PRENATAL ALCOHOL EXPOSURE AND PREMATURE AGING

衰老的糖皮质激素级联假说预测，成年期肾上腺类固醇如皮质醇或皮质酮（CORT）的分泌过多将加速衰老过程（Landfield等人，1978; Sapolsky等人，1986）。一个一致的发现，在胎儿酒精暴露（FAE）的动物是，他们响应适度的压力，在成年期高分泌的CORT。这种长期效应似乎反映了妊娠期间乙醇诱导的边缘系统结构（如下丘脑和海马）正常发育的中断，这些结构调节应激，从而调节CORT分泌。由于这种破坏，预计FAE动物在其一生中将暴露于比正常暴露更多的CORT。基于这种边缘系统发育的早期中断和延长CORT暴露的组合，我们假设，下丘脑整合的行为和生理过程的调节，如昼夜节律和应激反应，将在老化的FAE动物比对照组下降得更快。初步数据支持这一假设，显示FAE动物提前发病的年龄a）无排卵性不孕症，B）的年龄的雌激素诱导的脑啡肽原mRNA在下丘脑中的损失，和c）的年龄，在响应于压力的体温调节受损可以检测到。基于这些发现，拟议的研究旨在检验三个假设：1）产前乙醇暴露将加速由下丘脑整合的生理和行为系统的正常老化，2）在成年早期将FAE动物暴露于亚慢性应激方案将加剧这些系统的老化速率，3）在出生后应激低反应期的处理将改善出生前乙醇暴露对衰老速度的影响。为了解决这些假设，我们将研究FAE动物的整个生命周期。将在妊娠最后一周（下丘脑分化期）暴露于乙醇的FAE雄性和雌性动物与4-5、9-10、18-19和24-25月龄的配对喂养和饲料喂养对照组进行比较。评估的生理和行为测量将包括运动活动的昼夜节律、核心体温的昼夜节律和激素分泌的昼夜节律。此外，将测量内分泌和核心体温对束缚应激的反应，以揭示在基础条件下可能不明显的年轻时对HPA功能的潜在老化影响。产前暴露于亚致畸水平的乙醇和加速衰老的速度之间的潜在关系有着广泛的影响，NIH方面的治疗，健康教育和临床服务。

The glucocorticoid cascade hypothesis of aging predicts that hypersecretion of adrenal steroids such as cortisol or corticosterone (CORT) during adulthood will accelerate the aging process (Landfield et al., 1978; Sapolsky et al. 1986). A consistent finding in fetal alcohol exposed (FAE) animals is that they respond to moderate stress during adulthood with a hypersecretion of CORT. This long-term effect appears to appears to reflect an ethanol-induced disruption during gestation of the normal development of limbic structures such as hypothalamus and hippocampus that regulate stress, and consequently CORT secretion. Stemming from such disruption, FAE animals would be expected to be exposed to a greater than normal exposure to CORT during their lifetime. Based upon this combination of early disruption of limbic development and extended CORT exposure over the lifetime, we hypothesize that the regulation of behavioral and physiological processes that are integrated by the hypothalamus, such as circadian rhythms and stress-responsiveness, will decline more rapidly in aging FAE animals compared to controls. Preliminary data support this hypothesis by showing advanced onset in FAE animals for a) the age of anovulatory sterility, b) the age for loss of estrogen induction of proenkephalin mRNA in the hypothalamus, and c) the age at which impairment of thermoregulation in response to stress can be detected. Based upon these findings, the proposed studies are designed to test three hypotheses: 1) that prenatal ethanol exposure will accelerate the normal aging of physiological and behavioral systems integrated by the hypothalamus, 2) that exposing FAE animals to a subchronic stress regimen in early adulthood will exacerbate the increased rate of aging in these Systems, and 3) that handling during the postnatal stress hyporesponsive period will ameliorate the effects of prenatal ethanol exposure on the rate of aging. To address these hypotheses, we will study FAE animals across the lifespan. FAE males and females exposed to ethanol during the last week of gestation, the period of hypothalamic differentiation, will be compared to pair-fed and chow-fed controls at 4-5, 9-10, 18-19, and 24-25 months of age. Physiological and behavioral measures assessed will include circadian rhythms of locomotor activity, circadian rhythm o core body temperature, and circadian rhythms of hormone secretion. In addition, endocrine and core body temperature responses to restraint stress will be measured in order to unmask potential aging effects on HPA function at younger ages which may not be apparent under basal conditions. A potential relationship between prenatal exposure to subteratogenic levels of ethanol and an accelerated rate of aging has broad implications for NIH with regard to treatment, health education, and clinical services.