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The effect of gonadectomy on the hypothalamic-pituitary-adrenal responsiveness in male rats prenatally exposed to ethanol Lan, Ni

Abstract

Prenatal ethanol (E) exposure has many adverse effects on offspring development. Exposure to chronic high levels of alcohol can result in Fetal Alcohol Syndrome (FAS), one of the leading known causes of mental retardation in the Western world. Prenatal exposure to lower doses of alcohol can result in partial FAS or Alcohol-Related Neurodevelopmental Disorder (ARND), characterized primarily by physiological and behavioral abnormalities; and Alcohol-Related Birth Defects (ARBD), characterized primarily by physical abnormalities. Work in our lab has focused on the effects of prenatal ethanol exposure on the hypothalamic-pituitary-adrenal (HPA) axis, a critical system for the stress response. Previous studies have shown that prenatal ethanol exposure reprograms the fetal HPA axis such that E offspring are hyperresponsive to stressors in adulthood. Rats prenatally exposed to ethanol (E rats) show increased HPA activation and/or delayed or deficient recovery to basal levels following stress. Previous data in our lab and others showed that there are marked sex differences in stress responsiveness and HPA regulation at different levels of the axis in E rats, and also, that E males and females differ from their control counterparts, suggesting that the balance between HPA drive and feedback is differentially altered in E males and females compared to their control counterparts. The aim of the present study was to investigate the influence of gonadal hormones on HPA responsiveness in E compared to control males. Experiments were carried out on adult (~70d) male offspring from E, pair-fed (PF) and ad-lib fed control (C) dams. All the animals were subjected to either sham-gonadectomy (intact) or gonadectomy (GDX). Animals were tested at the circadian trough at 0 (basal), 30 (stress) or 90 min (recovery) after the onset of a 30 min restraint stress. Plasma testosterone, luteinizing hormone (LH), corticosterone (CORT), and adrenocorticotropin (ACTH) levels were measured as an index of hypothalamic-pituitary-gonadal (HPG) and HPA function. Testosterone concentrations in GDX rats were below the detectable range. In intact rats, PF and C rats had higher testosterone at 30 than at 0 min, whereas E rats did not differ in testosterone across time. As expected, GDX markedly increased LH levels. In intact rats, overall, LH level increased at 30 min and decreased to basal levels at 90 min. This increase at 30 min mainly reflects a significant increase in LH in intact C rats, whereas E and PF males showed no significant change over time. Following GDX, LH levels were higher at 0 min than at 30 min, and higher at 30 min than at 90 min in all prenatal groups. There were no significant differences among E, PF and C across time in GDX condition. CORT levels were higher at 30 min and 90 min than at 0 min, and higher at 30 min than at 90 min in all animals under both sham and GDX treatments. ACTH levels were higher in 30 min than in 0 and 90 min in all animals, under both sham and GDX treatments. Importantly, intact E rats had significantly higher ACTH levels than C rats at 30 min, and the difference was eliminated by GDX. There was a strong negative correlation between the testosterone and CORT response to restraint stress at 30 min in intact E but not PF and C males. Furthermore, following GDX, there was a strong positive correlation between the LH and ACTH responses to stress in PF and C but not E male rats. These data indicated that the stimulatory effect of GDX on stress-induced ACTH release is impaired in E rats, suggesting a reduced effect of androgens on HPA responsiveness or a decreased sensitivity to androgens in E males. The findings from the present study support the hypothesis that HPA alterations are mediated, at least in part, by ethanol induced changes in androgens regulation or HPA sensitivity to androgens. HPA hyperresponsiveness results in prolonged or chronic CORT elevations, with concomitant adverse physiological and behavioral consequences that could compromise health and even survival. Early life events (ie. prenatal ethanol) that result in greater reactivity to stress and increased CORT levels throughout the life span can increase the vulnerability to illnesses later in life. Therefore, research aimed at elucidating the mechanisms underlying this hyperresponsiveness of prenatal ethanol exposure, will significantly advance our understanding of the long term adverse consequences of prenatal ethanol exposure, and will have important implications for the development of interventions and treatments.

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