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）的高分泌会加速衰老过程（Landfield et al., 1978; Sapolsky et al. 1986）。胎儿酒精暴露（FAE）动物的一致发现是，它们在成年期对中度应激的反应是CORT的高分泌。这种长期影响似乎反映了乙醇在妊娠期间诱导的边缘结构如下丘脑和海马体的正常发育的破坏，这些结构调节应激，从而导致CORT分泌。由于这种破坏，FAE动物在其一生中暴露于比正常水平更高的CORT暴露。基于边缘发育的早期破坏和一生中长期暴露于CORT的结合，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，在衰老的FAE动物中比对照组下降得更快。初步数据支持这一假设，显示FAE动物的发病时间提前：a)无排卵性不育的年龄，b)下丘脑中雌激素诱导前脑啡肽mRNA丧失的年龄，以及c)可以检测到应激反应中体温调节功能受损的年龄。基于这些发现，拟议的研究旨在测试三个假设：1)产前乙醇暴露会加速下丘脑整合的生理和行为系统的正常衰老；2)成年早期暴露于亚慢性应激方案会加剧这些系统的衰老速度；3)在产后应激反应低下期处理会改善产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。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，将在4- 5,9 - 10,18 -19和24-25月龄时与成对饲养和周食饲养的对照组进行比较。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，我们将测量内分泌和核心体温对约束应激的反应，以揭示潜在的衰老对年轻时HPA功能的影响，这些影响在基础条件下可能不明显。产前暴露于亚致畸水平的乙醇和加速衰老之间的潜在关系对NIH在治疗、健康教育和临床服务方面具有广泛的意义。

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.