Dissecting epigenetic mechanisms for the transgenerational inheritance of glucocorticoid programming.

Low birthweight babies are at increased risk of diabetes and heart disease in adulthood. This has led to the concept of ‘fetal programming‘, suggesting a factor acting during early life can affect development and predispose to later disease. Additionally, studies in humans and in animal models have shown that this increased disease risk can be passed to the next generation, however the mechanisms underlying ‘fetal programming‘ and this ‘intergenerational‘ effect are unknown.
We proposed that exposure of the fetus to excess ‘stress‘ steroid hormones (glucocorticoids) might be important in ‘programming‘. Glucocorticoids are present in mother and baby and are used as treatment during premature labour, but can reduce birthweight and affect later blood pressure. Stress and illnesses increasing glucocorticoid levels during pregnancy have similar long-term effects. Using an animal model, we have shown that exposure of the fetus to glucocorticoid hormones permanently alters the control of several genes and these changes cross into the next generation.
In this project we wish to increase our knowledge of how overexposure to glucocorticoids can permanently alter gene expression and how this is transmitted to the next generation. Crucially, the work may indicate ways for us as paediatricians, to prevent the complications associated with low birthweight.

Epidemiological studies have demonstrated an association between low birthweight and an increased prevalence of cardio-metabolic disorders. Evidence suggests that this phenomenon of ‘fetal programming‘ is not limited to the first generation. In our model, antenatal dexamethasone administration is associated with reduced birthweight, increased expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and adult hyperglycaemia. Additionally, we have shown that prenatal dexamethasone exposure has intergenerational effects on birthweight, PEPCK and glucose tolerance. The persistence of such effects in a second generation, transmitted by both maternal and paternal lines indicates the likely importance of epigenetic factors in the intergenerational inheritance of the ‘programming phenotype‘.
The object of the proposed research is to elucidate the fundamental mechanisms through which a brief exposure to glucocorticoids can alter gene expression and how this phenotype is transmitted to the offspring. We hypothesise that glucocorticoids mediate these effects epigenetically by modifying chromatin structure in a heritable manner. We propose to test this hypothesis by delineating the epigenetic effects of prenatal dexamethasone exposure and to identify key genes that may be altered in this model. We plan to examine global differences in DNA methylation following exposure to dexamethasone in utero, using techniques that support the identification of target genes contributing to the programmed phenotype. Additionally we will study the effects of agents known to alter histone acetylation patterns on the dexamethasone-programmed phenotype. We will then explore whether the transgenerational inheritance of such epigenetic modifications explains the transmission of the programmed phenotype to subsequent generations, by extending this study into a second generation to explore the inheritance of these epigenetic effects.
This research will increase knowledge and understanding of the role which epigenetic modifications may play in the early life origins of disease and whether epigenetic modification might represent a mechanism by which the environment might modulate the genetic predisposition to disease in human populations. Additionally, this study will demonstrate whether these effects are heritable and therefore provide a basis for the inherited association between low birthweight and cardiovascular risk factors.
In the long-term, we plan to extend this research into the mechanisms underpinning the intergenerational inheritance of disease risk in humans. Ultimately, this study may suggest methods that would allow the early identification of individuals at risk of later disease and potential interventions to decrease this risk.