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Gender differences in the effect of prenatal alcohol exposure on the hypothalamic-pituitary-adrenal axis response to
1Clayton Foundation Laboratories for Peptide Biology, Salk Institute, La Jolla, CA 92037, USA.
Insights
Prenatal alcohol exposure alters stress responses in rat offspring. Post-puberty, alcohol-exposed rats show exaggerated ACTH release to immune challenges, a change influenced by sex hormones.
Area of Science:
- Neuroendocrinology
- Developmental Neuroscience
- Immunology
Background:
- Prenatal exposure to ethanol (E) affects offspring stress responses.
- Immature rats exposed to E show blunted ACTH response to immune signals.
- Mature offspring exhibit exaggerated hypothalamic-pituitary-adrenal (HPA) axis activation to physical stress.
Purpose of the Study:
- To investigate the differential influence of prenatal E exposure on HPA axis responses to various stressors.
- To determine if sexual maturation modifies these stress responses.
- To explore the role of sex steroids in modulating E's effects on HPA axis activity.
Main Methods:
- Rats were exposed to ethanol (E), pair-fed (PF), or control (C) diets during gestation.
- Offspring were tested at 5 and 9 weeks of age for ACTH release in response to interleukin-1 beta (IL-1 beta), lipopolysaccharide (LPS), and turpentine.
- Ovariectomy was performed before puberty in female offspring to assess the role of sex steroids.
Main Results:
- At 5 weeks, E-treated males showed reduced ACTH to IL-1 beta but augmented responses to LPS and turpentine; E-treated females showed increased ACTH to all immune stimuli.
- By 9 weeks, both E-treated males and females exhibited significantly larger ACTH responses to all three immune stimuli.
- Ovariectomy in E-exposed females attenuated the exaggerated ACTH response to immune challenges.
Conclusions:
- Prenatal E exposure alters HPA axis reactivity to immune stressors, with effects changing qualitatively after puberty.
- Post-pubertal exaggerated ACTH release in E-exposed offspring resembles responses to physical stress.
- Female sex steroids modulate the effects of prenatal E exposure on HPA axis regulation, suggesting an interaction between these pathways.
Abstract:
Immature (3 week old) rat offspring of alcohol (E)-fed dams show a blunted ACTH response to immune signals such as interleukin-1 beta (IL-1 beta) and endotoxin (LPS). In contrast, mature offspring respond to physical stresses with an exaggerated activation of their hypothalamic-pituitary-adrenal (HPA) axis. The present work was aimed at determining if there was a differential influence of prenatal E exposure on the HPA axis responses to various stressors or if, alternatively, sexual maturation modified these responses. When administered IL-1 beta at 5 weeks age, E-treated intact male offspring released less ACTH, compared to control (C) or pair-fed (PF) animals. However, they showed an augmented response to LPS and a local inflammatory process induced by turpentine injection. At this same age, intact E females secreted significantly more ACTH in response to IL-1 beta, LPS and turpentine, than C or PF offspring. By 9 weeks of age, both E males and E females exhibited larger (p < .05) ACTH responses to all three immune stimuli. In order to determine whether sex steroids modulate the influence of E in females, ovariectomy was done prior to puberty. This treatment decreased the difference in the ACTH released by E and C rats in response to IL-1 beta, LPS and turpentine. These results show that while immature rats exposed to E prenatally released less ACTH in response to cytokines than C or PF animals did, this response was qualitatively reversed after puberty. At that time, the larger amounts of ACTH secreted by E offspring, compared to the other groups, were reminiscent of the hyperactive response of the HPA axis when these offspring were exposed to physical stress. Interestingly, removal of circulating ovarian steroids prevented the influence of E from being exerted. This suggests the presence of a functional relationship between the pathways influenced by prenatal E and those influenced by female sex steroids, that are important in regulating the activity of the HPA axis.