Effect of prenatal exposure to ethanol on the activity of the hypothalamic-pituitary-adrenal axis of the offspring: Importance of the time of exposure to ethanol and possible modulating mechanisms.

The ability of immature (21-day-old) rats to release ACTH and corticosterone (CORT) in response to stress is known to be enhanced by in utero exposure to ethanol (EtOH). However, the precise time during which EtOH is effective, as well as the mechanisms mediating these effects, has not been elucidated. The first part of the present study was designed to evaluate the time course of action of EtOH during various times of gestation. The second part examined the possible role of maternal adrenal steroids, as well as changes in the pups' hypothalamic corticotropin-releasing factor (CRF) biosynthesis and/or expression, in mediating the deleterious action of EtOH. Pregnant intact or adrenalectomized (ADX) Sprague-Dawley rats were exposed to EtOH vapors. Control rats were kept in a normal atmosphere. At 21 days of age, the offspring were either decapitated under nonstressed conditions or exposed to mild, inescapable electroshocks (1.5 mA; 1 s duration) over a 10-min period, then sacrificed. ACTH and CORT levels were measured by radioimmunoassay. When exposed to the shocks, 21-day-old rats born to intact mothers exposed to EtOH during the second, but not the first or third week of gestation, demonstrated significantly enhanced ACTH secretion (P 0.05), but unaltered CORT secretion compared to controls. Measurement of CRF biosynthesis by Northern blot analysis and in situ hybridization indicated a significant (P 0.01) increase in CRF mRNA levels, and a marked accumulation of CRF mRNA in the parvocellular division of the paraventricular nucleus. Rats born to ADX control mothers had significantly (P 0.01) higher stress-induced ACTH, but lower CORT secretion, than the offspring of intact control dams. In contrast to what we observed in pups born to intact dams, the offspring of ADX mothers (whether control or exposed to EtOH) showed no measurable increase in ACTH secretion when exposed to electroshocks, nor did they exhibit any measurable difference in the levels of CRF mRNA levels. We conclude that (i) prenatal exposure to EtOH during the second, but not the first or third week of gestation, alters the hypothalamic-pituitary-adrenal response to stress at 3 weeks of age, and (ii) a significant increase in CRF biosynthesis and expression, which may be at least in part a consequence of past elevated circulating corticosterone levels in EtOH-exposed dams, may modulate this augmented ACTH secretion in response to stress.