Erythropoiesis in the fetus and adult is regulated by the hormone erythropoietin (Epo). In the adult, Epo is produced in the kidney. Epo in the fetus is believed to be produced mainly by the liver, with the kidneys becoming an important source only late is gestation. However, with molecular techniques, high levels of Epo gene expression are found in the fetal kidney throughout gestation whereas Epo gene expression in the fetal liver is low. Further, new studies suggest that the placenta, which is fetal tissue, produces Epo. The factors which stimulate Epo production are hypoxia and anemia. However, the characteristics of the hypoxic and anemic effects on Epo gene expression have not been examined in the fetus. The proposed studies are designed to explore the regulation of Epo gene expression and plasma Epo concentration in the ovine fetus by combining physiological and molecular approaches.
Specific Aim 1 will establish the normal patterns of Epo gene expression in placenta, fetal liver and kidneys from 50 days gestation to term (150 days). The techniques of Northern analysis and competitive reverse transcription-polymerase chain reaction will be used for the quantification of Epo messenger RNA (mRNA). The localization of the cell types which express Epo mRNA and protein will be accomplished by the methods of in situ hybridization and immunohistochemistry. The hypothesis is that each tissue displays different patterns across gestation.
Specific Aim 2 will explore the effects of fetal hypoxia induced by maternal hypoxemia on Epo mRNA abundance in kidney, liver and placenta of fetuses from 100 to 150 days gestation. The hypothesis is that Epo gene expression will be enhanced more in the placenta and fetal kidney than in the liver.
Specific Aim 3 will explore Epo gene expression responses to hypoxia induced by fetal anemia in fetuses from 100-150 days gestation. The hypothesis is that fetal anemia induces Epo mRNA in the kidney and liver but not the placenta. Our overall hypothesis is that the placenta, fetal liver and kidney differentially express Epo across gestation and that the hypoxic induction of Epo gene expression in each tissue depends on the type of hypoxia. These studies are significant because they could significantly improve our understanding of the regulation of Epo and red cell production in the fetus and are important because they could help improve the diagnosis and treatment of human fetuses and neonates with anemia and/or hemolytic disease, thereby improving perinatal outcome.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Human Embryology and Development Subcommittee 1 (HED)
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University of California San Diego
Obstetrics & Gynecology
Schools of Medicine
La Jolla
United States
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Brace, Robert A; Cheung, Cecilia Y; Davis, Lowell E et al. (2006) Sources of amniotic fluid erythropoietin during normoxia and hypoxia in fetal sheep. Am J Obstet Gynecol 195:246-54
Davis, Lowell E; Widness, John A; Brace, Robert A (2003) Renal and placental secretion of erythropoietin during anemia or hypoxia in the ovine fetus. Am J Obstet Gynecol 189:1764-70
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Wolf, R B; Moise Jr, K J; Brace, R A (2001) Antibody-induced anemia in fetal sheep: model for hemolytic disease of the fetus and newborn. J Soc Gynecol Investig 8:224-32
Hull, A D; Brace, R A (2001) Erythrocyte and erythropoietin responses to hemorrhage in the immature and near term ovine fetus. Am J Obstet Gynecol 185:501-6
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