Effects of Prenatal Ethanol Exposure on Hypothalamic‐Pituitary‐Adrenal Responses to Chronic Cold Stress in Rats

Abstract

Animals prenatally exposed to ethanol typically exhibit hypothalamic-pituitary-adrenal (HPA) hyperresponsiveness to stressors. In contrast to previous studies that have investigated effects of prenatal ethanol exposure on HPA responses to acute or intermittent stressors, our study investigated HPA responses to a chronic continuous stressor, cold stress (4 degrees C for 0, 1, or 3 days). We tested the hypothesis that prenatal ethanol exposure would result in increased plasma corticosterone (CORT) and adrenocorticotropin (ACTH) responses and increased peptide [corticotropin-releasing factor and vasopressin] mRNA levels in the paraventricular nucleus (PVN) of the hypothalamus compared to that in control animals. In addition, CORT and ACTH responses were measured after exposure to an acute stressor (i.p. isotonic saline injection), superimposed during chronic cold exposure, to examine possible sensitization of the HPA response to the acute stress. Thus, blood samples were collected at the end of each of the three periods of cold exposure, either before (0 min) or 15 min after acute stress. The subjects were adult male and female Sprague-Dawley rat offspring from prenatal ethanol (E), pair-fed (PF), and ad libitum-fed control (C) treatment groups. Exposure to cold stress resulted in significant body weight loss in E males at 1 day and in both males and females of all prenatal treatment groups by 3 days of cold stress. Males in all prenatal groups also exhibited significant increases in adrenal weight:body weight ratios. Cold stress alone (0 min condition) increased CORT levels in E males and overall ACTH levels in E males and females compared to controls. ACTH levels were also higher overall in E compared to control males after acute stress (15 min condition). Sensitization of the CORT response to acute stress was observed in males but not females across all prenatal treatment groups. Corticotropin-releasing factor and vasopressin mRNA levels in the PVN were not significantly affected by prenatal treatment or chronic cold stress in either males or females. In contrast, both males and females displayed increases in PVN thyrotropin-releasing hormone (TRH) mRNA levels after cold stress. These data support and extend previous work demonstrating differential effects of prenatal ethanol exposure on HPA responsiveness of male and female offspring, and suggest that E males may be more vulnerable to the effects of chronic cold stress than E females.

Effects of Prenatal Ethanol Exposure on Basal Limbic–Hypothalamic–Pituitary–Adrenal Regulation: Role of Corticosterone

“…Despite the finding that plasma hormone levels are typically normal in both E males and females under basal, nonstressed conditions, increased basal CRH mRNA levels have been reported in 21‐day‐old pups (male and female data combined) (Lee et al., 1990), and increased basal levels of both CRH and POMC mRNA have been reported in 60‐day‐old male, but not in female, offspring (Redei et al., 1993). In contrast, we (Kim et al., 1999a) found no differences among adult E, pair‐fed (PF), and C males or females in basal CRH or arginine vasopressin (AVP) mRNA levels. Similarly, Lee et al.…”

“…While plasma and brain levels of corticosterone are increased in E compared with control pups at birth, during the stress hyporesponsive period, E animals exhibit even greater blunting of HPA responses than controls (Weinberg, 1989). In contrast, in adulthood, while E animals typically exhibit normal basal or nonstress levels of plasma corticosterone (CORT), adrenocorticotropic hormone (ACTH) and corticosteroid‐binding globulin (CBG) (Kim et al., 1999b; Taylor et al., 1986; Weinberg and Gallo, 1982), hormonal responses to stressors including foot shock (Lee et al., 2000; Nelson et al., 1986), novel environments (Weinberg, 1988), restraint (Lan et al., 2006; Weinberg, 1988, 1992; Weinberg et al., 1996), ether (Angelogianni and Gianoulakis, 1989; Osborn et al., 1996; Weinberg and Gallo, 1982), cold (Angelogianni and Gianoulakis, 1989; Kim et al., 1999a), and immune challenges (Lee and Rivier, 1996; Lee et al., 2000; Zhang et al., 2005) are typically increased and/or prolonged compared with those in controls. Furthermore, while this hyperresponsiveness is a robust phenomenon present in both E males and females, patterns of response may differ depending upon the nature and intensity of the stressor, the time course, and the hormonal endpoint measured (Halasz et al., 1997; Lee and Rivier, 1996; Weinberg, 1988, 1992; Weinberg et al., 1996).…”

Adolescent Ethanol Exposure Leads to Stimulus-Specific Changes in Cytokine Reactivity and Hypothalamic-Pituitary-Adrenal Axis Sensitivity in Adulthood

“…PAE has led to an enhanced HPA axis response in adults to stressors such as acute restraint and forced swim in female rats but not in males (Weinberg et al, 2008). In contrast, solely PAE-exposed male rodents have shown a hyper-reactive HPA response to prolonged restraint and exposure to cold (Kim et al, 1999; Weinberg et al, 2008). Both sexes have shown hyper-reactivity of the axis to immune challenges such as LPS and IL-1β challenge (Weinberg et al, 2008).…”

Infant Stress Reactivity and Prenatal Alcohol Exposure

“…Atrophy of neuronal processes in the hippocampus, due to elevated glucocorticoids (McEwen, 1997) resulting from prenatal stress or alcohol exposure, would lead to greater reactivity and slower recovery or regulation of the LHPA to potential stressors. In addition, PAE is related to alterations in the expression of specific types of glucocorticoid receptors in the hippocampus (Kim et al, 1999). For example, the expression of mineralocorticoid receptor (MR) mRNA in the hippocampus, which is involved in negative feedback to the L‐HPA, is decreased in alcohol‐exposed animals (Iqbal et al, 2005).…”