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The aim of the present study was to evaluate the possible presence of immunoreactive neuropeptide-gamma (irNPY) in human placenta. Acidic extracts of human placental tissue collected at term pregnancy contained high irNPY concentrations. The extracted irNPY eluted from HPLC with the same retention time as synthetic NPY. The presence of the peptide in placental cells was confirmed by immunohistochemical findings showing numerous cells of the cytotrophoblast layer positively staining for NPY. Further supporting local production of the peptide, primary cultures of human placental cells released irNPY into the culture medium and the addition of high K+ concentrations increased the release of the peptide. The finding of irNPY in human placenta stimulated the characterization of binding sites of NPY in the same tissue. Using autoradiographic techniques we showed specific binding of [125I]NPY in human placental tissue. The binding of [125I]NPY to the placental receptors was saturable and widely distributed within the placental tissue. Finally, the addition of NPY to the medium of cultured placental cells increased the release of immunoreactive CRF, suggesting a possible role of NPY in placental hormone production. The effect of NPY was dose related and augmented by the addition of norepinephrine (10 nM). These results showed that human placenta produces and secretes irNPY and that NPY receptors are present in placental tissue. Moreover, the evidence that NPY stimulated the release of immunoreactive CRF from cultured placental cells suggests an action of NPY in placental hormonogenesis.
Effects of hypophysectomy or reduction of the conceptus number on luteal steroidogenesis were studied in the pregnant rat. On day 7 of pregnancy (day 1 = day of insemination), the number of conceptuses was adjusted to one by aspirating all but one conceptus from the uterus. Another group of rats received hypophysectomy on day 12 of pregnancy. On day 15 of pregnancy, the weights of the corpora lutea (CL), serum progesterone levels, and luteal concentrations of cholesterol, pregnenolone, and progesterone were determined. The aspiration group showed significant a decrease in the weight of the CL and in the serum progesterone level compared with those of the hypophysectomy or control group. However, there were no significant changes in the luteal concentrations of cholesterol, pregnenolone or progesterone. On the other hand, hypophysectomy caused a significant decrease in the luteal concentration cholesterol, whereas no change was observed in the weight of the CL, serum progesterone level or the concentrations of pregnenolone or progesterone in the CL. These results indicated that in mid-pregnancy the pituitary regulated the uptake or storage of cholesterol of the CL, while the placental hormones regulated the serum progesterone level mainly by affecting the growth of the CL.
The study of an experimental model, the induction of breast carcinomas by administration of the chemical carcinogen 7,12-dimethylbenz(a)anthracene (DMBA) to virgin rats, has allowed us to determine that the susceptibility of the mammary gland to a carcinogen depends upon its degree of differentiation at the time of exposure. The mostly undifferentiated gland of young virgin rats is highly susceptible due to the high proliferative rate of the terminal ductal structures or terminal end buds (TEBs), ready for differentiation into alveolar buds (ABs) which avidly bind the carcinogen. Complete differentiation through a full-term pregnancy renders the gland resistant to carcinogenesis due to the replacement of TEBs by lobules whose epithelium has a low proliferative rate and low DMBA binding. Although pregnancy is the most complete stimulus, differentiating the highly susceptible TEBs of the virgin female into more resistant lobules, administration of certain pituitary, ovarian or placental hormones considerably modifies the mammary gland structure, thus influencing its response to chemical carcinogenesis. The observation that contraceptive agents administered for a short period of time also exert a protective effect allows us to postulate that this model could be developed as a protocol for breast cancer prevention.
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Review of the structure of the symphysis pubis, based on my extensive study of the pelvic joints ('31) shows changes from age, function, pregnancy hormones and stress of parturition. Primary physiologic shearing clefts and secondary traumatic clefts in cartilage are more frequent in females. Interdigitations in the young osteocartilaginous border secure the vulnerable growth cartilage against increasing shearing forces. The retropubic eminence, ligamentous or cartilaginous, forms earlier in females, later, due to bony lipping in males, secondary to extrusion of disc cartilage. Ovarian and placental hormones in pregnancy cause remodeling and resorption of the posterior margin of the pubic facette and adjacent cortex, making a (variably) deep bony groove for greatly hypertrophied transverse ligaments. Delivery of a mature infant produces traumatic changes leading to extrusion of torn fibrocartilage in any direction, progressively loosening the symphysis, producing cartilage nodules, cysts and reactive bone formation. Older age degenerative arthritis is more frequent in parous females.
