Fetal growth and bone mineralization require transplacental transfer of calcium ions (Ca++) from the maternal to fetal circulation. Available experimental evidence suggests that this process is active transport which is subject to fetoplacental hormonal regulation. The calcitropic hormones parathyroid hormone (PTH) and 1,25 (OH)2 vitamin D are known to induce metabolic changes in placental cells and may modulate transplacental Ca++ transport by mechanisms presently undefined. However, since many PTH immunoassays cannot detect immunoreactive hormone or detect low levels in umbilical cord blood it has been assumed that the hypercalcemia of late gestation may suppress fetal parathyroid secretion of PTH. My preliminary results indicate that human umbilical venous plasma, in fact, contains significant PTH-like biological activity that is not immunoreactive native hormone. Other investigators recently have reported that circulating PTH-like bioactivity in fetal lambs is partially independent of the presence of the parathyroid glands. Furthermore, it appears that sheep placenta contains PTH-like bioactive factors that may resemble the PTH-like proteins associated with the syndrome of humoral hypercalcemia. I propose to characterize the factor(s) responsible for umbilical plasma PTH-like bioactivity by means of biochemical, molecular biological and physiological techniques.
The specific aims will address comparison of the biochemical and biological properties of these factors with the properties of human PTH and a recently cloned PTH-like peptide associated with humoral hypercalcemia of malignancy. I will examine: size, by means of bioactivity profiles of umbilical venous plasma subjected to gel chromatography; immunoreactivity, by investigating neutralization of bioactivity with different regionspecific PTH and PTH-like peptide antisera; adenylate cyclase-stimulating activity, determining relative specific activities in different bioassay systems; and encoding RNA, by probing placenta for message for PTH and a PTH-like peptide. Characterization of factors(s) responsible for this bioactivity should advance our understanding about the regulation of intrauterine Ca++ metabolism and transplacental Ca++ transport in normal pregnancies and those complicated by maternal disease or intrauterine growth retardation. Characterization of the factor(s) might also illuminate other problemmatic areas of calcium physiology and pathophysiology in humans.
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