The role of estradiol in mediating hypothalamic-pituitary-adrenal axis activity in female rats prenatally exposed to ethanol

Prenatal ethanol exposure results in a broad range of physical, physiological and behavioral abnormalities. Experiments in this thesis focused on ethanol-induced alterations in physiological function. Two important systems that are altered by prenatal ethanol exposure are the hypothalamic-pituitary-adrenal (HPA) and -gonadal (HPG) axes, which are involved in the stress response and reproductive function. Previous studies have shown that rats prenatally exposed to ethanol (E) are typically hyperresponsive to stressors and have altered reproductive development and function. Furthermore, the normal sexual dimorphism of the HPA axis is differentially altered in E males and females, suggesting altered HPA-HPG interactions in E compared to control animals. Since the HPA and HPG axes develop in parallel and interact in a bi-directional manner, the aim of the present study was to determine the possible role of estradiol (E2) in the altered HPA response to stress in E females. We hypothesized that prenatal ethanol exposure would alter HPG development and activity and that altered HPA activity in E females may be due, at least in part, to altered HPA axis sensitivity to E2. Female offspring from E, pair-fed (PF) and ad lib-fed (C) dams were tested in adulthood. Animals were randomly assigned to one of four surgical groups: Sham, Ovariectomized (OVX), OVX + low (OVX-L) or high (OVX-H) E2 replacement. At testing animals were terminated directly from the home cage or following 30 min restraint stress and plasma, organs and brains were collected for analysis. E females had decreased uterine sensitivity to E2 compared to C females and lower GnRH mRNA expression/neuron in the MPOA following stress compared to PF females. Furthermore, acute stress failed to increase plasma E2 in E and PF females, as it did in controls. Following OVX, E and PF females had lower basal plasma CORT levels compared to C females. In addition, under both basal and stress conditions, E females had lower plasma ACTH levels compared to C females overall. Moreover, under stress conditions, plasma ACTH levels in E females did not change across surgical treatments, while PF and C females had increased ACTH levels following OVX, which returned to Sham levels with E2 replacement. Also, under resting conditions, AVP mRNA expression was higher in E compared to C females and both CRH and AVP mRNA expression were increased in PF compared to C females. The present data suggest that E females have altered HPG activity and HPA responsiveness to stressors as well as altered bidirectional interactions between the HPA and HPG axes. Overall, E females appear to be less responsive than controls to the effects of E2 on both reproductive and non-reproductive measures. Furthermore, E females appear to have decreased tissue responsiveness to E2 and altered HPG sensitivity to acute stress at various levels of the axis.Medicine, Faculty ofGraduat