Pregnancy has commonly been viewed as a cooperative interaction between a mother and her fetus. The effects of natural selection on genes expressed in fetuses, however, may be opposed by the effects of natural selection on genes expressed in mothers. In this sense, a genetic conflict can be said to exist between maternal and fetal genes. Fetal genes will be selected to increase the transfer of nutrients to their fetus, and maternal genes will be selected to limit transfers in excess of some maternal optimum. Thus a process of evolutionary escalation is predicted in which fetal actions are opposed by maternal countermeasures. The phenomenon of genomic imprinting means that a similar conflict exists within fetal cells between genes that are expressed when maternally derived, and genes that are expressed when paternally derived. During implantation, fetally derived cells (trophoblast) invade the maternal endometrium and remodel the endometrial spiral arteries into low-resistance vessels that are unable to constrict. This invasion has three consequences. First, the fetus gains direct access to its mother's arterial blood. Therefore, a mother cannot reduce the nutrient content of blood reaching the placenta without reducing the nutrient supply to her own tissues. Second, the volume of blood reaching the placenta becomes largely independent of control by the local maternal vasculature. Third, the placenta is able to release hormones and other substances directly into the maternal circulation. Placental hormones, including human chorionic gonadotropin (hCG) and human placental lactogen (hPL), are predicted to manipulate maternal physiology for fetal benefit. For example, hPL is proposed to act on maternal prolactin receptors to increase maternal resistance to insulin. If unopposed, the effect of hPL would be to maintain higher blood glucose levels for longer periods after meals. This action, however, is countered by increased maternal production of insulin. Gestational diabetes develops if the mother is unable to mount an adequate response to fetal manipulation. Similarly, fetal genes are predicted to enhance the flow of maternal blood through the placenta by increasing maternal blood pressure. Preeclampsia can be interpreted as an attempt by a poorly nourished fetus to increase its supply of nutrients by increasing the resistance of its mother's peripheral circulation.
The control of secretion of the placental hormones human chorionic gonadotrophin (hCG) and human placental lactogen (hPL), and the trophoblastic protein pregnancy-specific beta-glycoprotein (SP1), is not well understood. During pregnancy, the hCG concentrations peak in the first trimester then decrease, while hPL and SP1 increase steadily throughout gestation. In order to determine whether the discordance between hCG secretion and that of hPL and SP1 observed in vivo also occur in vitro, we cultured placental explants with and without dibutyryl cyclic AMP (dbcAMP) and theophylline. Between 5 and 12 explants were used for each treatment in each experiment. The concentration of the proteins secreted into the media each day was measured by specific radioimmunoassays. The quantities of hPL and SP1 secreted per day declined in a parallel fashion after 24 hours under both basal and dbcAMP-stimulated conditions. The hCG output progressively decreased in the unstimulated cultures until 48 hours, at which time an increase in hCG secretion was observed. The dbcAMP-stimulated placentae significantly increased their hCG output at both 48 and 72 hours. These data show that hCG secretion is regulated differently from that of hPL and SP1. The results do not negate the possibility that term placental tissue may contain an inhibitor of hCG release that is removed by experimental manipulation in vitro.
Blood was obtained from 218 women between 6 and 13 weeks of gestation. Measurements of serum insulin-like growth factor binding protein-1 (IGFBP-1) and placental protein 14 (PP14) concentrations were compared with maternal weight and height, maternal smoking habit, indices of maternal haematological status and two placental hormones [human chorionic gonadotrophin (HCG) and human placental lactogen (HPL)]. IGFBP-1 concentration was negatively correlated with maternal weight (P < 0.001) and body mass index (P < 0.001); PP14 concentration was not correlated with these measurements. PP14 concentration was negatively correlated with maternal haemoglobin concentration (P = 0.010), mean corpuscular volume (P = 0.003) and serum ferritin concentration (P = 0.016). The concentrations of PP14 were significantly less among smokers (P < 0.001); IGFBP-1 concentrations were uninfluenced by smoking. IGFBP-1 concentration was positively correlated with maternal serum HCG (P = 0.003) and maternal serum HPL (P = 0.002). PP14 concentration was positively correlated with maternal serum HCG (P < 0.0001) but not with HPL. These findings demonstrate that the maternal environment has an early influence on both endometrial and placental function.
