London, UK: Exposure of the developing foetus to excessive levels of stress hormones in the womb can cause mood disorders in later life and now, for the first time, researchers have found a mechanism that may underpin this process, according to research presented at the British Neuroscience Association Festival of Neuroscience (BNA2013) in London.
The concept of foetal programming of adult disease, whereby the environment experienced in the womb can have profound long-lasting consequences on health and risk of disease in later life, is well known; however, the process that drives this is unclear. Professor Megan Holmes, a neuroendocrinologist from the University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science in Scotland (UK), said: “During our research we have identified the enzyme 11ß-HSD2 which we believe plays a key role in the process of foetal programming.”
Adverse environments experienced while in the womb, such as in cases of stress, bereavement or abuse, will increase levels of glucocorticoids in the mother, which may harm the growing baby. Glucocorticoids are naturally produced hormones and they are also known as stress hormones because of their role in the stress response.
“The stress hormone cortisol may be a key factor in programming the foetus, baby or child to be at risk of disease in later life. Cortisol causes reduced growth and modifies the timing of tissue development as well as having long lasting effects on gene expression,” she said.
Prof Holmes described how her research has identified an enzyme called 11ß-HSD2 (11beta-hydroxysteroid dehydrogenase type 2) that breaks down the stress hormone cortisol to an inactive form, before it can cause any harm to the developing foetus. The enzyme 11ß-HSD2 is present in the placenta and the developing foetal brain where it is thought to act as a shield to protect against the harmful actions of cortisol.
Prof Holmes and her colleagues developed genetically modified mice that lacked 11ß-HSD2 in order to determine the role of the enzyme in the placenta and foetal brain. “In mice lacking the enzyme 11ß-HSD2, foetuses were exposed to high levels of stress hormones and, as a consequence, these mice exhibited reduced foetal growth and went on to show programmed mood disorders in later life. We also found that the placentas from these mice were smaller and did not transport nutrients efficiently across to the developing foetus. This too could contribute to the harmful consequences of increased stress hormone exposure on the foetus and suggests that the placental 11ß-HSD2 shield is the most important barrier.
“However, preliminary new data show that with the loss of the 11ß-HSD2 protective barrier solely in the brain, programming of the developing foetus still occurs, and, therefore, this raises questions about how dominant a role is played by the placental 11ß-HSD2 barrier. This research is currently ongoing and we cannot draw any firm conclusions yet.
“Determining the exact molecular and cellular mechanisms that drive foetal programming will help us identify potential therapeutic targets that can be used to reverse the deleterious consequences on mood disorders. In the future, we hope to explore the potential of these targets in studies in humans,” she said.
Prof Holmes hopes that her research will make healthcare workers more aware of the fact that children exposed to an adverse environment, be it abuse, malnutrition, or bereavement, are at an increased risk of mood disorders in later life and the children should be carefully monitored and supported to prevent this from happening.
In addition, the potential effects of excessive levels of stress hormones on the developing foetus are also of relevance to individuals involved in antenatal care. Within the past 20 years, the majority of women at risk of premature delivery have been given synthetic glucocorticoids to accelerate foetal lung development to allow the premature babies to survive early birth.
“While this glucocorticoid treatment is essential, the dose, number of treatments and the drug used, have to be carefully monitored to ensure that the minimum effective therapy is used, as it may set the stage for effects later in the child’s life,” said Prof Holmes.
Puberty is another sensitive time of development and stress experienced at this time can also be involved in programming adult mood disorders. Prof Holmes and her colleagues have found evidence from imaging studies in rats that stress in early teenage years could affect mood and emotional behaviour via changes in the brain’s neural networks associated with emotional processing.
The researchers used fMRI (Functional Magnetic Resonance Imaging) to see which pathways in the brain were affected when stressed, peripubertal rats responded to a specific learned task. .
Prof Holmes said: “We showed that in stressed ‘teenage’ rats, the part of the brain region involved in emotion and fear (known as amygdala) was activated in an exaggerated fashion when compared to controls. The results from this study clearly showed that altered emotional processing occurs in the amygdala in response to stress during this crucial period of development.”
Abstract title: “Perinatal programming of stress-related behaviour by glucocorticoids”. Symposium: “Early life stress and its long-term effects – experimental studies”, at 15.15 hrs BST on Sunday 7 April, Cinema 1.
 “Imaging conditioned fear circuitry using awake rodent fMRI”, by Brydges NM and colleagues. PLoS One journal.2013;8(1):e54197.