PRENATAL MATERNAL STRESS AND PREMATURE OFFSPRING AGING

来自几个物种的令人信服的数据表明，产前和出生后早期的糖皮质激素治疗对肺发育和表面活性物质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，众所周知，这种治疗会在各种生理系统(如血压、葡萄糖代谢)的功能上产生长期缺陷，在许多方面类似于正常个体随年龄增长而出现的变化。然而，这些变化发生在生命的早期，并伴随着发育过程中不适当的糖皮质激素暴露。人类人口统计数据表明，大多数怀孕的职业女性将在怀孕期间工作很大一部分时间。本提案的核心是这样一个论点，即怀孕期间工作对母亲来说是一种心理压力，随着怀孕的进展，这种压力可能会增加。虽然来自人类和动物研究的数据已经积累了怀孕期间压力对围产期的直接后果，但关于这种压力对后代晚年健康或寿命的长期影响的数据很少。这项应用建议使用怀孕大鼠在整个怀孕期间处于心理应激状态来研究后代的衰老。假设是：在怀孕期间每天承受压力的雌性大鼠会产生相同年龄的后代，并且比非应激对照组的后代更快死亡。这一模式从怀孕当天开始，将怀孕的母亲放在标准的老鼠束缚室内，每天持续45分钟。检查的终点是压力反射、糖耐量和死亡时的年龄。大鼠是一个成熟的衰老研究模型，该模型中使用的产前母体心理应激被认为会导致子代海马体(与衰老相关的关键脑区)的长期缺陷。如果得到资助，这一模型的进一步发展将：1)提供关于怀孕期间心理压力的长期后果的迫切需要的信息，2)最终提供关于过早衰老的风险窗口的信息，以及3)帮助设计战略，以最大限度地减少和/或防止这种不良后果的发生。

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.