Stressful events can have long-term consequences on health and disease. The function of the body is greatly altered during stress on top of psychological and emotional changes. It is partly due to the increased secretion of the stress hormone, glucocorticoids, which has multiple effects on our body function. One of the major effects of stress hormone is to suppress immune function and spare energy for a more essential part of the body. Though these changes with glucocorticoids should have a beneficial value for the adaptation to the stressful environment, they can also generally decrease the quality of life and potentially promote disease development.
The production of glucocorticoids is tightly regulated. Our brain is the center for the proper regulation of glucocorticoids. Several parts of brain integrate internal and external information of our body for potential threats and induce the cascade of hormones for eventual glucocorticoid production upon stress. The brain also reacts to maintain the level of glucocorticoid low under normal circumstances. Some stressful events can have long-lasting effects by leaving a persistent change in the brain, affecting the regulation of glucocorticoids
Important regulating center in the brain for glucocorticoids is mainly developed early in life. Accumulated basic and clinical studies suggest that stressful events early in life may affect the development of important tissues including the central nervous system, resulting in long-term consequences on health and disease in later life. However, mechanistic understanding on this subject is largely lacking. In this context, we decided to test the role of early-life glucocorticoids on later-life disease development using the mice model. We treated the pregnant and lactating mothers with the stress hormone, which can mimic the maternal stress during pregnancy and lactation. After the treatment during perinatal periods, we waited for the offspring to grow and become adults and then tested for their multiple biological functions.
With the close assessment of these mice, we found that perinatal treatment of glucocorticoids leads to long-term changes in immunity. Particularly, we found the functional change in cytotoxic T cells. Cytotoxic T cells, as the name implies, are important immune cells that can kill the pathogen-infected cells. Some pathogens such as intracellular bacteria or viruses can conceal their identity within infected cells and proliferate. Cytotoxic T cells can identify and destroy it with its cytotoxic activity. Moreover, these cells can also recognize and kill tumor cells, which is the foundation of cancer immunotherapy conducted these days. We found that perinatal glucocorticoid exposure significantly decreases the function of these cytotoxic T cells. As a result, the mice exposed to stress hormones in early life become more susceptible to adulthood bacterial infection and showed impaired control of tumor growth.
Though glucocorticoids are induced with various stressors, this hormone is even produced basally without any stress. As medical conditions such as adrenal insufficiency or adrenal crisis show, the basal level of glucocorticoids has a very important function in many tissues. We found that perinatal exposure to the stress hormone significantly decreases the level of basal glucocorticoids in later life. This happens with the persistent change in neuronal development in the hippocampus, a control center for glucocorticoid production. We finally proved that having a consistently lower level of glucocorticoids was sufficient to elicit compromised cytotoxic T cell function.
Overall, we found that perinatal exposure to glucocorticoids has long-term consequences on health and disease utilizing the mouse model. Stress hormone exposure programmed the set point of a basal glucocorticoid to be low, resulting in compromised cytotoxic T cell function. This leads to adulthood susceptibility to tumors and bacterial infection. However, it is uncertain how exactly our work can be translated to humans because humans and mice have very different timelines for the development of multiple tissues. Nevertheless, we think our study adds to the evidence that maternal and early-life stress can have long-term consequences on health and disease by affecting important developmental procedures. Regarding the long-lasting stability of the changes made in early life, prevention would be the best strategy to avoid unwanted outcomes for long-term health. We hope our work may promote the research and discussion on the subject of characterizing perinatal risk factors and controlling maternal and perinatal stress.