to ferry information read from a gene to the cellular factories that create the required protein. Micro-RNA renders messenger RNA inactive, reducing the activity of the gene in question—and it can travel in sperm alongside DNA.

Sure enough, upon screening the men’s sperm, the researchers found that concentrations of two types of micro-RNAs, miR-34 and miR-449, were as much as 100 times lower in samples from abused men.

The team then turned to their mice. A standard way to stress mice is to move them to new cages, with new mice, from time to time until they reach adulthood. When the team did this they found that the stressed males had lower levels of miR-34 and miR-449 in their sperm. They mated these males with unstressed females. The resulting embryos also had low levels of the two micro-RNAs. And so in turn did sperm produced by the male offspring of these unions.

Dr Feig and others have shown that the female offspring of stressed male mice tend to be more anxious and less sociable. Furthermore, the sons of stressed fathers themselves produce stressed daughters. The effects of cage-shuffling, in other words, seem to last for at least three generations. The researchers have not demonstrated conclusively that miR-34 and miR-449 are responsible. But their results are suggestive.

To try to nail their case, the researchers plan to carry out a bigger study. This time, they will give questionnaires to their human subjects’ fathers, to tease out whether any epigenetic changes they observe arise from the childhood experiences of the subject or his father. Sisters and daughters may be included in the study, too. That is an ambitious goal. It is also a worthy one. Unless genetic engineering can one day be perfected, changes in genes are hard-wired. But epigenetic effects might be treatable, by boosting levels of particular micro-RNAs in sperm, for example. That could mean the legacy of abuse is no longer passed to future generations.