The overall goal of the experiments performed in this laboratory are to identify the mechanisms controlling the activity of the hypothalamus-pituitary-adrenal (HPA) axis in fetal sheep. Providing a more complete understanding of the activity of the HPA axis will be key to understanding fetal stress, homeostasis, and (in sheep and perhaps in other species) the control of parturition. In past years, we have investigated several of the physiological and endocrine mechanisms controlling the activity of the ovine fetal HPA axis. We have reported that estrogen potently stimulates the fetal HPA axis, that the major circulating form of estradiol is estradiol-3-sulfate, and that exogenous estradiol-3-sulfate effectively stimulates fetal HPA axis activity. We have hypothesized that estradiol-3-sulfate could be taken up by the fetal brain directly through one or more organic anion transporters (OAT's), transporters that are known to transport sulfoconjugated estrogens. We have also hypothesized that the estradiol-3- sulfate might be deconjugated prior to both uptake and action. The proposed experiments are designed to test these hypotheses mechanistically. Specifically, we propose three specific aims: 1) to elucidate the roles of Organic Anion Transporters (OAT's) and steroid sulfatase (STS) in the uptake of sulfoconjugated estrogens by the fetal brain;2) to test OAT's as mediators of estradiol-3-sulfate action in the fetal HPA axis;and 4) to test the physiological roles of estrogen receptors in HPA Axis responses to estradiol-3-sulfate. To achieve these aims, we will perform experiments using a combination of in vivo, pharmacological, biochemical, and molecular techniques. Together, these techniques will allow us to quantify estradiol-3-sulfate secretion and clearance kinetics and brain uptake in vivo, and use specific blockers of OAT and STS activity to test the roles played by these transport and deconjugation systems in vivo. Using physiological, biochemical, and molecular techniques well established in this laboratory, we will also be able to test the roles of these systems in the HPA axis response to estradiol-3-sulfate. We anticipate that the results of these studies will lead to the design of pharmacologic strategies for manipulating fetal HPA activity in utero.

Public Health Relevance

Fetal stress is a prevalent cause of fetal death and morbidity in utero. Nevertheless, little is known about the mechanisms controlling the fetal stress hormones and we lack safe and effective ways of manipulating fetal stress hormone secretion. This proposal is aimed at providing a novel understanding of fetal stress hormones and novel approaches towards manipulating the fetal stress response.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-K (03))
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Raju, Tonse N
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University of Florida
Schools of Medicine
United States
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Wood, Charles E; Rabaglino, Maria Belen; Richards, Elaine et al. (2014) Transcriptomics of the fetal hypothalamic response to brachiocephalic occlusion and estradiol treatment. Physiol Genomics 46:523-32
Rabaglino, Maria B; Keller-Wood, Maureen; Wood, Charles E (2014) Transcriptomics of the late gestation ovine fetal brain: modeling the co-expression of immune marker genes. BMC Genomics 15:1001
Wood, Charles E; Rabaglino, Maria Belen; Chang, Eileen I et al. (2013) Genomics of the fetal hypothalamic cellular response to transient hypoxia: endocrine, immune, and metabolic responses. Physiol Genomics 45:521-7
Winikor, Jared; Schlaerth, Christine; Rabaglino, Maria Belen et al. (2011) Complex actions of estradiol-3-sulfate in late gestation fetal brain. Reprod Sci 18:654-65
Wood, Charles E (2011) Fetal hypothalamus-pituitary-adrenal responses to estradiol sulfate. Endocrinology 152:4966-73
Cousins, Roderick; Wood, Charles E (2010) Expression of organic anion transporters 1 and 3 in the ovine fetal brain during the latter half of gestation. Neurosci Lett 484:22-5