PRENATAL MATERNAL STRESS AND PREMATURE OFFSPRING AGING

来自几个物种的令人信服的数据表明，产前和产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，已知这种治疗会在各种生理系统的功能中产生长期缺陷（例如，血压，葡萄糖代谢），这些变化在许多方面与正常个体随年龄增长而发生的变化相似。然而，这些变化发生在生命的早期，并且在发育期间暴露于不适当的糖皮质激素之后。人口统计数据表明，大多数怀孕的工作妇女在怀孕期间将工作很长一段时间。本提案的核心论点是，怀孕期间工作对母亲造成心理压力，这种压力可能随着怀孕的进展而增加。虽然从人类和动物研究的数据积累了在怀孕期间的压力的直接围产期的结果，很少有数据存在的长期后果，这种压力的健康或寿命的后代在以后的生活。本申请提出使用在整个妊娠期间受到心理应激的孕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非压力对照组的后代衰老和死亡更快。所使用的范例将怀孕的母亲在标准的大鼠束缚室中每天45分钟，从繁殖的那天开始，在整个怀孕期间。检查的终点是压力反射、葡萄糖耐量和死亡时的年龄。大鼠是一种成熟的衰老研究模型，已知该模型中使用的产前母体心理应激会导致子代海马体（一个关键的衰老相关脑区）的长期缺陷。如果得到资助，该模型的进一步发展将：1）提供急需的信息，说明怀孕期间心理压力的长期后果; 2）最终提供有关过早衰老风险窗口的信息; 3）帮助设计策略，以尽量减少和/或预防此类不良后果的发生。

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.