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

 描述(申请人提供)：这项申请提出了一个研究项目，通过调查胚胎发育过程中经历的条件影响以后生活中的疾病易感性的机制。不利的产前条件与成人疾病患病率的增加有关，这可能部分是由于胚胎接触母体糖皮质激素的增加所致。幸运的是，胎盘起到了“代谢缓冲”的作用，当糖皮质激素从母体循环进入胎儿循环时，胎盘能够代谢很大一部分糖皮质激素(80%-90%)。不幸的是，几乎不可能检测发育中的胚胎对糖皮质激素增加的直接反应，因为糖皮质激素水平的变化也会改变母亲的生理，这可能间接影响胚胎发育。这项建议利用了一种新的鸟类研究系统，日本鹌鹑(Coturnix Japan Onica)，其中胚胎发育发生在母体环境之外，以研究(I)胚胎如何调节母体糖皮质激素的暴露，(Ii)胚胎如何对糖皮质激素暴露增加做出反应，以及(Iii)糖皮质激素暴露增加的长期影响。这项研究将检验这样一种假设，即增加胚胎对糖皮质激素的暴露会改变糖皮质激素对不利条件的反应，并导致对氧化应激、端粒缩短和后代存活的终身影响。使用LC/MS/MS对广泛的类固醇进行定量，将检测糖皮质激素暴露增加对胚胎内分泌环境的影响。纵向研究将被用来描述增加糖皮质激素暴露对整个禽类寿命的糖皮质激素产生、氧化应激和端粒动态的影响。在该项目结束时，研究小组将确定胚胎调节其接触母源性糖皮质激素的代谢途径，表征胚胎内分泌环境对糖皮质激素暴露增加的反应，并研究这种暴露对终身应激的影响。这项工作的结果将极大地促进对发育过程中糖皮质激素暴露的原因和后果的潜在机制的理解。这些信息应被证明对减轻胚胎暴露和减轻暴露的长期后果的努力至关重要。

 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.