Thyroid hormone is essential for normal human development, and disruption of thyroid hormone homeostasis at critical developmental stages can result in severe and often long-term effects on crucial organs such as the brain and lungs. Numerous factors control the bioavailability of receptor active thyroid hormone T(3). Sulfation, catalyzed by sulfotransferase enzymes (SULTs), is an important pathway of thyroid hormone metabolism by which T(4) is irreversibly converted to inactive reverse T(3) rather than active T(3). The human fetus and neonate have high levels of circulating sulfated iodothyronines, although the source of these is not clear. The placenta forms the link between the fetus and its mother and is involved in transfer of thyroid hormone early in pregnancy, although its capacity for sulfation is unknown. We therefore examined expression of the SULTs involved in iodothyronine metabolism during human placental development. SULT activity was measured in human placental cotyledon and membranes (amnion, chorion, and decidua basalis) from 13-42 wk of gestation, and Western blot analysis was employed to verify enzyme activity data. Phenol and catecholamine sulfotransferases were expressed at the highest levels and were generally higher in the villous than membranous tissues. SULT1A1 activity showed significant correlation with sulfation of 3,3'-T(2), suggesting that this enzyme is primarily responsible for placental T(2) sulfation. Estrogen sulfotransferase was present at extremely low levels during early pregnancy, although in mid- and late gestation increased expression in the (predominantly maternal-derived) decidual component of the placenta was observed. Hydroxysteroid sulfotransferase, T(3), reverse T(3), and T(4) SULT activities were also low in all tissues examined, and expression of SULTs 1B1 and 1C2 were essentially undetectable by Western blot analysis. The results highlight a tissue-specific regulation of SULT expression during placental development, demonstrate very low sulfation of iodothyronines suggesting that the placenta is not a major source of circulating sulfated iodothyronines in the fetus.
The human placenta arises from the zygote through single cell intermediates called cytotrophoblasts that in turn give rise to a syncytium. In culture, mononucleated cytotrophoblasts exhibit little, if any, cell division but are converted to multinucleated cells. Choriocarcinoma, the malignant tumor of placenta trophoblast, comprises a mixed population of dividing cellular intermediates that resemble cytotrophoblasts but are less differentiated. Because the choriocarcinoma intermediates arise from dividing cells, the tumor may contain one or more cell types in abundance not present in the population of isolated placental cells. To study placental differentiation through cell-cell interaction, choriocarcinoma cell lines were co-cultured with placenta-derived cytotrophoblasts, and placental hormone biosynthesis, as a marker of differentiation was examined. We reasoned that intermediates formed by the tumor might interact with and complement those intermediates in the placenta-derived cytotrophoblast population. Co-culturing either the JAr or JEG choriocarcinoma cell lines with cytotrophoblasts elevated the synthesis of the chorionic gonadotropin alpha and beta subunits 10-20 fold, and human placental lactogen 5-fold. The effect was specific for these trophoblast-derived cells, since comparable quantities of Chinese hamster ovary or HeLa cells did not affect the placental cytotrophoblast culture. Further experiments suggested that the source of enhanced synthesis was the cytotrophoblasts. We propose that an interaction between cytotrophoblasts and choriocarcinoma cells occurs, which results in an increased number of differentiating cytotrophoblasts. Such co-cultures may represent a model system for examining choriocarcinoma cell interaction with normal cells, a process known to occur in vivo. The data are also consistent with the hypothesis that the regulated chorionic gonadotropin production in the placenta is determined by interaction among trophoblast cells at different stages of differentiation.
The primary aim of this work was to produce specific monoclonal antibodies to human growth hormone (hGH) for use in a diagnostic RIA of hGH levels in serum. Three different schedules were used for immunization of BALB/c mice and the splenocytes from each mouse were fused with myeloma cells Sp 2/0 Ag 14. Each fusion resulted in the production of hundreds of hybridomas secreting hGH-directed antibodies. Six antibodies have been fully characterized and have been grouped into pairs which recognize 3 different epitopes on the hGH molecule. One pair exhibits no cross reaction with the structurally related placental hormone, human placental lactogen (hPL), a second pair has low cross reaction with hPL (1.6-3%) and a third pair reacts equally well with hGH and hPL indicating binding to a common epitope in the 2 molecules. The highest affinity antibody, 74/6, which has an affinity constant of 4.4 X 10(10) l/mol and 3% cross-reactivity with hPL, has been used to establish a RIA for serum hGH measurements. Evidence is provided that hGH levels measured in this assay correlate well with those obtained in a conventional rabbit antiserum assay.
