Award Title: The fetal microglial response to glucocorticoid exposure in utero
Funder: The Academy of Medical Sciences

Abstract: The objective is to investigate whether the adverse neurodevelopmental outcomes associated with intrauterine glucocorticoid exposure may be linked to impacts on fetal microglia. We aim to characterise the gene expression profile of murine fetal microglia after glucocorticoid exposure in pregnancy. We also aim to identify and describe the transcriptome of microglial clusters at this gestation.

Glucocorticoids (GC) act to increase surfactant production in fetal lungs, thereby reducing the likelihood of several life-threatening conditions at birth. Where delivery is expected to occur within the next 7 days, antenatal maternal glucocorticoid (AMGC) therapy is routinely offered to women before 34 weeks’ gestation. Resultantly, AMGC are given to 7–10% of women in Europe and North America at risk of preterm labour.

The potentially deleterious effects of AMGC therapy have been reported for decades using animal models. A recent study of >600,000 children has confirmed earlier concerns regarding the long-term impact of AMGC on cognitive/behavioural control. It was found that AMGC exposure was associated with a higher risk of any mental and behavioural disorder (12.01% vs 6.45%).

Microglia account for ~10% of all cells in the CNS and ~80% of the immune cells in the brain. Thought to be key to developmental synaptogenesis, microglial dysfunction has been linked to autism spectrum disorders. Microglial are highly diverse during development and are sensitive to glucocorticoids. They are key to embryonic brain development and in the response to injury/inflammation. The role of these cells in the context of AMGC administration has not previously been investigated.

Lay Abstract: When babies are expected to be delivered prematurely, pregnant mothers are usually offered a steroid drug to help speed-up the development of their babies’ lungs. This treatment is vital in avoiding many harmful and life-threatening conditions caused by an inability to breathe sufficiently at birth. Steroids are particularly useful in premature deliveries where the babies’ lungs are poorly developed. Towards the end of pregnancy however, the overall benefit of these steroids is reduced and babies may only benefit from avoiding mild or short-term breathing problems.

Whilst these drugs work well in helping babies’ lungs to function, they also potentially alter brain development, as the targets of the steroids are also found there. This may have an impact on normal brain development. Whilst experiments in animals have raised these concerns for years, it has recently emerged that there could be long-term behavioural consequences for human babies exposed to these drugs.

 A group of cells which are critically important in controlling brain development, called microglia, are known to be affected by steroid drugs. Thus, it is important to understand the impact of steroids on these cells and the developing brains they usually nurture. Therefore, we will analyse how the microglia genes respond to steroid drugs, and how this may affect their function. This information will help us to better understand the consequences of these drugs, and eventually may lead to new ways of giving steroids which cause less harm to babies’ brains.

Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: INFLAMMATORY AND IMMUNE SYSTEM;REPRODUCTIVE HEALTH AND CHILDBIRTH