Transgenerational Effects of Synthetic Glucocorticoids on Offspring Behaviour and HPA Development in Guinea Pigs

Glucocorticoids are essential for fetal maturation. However, exposure to high levels of glucocorticoids (i.e. maternal stress/anxiety or synthetic glucocorticoid treatment [sGC]) alters the trajectory of development and increases the risk for chronic diseases later in life. Approximately 10% of pregnant women are at risk for delivering prematurely and receive treatment with sGC to reduce neonatal morbidity and mortality. Studies in children and animals demonstrated that single- and multiple-course sGC program alterations in hypothalamic-pituitary-adrenal (HPA) function and stress-associated behaviours in first generation (F1) offspring. Emerging studies in animals determined that sGC results in transmission of HPA and behavioural effects to the next generation (F2) of offspring, but no study has investigated transmission to the third generation (F3). We hypothesized that prenatal treatment with sGC results in maternal and paternal transmission of altered HPA activity and stress-related behaviours to three generations of guinea pig offspring. Prenatal treatment with either single- or multiple-course sGC resulted in transmission of effects to F2, but there were fewer effects with single-course treatment. Prenatal treatment with multiple-course sGC resulted in maternal transmission to F3. The strongest effects of sGC occurred in juvenile females from the paternal line; increased HPA response to stress, hyperactivity, impaired attention. Molecular analyses in the brains of these animals revealed that sGC programs large changes in gene expression that dissipate across generations. DAVID pathway analysis identified significant changes in the expression of genes associated with the HPA and behavioural phenotypes. This is the first study to demonstrate transgenerational programming to F3 of HPA activity and behaviours resulting from prenatal sGC transmitted. Paternal transmission to F3 strongly implicates epigenetic mechanisms. Transgenerational programming by sGC is a hallmark of in utero sGC exposure irrespective of current or past dosing regimens. These studies highlight the importance of developing new treatment approaches that maximize therapeutic efficacy while minimizing long-term adverse outcomes.Ph.D.2019-11-03 00:00:0