Grant: Operating Grant

Approximately 10% of pregnant women are treated with glucocorticoid (GC) in late gestation, to promote lung maturation in babies at risk of preterm delivery. While GC therapy improves the ability of the baby to breathe, we have shown that such treatment can permanently alter the ability of offspring to mount a hormonal response to stress. Studies are also emerging indicating long-term effects in humans. Animal studies have shown that changes in the regulation of hormones associated with the stress response results in altered susceptibility to disease in later life, including hypertension and psychological illness. We have shown that the effects of antenatal GC therapy can pass to the second generation where endocrine effects are even more pronounced than in the first generation. Recently, we have also shown that antenatal GC therapy can lead to profound changes in the structure of genes, altering the way that they are switched on or off. The guinea pig will be used, since extensive brain and neuroendocrine development occurs during fetal life, and this is similar to humans. These studies will establish novel mechanisms (including glucocorticoid-induced changes in gene structure) by which adult endocrine function is 'programmed' by excess glucocorticoid exposure during fetal life. We will also determine the processes involved in transgenerational transmission. This knowledge will allow us to refine therapies, maximizing beneficial actions at the lung, while preventing any detrimental effects in the brain and developing endocrine system, which we have now shown to persist for multiple generations.