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H. S. Wang and T. Chard

Introduction

The size of the human infant at birth depends on the duration of gestation and the rate of fetal growth. Growth, and thus delivered weight, are determined by several factors: genetic constitution, nutritional status and pathological conditions (e.g. maternal diabetes, pre-eclampsia or eclampsia, smoking, infections etc.). However, despite extensive investigation, it has been difficult to identify any specific endocrine mechanism which plays an essential role in fetal growth (Chard, 1989). Recent attention has therefore focused on the autocrine and paracrine actions of growth factors, especially the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs). Here, we review evidence for the role of the IGFs and IGFBPs in the control of fetal growth, and present a hypothesis that secretion of these compounds by the maternal decidua may play an important part in the control of the growth process.

Structure and function of IGFs and IGFBPs

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H Wang, HC Christian, and JF Morris

The relationship between nitric oxide synthase (NOS) immunocytochemistry and NADPH-diaphorase (NADPH-d) histochemistry was investigated in the anterior and posterior pituitary of ovariectomized rats. NADPH-d activity was present throughout the posterior pituitary but could not be detected in the anterior pituitary. By contrast, an antibody raised against whole recombinant rat neuronal NOS revealed strongly NOS-immunoreactive gonadotrophs and folliculo-stellate cells scattered throughout the anterior pituitary in addition to immunoreactive fibres in the posterior pituitary. The study demonstrates that NADPH-d histochemistry is not always coincident with NOS and provides evidence for an as yet uncharacterized subtype of NOS in the rat anterior pituitary.

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H. S. Wang and T. Chard

ABSTRACT

Insulin-like growth factor-binding proteins (IGFBPs) in maternal and umbilical cord sera have been analysed by combinations of gel filtration chromatography, affinity cross-linking and electrophoresis. On gel filtration chromatography, the majority of circulating IGF-I in non-pregnant and pregnant women was present in the large molecular mass (150 kDa) binding proteins (IGFBP-3). In umbilical cord serum, by contrast, most IGF-I was present in the 40 kDa binding proteins (consisting of IGFBP-1 and IGFBP-2). Western blots demonstrated an apparent progressive attenuation of IGFBP-3 and IGFBP-2 in serum from pregnant women with an increase in IGFBP-1. After prior cross-linking with disuccinimidyl suberate, the 150 kDa fractions (IGFBP-3) from non-pregnant and pregnant serum showed a similar pattern on SDS-PAGE (several bands at different molecular masses). However, IGFBP-2 (one of the components of the 40 kDa fractions) was undetectable, even after cross-linking, in serum from pregnant women later than 8 weeks of gestational age and in a mixture of maternal serum at term delivery and serum from non-pregnant women. This suggests that serum IGFBP-2 was degraded by specific proteases present in pregnancy serum. Following acid treatment, the 150 kDa fractions from pregnancy serum were split into smaller subunits or fragments while the 40 kDa fractions remained unchanged, suggesting that the 40 kDa binding proteins are acid-stable. The present data demonstrate that IGFBP-3 is the principal IGFBP in pregnancy serum even though there is an apparent reduction in serum IGFBP-3 activity as revealed on Western blots. The absence of IGFBP-2 in serum from pregnant women may be due to degradation by proteases. In the fetal circulation IGFBP-1 and IGFBP-2 appear to be the major binding proteins for IGF-1.

Journal of Endocrinology (1992) 133, 149–159

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H Wang, H Wolosker, J Pevsner, SH Snyder, and DJ Selkoe

Little evidence is available for the physiological function of D-amino acids in species other than bacteria. Here we demonstrate that naturally occurring freed -aspartate (D-Asp) is present in all magnocellular neurons of rat hypothalamus. The levels of this naturally occurring D-amino acid were elevated during lactation and returned to normal thereafter in the magnocellular neurosecretory system, which produces oxytocin, a hormone responsible for milk ejection during lactation. Intraperitoneal injections of D-Asp reproducibly increased oxytocin gene expression and decreased the concentration of circulating oxytocin in vivo. Similar changes were observed in the vasopressin system. These results provide evidence for the role(s) of naturally occurring free D-Asp in mammalian physiology. The findings argue against the conventional concept that only L-stereoisomers of amino acids are functional in higher species.

