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INVESTIGATOR: Lemley, C.

PERFORMING INSTITUTION:
MISSISSIPPI STATE UNIV
MISSISSIPPI STATE, MISSISSIPPI 39762

ROLE OF MELATONIN DURING MID-GESTATION ON FETAL GROWTH IN SHEEP

NON-TECHNICAL SUMMARY: Mortality is increased in offspring of low birth weight, while surviving low birth weight offspring are associated with poor growth performance. Therefore, increasing fetal growth during gestation can decrease lamb mortality rates and improve offspring performance. The relationship between birth weight and offspring performance has a substantial impact on food production not only in the U.S. but other developing countries which rely heavily on sheep and goat production. The placenta is involved in transporting wastes and nutrients to the growing fetus; therefore, therapeutic supplements designed to improve blood flow to the placenta can have a direct impact on fetal growth and development. This project will examine the effect of melatonin supplementation on uterine and umbilical blood flow, both of which play an important role in supplying oxygen and nutrients to the growing fetus. We anticipate that melatonin will increase uterine and umbilical blood flow and improve fetal growth and development. In addition, we will evaluate the mechanism behind these melatonin mediated pathways, by chronically infusing pregnant sheep with a compound that blocks melatonin receptors. We anticipate that blocking melatonin receptors will result in decreased umbilical blood flow and fetal growth. The findings from this project will allow for the design and implementation of possible interventions that could be used to improve birth weights. In addition, novel research strategies could be developed to study placental and fetal development.

OBJECTIVES: The long-term goal is to determine the possible mechanisms that dietary supplements, particularly melatonin, may modify placental function and fetal development. Therefore, the central hypothesis is that melatonin supplementation during mid-gestation will improve uteroplacental blood flow, placental efficiency (fetal weight to placental weight ratio) and fetal growth. In addition, we are testing whether these responses are melatonin receptor mediated. The hypothesis will be addressed through the specific objectives, which are to: Objective 1: Determine uteroplacental blood flow and fetal growth during mid-gestation in undernourished and control ewes supplemented with or without melatonin. Objective 2: Determine uteroplacental blood flow and fetal growth following chronic in vivo uterine artery infusions of vehicle, melatonin or melatonin receptor antagonist during mid-gestation. Currently, we have completed the majority of the animal work for this USDA transfer project and we are in the process of analyzing samples via bioassays and histological procedures. We observed an increase in umbilical artery blood flow, fetal aorta blood flow, and fetal growth parameters following melatonin infusion during pregnancy (objective 2). Blocking placental melatonin receptors during mid-gestation, by infusing a melatonin receptor antagonist (luzindole), decreased umbilical artery blood flow and fetal descending aorta blood flow (or fetal cardiac output). The melatonin receptor mediated alterations in umbilical artery blood flow and fetal descending aorta blood flow may be dependent on increasing nitric oxide bioavailability; therefore, we are in the process of analyzing total nitrites (an indicator of nitric oxide production) in the placental vascular bed. For the remainder of this USDA transfer grant we will be analyzing melatonin receptor 1 and melatonin receptor 2 protein expression as well as immunolocalization of melatonin receptors in the placentome, caruncular (maternal placentome) artery, cotyledonary (fetal placentome) artery, and umbilical artery. We anticipate a greater expression of melatonin receptor 2 in the fetal portion of placenta compared to the maternal portion of the placenta. In addition, melatonin receptors will be localized to both endothelial cells and vascular smooth muscle cells of the caruncular, cotyledonary, and umbilical artery. This relationship describes a novel pathway, whereby melatonin may partially modulate uteroplacental blood flow and fetal development through placental melatonin receptors. In addition to the results, we have described a new experimental technique which will allow researchers to design future experiments on identifying placental vasomediators during pregnancy. The findings from this project will allow for the design and implementation of possible interventions that could be used to improve birth weights and potentially offspring performance.