PRENATAL MATERNAL STRESS AND PREMATURE OFFSPRING AGING

来自几个物种的令人信服的数据表明，在产前和产后早期，糖皮质激素治疗对肺部发育和表面活性剂的产生都有有益的影响。然而，它们也会导致器官系统和胎盘的生长迟缓。此外，已知此类治疗会导致各种生理系统（如血压、葡萄糖代谢）功能的长期缺陷，这在许多方面与正常人衰老时所见的变化相似。然而，这些变化发生在生命早期，并在发育期间不适当的糖皮质激素暴露。人口统计数据表明，大多数怀孕的职业妇女在怀孕期间的大部分时间都将工作。本建议的核心论点是，在怀孕期间工作对母亲来说是一种心理压力，这种压力可能会随着怀孕的进展而增加。虽然来自人类和动物研究的数据已经积累起来，说明怀孕期间压力对围产期的直接影响，但关于这种压力对后代日后健康或寿命的长期影响的数据却很少。本应用建议使用在整个怀孕期间受到心理应激的怀孕大鼠来研究后代的衰老。假设是：在怀孕期间每天承受压力的雌性大鼠产生的后代比没有压力控制的后代衰老和死亡得更快。该范式使用的是将怀孕的母亲从繁殖之日起，在整个怀孕期间每天45分钟的标准大鼠约束室中。检查的终点是气压反射、葡萄糖耐量和死亡年龄。大鼠是一种成熟的衰老研究模型，该模型中使用的产前母亲心理应激已知会导致后代海马（与衰老相关的关键脑区）的长期缺陷。如果获得资助，该模型的进一步发展将：1)提供有关怀孕期间心理压力长期后果的急需信息，2)最终提供有关过早衰老风险窗口的信息，3)帮助设计最小化和/或防止此类不良后果发生的策略。

Compelling data from several species demonstrates that glucocorticoid treatments both antenatally and in early postnatal life have beneficial effects on lung development and surfactant production. However, they also cause growth retardation of organ systems and the placenta. In addition, such treatments are known to produce long term deficits in the function of various physiological systems (e.g., blood pressure, glucose metabolism) that are similar in many respects to changes seen with aging in normal individuals. However, these changes occur much earlier in life and follow inappropriate glucocorticoid exposure at during development. Human demographic data indicate that the majority of working women who become pregnant will work for a large proportion of their pregnancy. Central to the present proposal is the thesis that working during pregnancy represents a psychological stress to the mother that may increase as pregnancy progresses. While data from human and animal studies has accumulated on immediate perinatal outcomes of stress during pregnancy, little data exists on the long term consequences of such stress on the health or life span of progeny in later life. This application proposes to use pregnant rats subjected to psychological stress throughout pregnancy to study aging of offspring. The hypothesis is: Female rats subjected to daily stress through pregnancy produce offspring that age and die more quickly than progeny from non stress controls. The paradigm used places pregnant mothers in a standard rat restraint chamber for 45 min per day throughout pregnancy starting on the day of breeding. The endpoints examined are the baroreflex, glucose tolerance and aged at death. The rat is a well established model for studies in aging and the prenatal maternal psychological stress used in this model is known to cause long term deficits in the hippocampus (a critical aging-related brain area) of progeny. If funded, further development of this model will: 1) provide sorely needed information on long term consequences of psychological stress during pregnancy, 2) ultimately provide information on windows of risk for premature aging and 3) help in the design of strategies to minimize and/or prevent the occurrence of such undesirable consequences.