GLUCOCORTICOID PROGRAMMING OF THE PITUITARY-ADRENAL AXIS

University Of Texas Hlth Sci Ctr San Ant, San Antonio TX

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Abstract

DESCRIPTION: (provided by applicant) Studies in precocial and altricial rodents and sheep from our own and other laboratories throughout the world provide compelling evidence that fetal exposure to inappropriate amounts of glucocorticoid (GO) has profound effects on fetal growth, placental CRH production, fetal and post-natal brain and hippocampal-hypothalamo-pituitary-adrenal (HHPAA) function and neuronal protein concentrations. Depending on the nature and timing of prenatal challenges, postnatal HHPAA activity increases or decreases. Experimental outcomes resemble altered HHPAA activity observed in human conditions such as depression and anxiety. Overall Hypothesis: Our overall general hypothesis is that exposure of the fetal baboon at the equivalent of 24-25 weeks human gestation to inappropriate amounts of GC (multiple course betamethasone (betaM) administration equivalent to that administered to pregnant women in premature labor) will alter the program and trajectory of fetal development. Specific hypotheses: Exposure of the fetal baboon to inappropriate amounts of GC will: 1) result in fetal intrauterine growth retardation characterized by low fetal and placental weight; 2) increase placental 11 beta hydroxy steroid dehydrogenase (11BHSD) function and CRH production, 3) reset fetal HHPAA function and decrease critical, neuronal proteins in the fetal brain; 4) result in long term programming effects. For Specific Aim 4 in year 1 we will treat 16 pregnant baboons with BM and 16 with vehicle and allowed them to deliver. These animals will be 4 years old and post-pubertal when the current period of requested funding ends. We will then be in a position to propose studies on them as a follow up RO1. Approach: The proposed work begins a series of studies on GC programming of fetal development in nonhuman primates. We will combine state-of-the-art techniques from whole animal to gene function to examine effects of clinically relevant GO exposure in final two thirds of pregnancy on 1) fetal and placental growth; 2) placental 11BHSD 1 and 2 message, protein and activity; 3) brain and HHPAA structure and function, especially GR and neuronal proteins. The significance of the proposed studies lies in information they will provide relevant to the fetal origin of adult disease, specifically resetting of critical HHPAA function by GO. The data address both steroid administration in clinical management and effects of increased GC in maternal stress on the fetus. The work addresses current concepts of the fetal origins of adult disease, known as the "Barker Hypothesis." These studies will improve understanding of how GO affects central features of fetal development. The proposal also involves preparation for follow up studies in nonhuman primates allowed to survive into adult life.