BACKGROUND: Systemic lupus erythematosus (SLE) with or without evidence of antiphospholipid antibodies (aPA) and antiphospholipid syndrome (APS) is associated with a high rate of spontaneous abortions. The placenta is thought to be the site of pathological damage in many of these abortions. To test this hypothesis, we studied the effects of sera obtained from women with SLE with or without treatment on human placental explants in culture. METHODS: We cultured 5.5- to 7.5-week-old human placental explants in a culture medium containing F-12 DMEM and 10% FCS or in 90% human serum obtained from nonpregnant women with SLE prior to or after treatment. Culture was carried out for 96 hr. At the end of the culture period, we studied the secretion of the placental hormones estrogen (E2), progesterone (PGN), and human chorionic gonadotropin (hCG). In addition, we studied the proliferation rate (using PCNA staining) and the rate of apoptosis (using ApoTag) of the trophoblastic cells. RESULTS: Placentae grew better in normal human serum than in a chemically defined medium of F-12 DMEM and 10% FCS. Enhanced growth and higher secretion rates for hCG and estradiol (E2) were manifested in placentae cultured in control sera with no change in PGN secretion. Secretion rates of hCG and PGN (but not of E2 in the treated group) by placental explants were similar to that of controls. However, the serum levels prior to culture were not measured. Further, explants in serum from untreated women with SLE produced a significant decrease in the proliferation rate of the trophoblastic cells and an increase of apoptosis. Treatment significantly reduced the apoptotic rate and increased cell proliferation, but the cell proliferation rate was still lower than that noted in controls. CONCLUSIONS: We conclude that sera from women with SLE may directly damage the developing placenta reducing proliferation and enhancing apoptosis. Successful treatment of the women reduces that damage.
The effect of a human placental hormone (UTPH) and UTPH-antiserum upon development of preimplantation mouse embryos was studied in vitro. UTPH at a concentration of 90 micrograms/ml had a tendency to increase the mean number of blastomeres pre embryo, and increased significantly (P less than 0.01) upon the cleavage rate. These data suggest an influence of the UT UTPH upon the early development of the embryo in mammals.
Human embryonic stem (ES) cells can proliferate without a known limit and can form advanced derivatives of all three embryonic germ layers. What is less widely appreciated is that human ES cells can also form the extra-embryonic tissues that differentiate from the embryo before gastrulation. The use of human ES cells to derive early human trophoblast is particularly valuable, because it is difficult to obtain from other sources and is significantly different from mouse trophoblast. Here we describe a method by using bone morphogenetic protein (BMP)4, a member of the transforming growth factor (TGF)-beta superfamily, to induce the differentiation of human ES cells to trophoblast. Immunoassays (as well as DNA microarray and reverse-transcription polymerase chain reaction analyses--data not shown) demonstrate that the differentiated cells express a range of trophoblast markers and secrete placental hormones. When plated at low density, the BMP4-treated cells form syncytia that express chorionic gonadotrophin (CG). This technique underscores fundamental differences between human and mouse ES cells, which differentiate poorly, if at all, to trophoblast. Human ES cells thus provide a tool for studying the differentiation and function of early human trophoblast and could provide a new understanding of some of the earliest differentiation events of human postimplantation development.
Hormonal regulation of mammary tumor virus (MTV) production, has been analyzed with normal mammary epithelial cells from chronically infected BALB/cfC3H mice. The effect of prolactin in terms of increased MTV production was not reproducibly observed in cells cultured in tissue culture dishes, whereas the cells grown on floating collagen gels consistently responded to prolactin in a dose-dependent manner. Of the three media tested. Dulbecco's modified Eagle's medium was found to be the best in terms of responsiveness to prolactin and in maximal MTV production. Specificity studies with other pituitary and placental hormones in place of prolactin have shown that both growth hormones and human placental lactogen can replace prolactin, whereas follicle-stimulating hormone, luteinizing hormone, and thyrotrophin were ineffective. Contrary to the mammary tumor systems, where it has been shown that insulin and glucocorticoid can maximally stimulate MTV production, these hormones alone elicited only a small response in the absence of prolactin in normal mammary epithelial cells. Although prolactin alone had very little effect by itself, its presence was necessary (permissive effect) in order for the glucocorticoids to be able to maximally stimulate MTV production in normal cells.
A new prolactin-like cDNA clone, bPLP-IV, was isolated from a bovine placental cDNA library and the complete nucleotide sequence was determined. The bPLP-IV encodes a protein consisting of 237 amino acids, which is related to, but different from seven other known bovine prolactin-like proteins including two placental lactogens. The predicted amino acid sequence of the bPLP-IV shows over 52% identity to other known members of bovine prolactin-like proteins, 48% to bovine prolactin, 40% to both two bovine placental lactogens and only 22% to bovine growth hormone. The bPLP-IV protein has a unique feature in its primary structure, lacking the two C-terminal cysteine residues which are completely conserved in all other known members of prolactin-growth hormone-placental lactogen gene family. The expression of bPLP-IV in developing bovine placenta was apparently stage-specific, being maximal in the full-term placenta.
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