Fetal alcohol exposure (FAE) impairs the functioning of the immune system and decreases resistance to various infectious diseases. FAE also alters the development of neural and neuroendocrine systems, and thus may interfere with the bidirectional communications between the immune and the nervous system of offspring. Data indicate that FAE impairs the interactions between the immune and nervous systems. For example, we have shown that FAE blunts the febrile response induced by a pathogen product, lipopolysaccharide (LPS), and one of the cytokines, interleukin-1 beta (IL1), induced by LPS. Moreover, maternal adrenalectomy was found to prevent the blunted febrile response. The effects of FAE are probably mediated by developmentally-induced alterations in brain mechanisms, since FAE also blunts the febrile response following intracerebroventricular (icv) administration of IL1. Given the essential role of fever in the host defense response to infection, we hypothesize that the attenuated febrile response following FAE reflects a general impairment in neuroimmune interactions which may contribute to the predisposition to infection resulting from FAE. One corollary hypothesis states that FAE affects the adult expression of neural mediators of the febrile component of the acute phase response to infection. A second corollary hypothesis states that prevention of FAE-induced alterations in neuroimmune interactions mediating the febrile response to LPS can be achieved by hormonal manipulations pre-or postnatally. Specifically, we aim to: 1) Characterize the effects of LPS administered ip on certain mediators of the febrile response in adult male fetal alcohol-exposed and control rats, i.e., a) prostaglandin E2 (PGE), b) norepinephrine (NE), c) nitric oxide (NO), d) arginine vasopressin (AVP), e) alpha-melanocyte stimulating hormone (MSH), f) ACTH and corticosterone and g) IL1; 2) Investigate a possible role for neonatal or adult testosterone levels in mediating the effects of FAE on the LPS-induced febrile response and on its neurochemical mediators, as identified in Aim 1; and 3) Determine whether the prevention of the blunted LPS-induced febrile response by maternal adrenalectomy is (a) mediated by adreno-medullary or -cortical products, (b) is accompanied by changes in any of the neurochemical mediators of the febrile response identified as being affected by FAE in Aim 1, and (c) is accompanied by a reversal of the FAE-induced reduction in testosterone levels in neonatal and/or adult rats.
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