Glucocorticoid exposure during prenatal development: Embryonic modulation and long-term consequences on oxidative stress and aging



 DESCRIPTION (provided by applicant): This application proposes a research project that investigates the mechanisms through which conditions experienced during embryonic development influence disease susceptibility later in life. Adverse prenatal conditions are linked to increased disease prevalence in adults, and this may be mediated in part by increased embryonic exposure to maternal glucocorticoids. Fortunately, the placenta serves as a "metabolic buffer", and it is capable of metabolizing a large portion of glucocorticoids (80- 90%) as they pass from the maternal circulation to the fetal circulation. Unfortunately, it is nearly impossible to examine the direct responses of developing embryos to increased glucocorticoids, because changes in glucocorticoid levels also alter maternal physiology, which may indirectly influence embryonic development. This proposal utilizes a novel avian study system, the Japanese quail (Coturnix japonica), where embryonic development takes place outside of the maternal environment to examine (i) how embryos regulate exposure to maternal glucocorticoids, (ii) how embryos respond to increased glucocorticoid exposure, and (iii) the long- term effects of increased glucocorticoid exposure. This study will test the hypothesis that increased embryonic exposure to glucocorticoids alters glucocorticoid responses to adverse conditions and results in life-long effects on oxidative stress, telomere shortening, and survival in offspring. Using LC/MS/MS to quantify a wide range of steroids, the effect of increased glucocorticoid exposure on the embryonic endocrine environment will be examined. Longitudinal studies will be used to characterize the effects of increased glucocorticoid exposure on glucocorticoid production, oxidative stress, and telomere dynamics throughout the avian lifespan. At the end of this project, the research team will have identified the metabolic pathway through which embryos regulate their exposure to maternally-derived glucocorticoids, characterized the response of embryonic endocrine environment in response to increased glucocorticoid exposure, and examined the consequences of this exposure on life-long stress. Results from this work will greatly advance understanding of the mechanisms underlying both the causes and consequences of glucocorticoid exposure during development. This information should prove vital to attempts to mitigate embryonic exposure and alleviate the long-term consequences of exposure.