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Stress Hormone Causes Epigenetic Changes

Researchers found that chronic exposure to a stress hormone causes modifications to DNA in the brains of mice, prompting changes in gene expression. The new finding provides clues into how chronic stress might affect human behavior.

During stressful situations, we produce steroid hormones called glucocorticoids that affect many systems throughout the body. These effects are mediated by the hypothalamic-pituitary-adrenal (HPA) axis, a network involving the hypothalamus and pituitary gland in the brain and the adrenal glands near the kidneys.

Past studies have found that glucocorticoids alter gene expression in the brain. A group led by Drs. James B. Potash and Gary S. Wand at the Johns Hopkins University School of Medicine set out to investigate how glucocorticoids affect genes central to the HPA axis. They hypothesized that the hormones may affect the HPA axis through epigenetic modifications—changes to DNA that don’t alter sequences but influence gene expression.

The researchers added corticosterone—the major hormone that mice produce in stressful situations—to their drinking water for 4 weeks. After exposure, and again after a 4-week recovery period without corticosterone, the scientists tested the mice for behavioral and physiological changes. They examined the expression levels of 5 HPA axis genes in the hippocampus, hypothalamus and blood. They also tested the genes' methylation levels—a common epigenetic modification that affects gene expression. The study was funded by grants from NIH's National Institute on Alcohol Abuse and Alcoholism (NIAAA), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Institute of Mental Health (NIMH).

In the September 2010 issue of Endocrinology, the researchers reported that mice given corticosterone appeared more anxious during a maze test. Chronic exposure to corticosterone altered the expression of 3 HPA axis genes, including higher levels of Fkbp5 in the hippocampus, hypothalamus and blood. The protein that Fkbp5 codes for is part of a molecular complex that interacts with the glucocorticoid receptor. In addition, the researchers found decreased Fkbp5 methylation levels in the mice exposed to corticosterone.

Genetic variations in Fkbp5 have been associated with posttraumatic stress disorder and mood disorders, which are characterized by abnormal glucocorticoid regulation. These results suggest that methylation of Fkbp5 may play a role in mediating the effects of glucocorticoids on behavior.

"This gets at the mechanism through which we think epigenetics is important," says Potash. Epigenetic marks added to DNA through life experience may prepare an animal for future events, he explains. "If you think of the stress system as preparing you for fight or flight, you might imagine that these epigenetic changes might prepare you to fight harder or flee faster the next time you encounter something stressful."

With modern stressors, such as work deadlines, we can’t fight or flee, and chronic stress may instead lead to depression or other mood disorders. Understanding the mechanism by which chronic stress leads to these conditions might help us find new ways to prevent or treat them in the future. This research suggests that epigenetic changes could play a role in the process. However, it’s important to note that the connection is still speculative. Future studies will be needed to better understand the effects of chronic stress.

—by Harrison Wein, Ph.D.