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Y-F Wang, H Negoro, and K Honda

Abstract

Unilateral knife cuts were performed in the midbrain of lactating rats and the activities of oxytocin neurones were recorded extracellularly from the supraoptic nuclei (SON) in order to investigate the location of the neural mechanism responsible for the synchronization of milk-ejection bursts of oxytocin neurones in different magnocellular nuclei of the hypothalamus. The lesions involved the mesencephalic lateral tegmentum, the intermedial tegmentum and the central grey. Ninety-six SON neurones were antidromically activated by neurohypophyseal stimulation and were also identified as oxytocin neurones, which included 17 pair-recorded neurones. First, the response of oxytocin neurones recorded from the unilateral SON to bilateral or unilateral suckling was tested. During bilateral suckling, not only the oxytocin neurones recorded from the SON on the intact side (n=34) but also those recorded from the SON on the lesioned side (n=58) displayed milk-ejection bursts. When only the nipples ipsilateral to the lesion were suckled (ipsilateral suckling), bursts were induced in most of the oxytocin neurones on the intact (83·3%, n=12) and lesioned side (88·9%, n=27). In contrast, none of the oxytocin neurones (n=37) produced bursts and none of the rats tested (n=23) showed milk ejections during contralateral suckling. Secondly, some characteristics of the bursts of pair-recorded neurones during bilateral suckling and their response to different modes of suckling were investigated. When oxytocin neurones on both sides displayed milk-ejection bursts, they were always well synchronized but the mean burst amplitude of the neurones on the lesioned side (55·6 ±4·9 spikes, n=43) was significantly (P<0·05) lower than that of the neurones on the intact side (65·7 ±5·6 spikes, n=43). Late-recruited neurones were observed in 6 pairs of oxytocin neurones, and these mainly occurred in the neurones on the lesioned side (5/6). In 5 pair-recorded oxytocin neurones, bursts could also be induced synchronously by ipsilateral suckling but not by contralateral suckling. Thus it is very likely that the major mechanism synchronizing the milk-ejection bursts of oxytocin neurones in the bilateral SON is located in the region rostral to the midbrain.

Journal of Endocrinology (1995) 144, 463–470

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SJ McPherson, TZ Thomas, H Wang, CJ Gurusinghe, and GP Risbridger

Activins are growth and differentiation factors which have been shown to have proliferative and antiproliferative actions in many tissues. In addition, they have been implicated in tumourigenesis in reproductive tissues. Although activin and inhibin are present in rat ventral prostate, inhibin beta, but not alpha, subunit proteins have been detected in the human prostate epithelial tumour cell lines LNCaP, DU145 and PC3. With this absence of capacity to produce inhibins, the aims of this study were to determine the effect of activin A and B and follistatin on DNA synthesis by these human prostate tumour cell lines. The results demonstrate a differential response to exogenously added activin A and B on DNA synthesis in vitro by the tumour cell lines. The inhibitory effects were observed on LNCaP cells in the absence or presence of stimulation with 1 nM 5 alpha-dihydrotestosterone and on the androgen-independent DU145 cells, but not the PC3 cells. Activin A caused a dose-dependent inhibition of DNA synthesis and proliferation by LNCaP and androgen-independent DU145 cells which was maximal at 8 ng/ml. The effect of exogenously added activin A was completely reversed by follistatin, but not by inhibin A. The addition of human recombinant FS 288 alone (400 ng/ml) did not have any effect on DNA synthesis, whereas inhibin A alone (400 ng/ml) caused a significant inhibition of DNA synthesis. The capacity of all three cell lines to produce activins and follistatins was demonstrated by the expression of the mRNAs and confirmed by the localisation of immunoreactivity for these ligands to the cytoplasm of the tumour cells. The growth inhibitory response to activins A and B by LNCaP and DU145 cells, and the ability of follistatin to block these effects, suggest that the autocrine interactions between activins and follistatins have a role in the regulation of LNCaP and DU145 prostate tumour cell growth.

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S. Baldwin, T. Chung, M. Rogers, T. Chard, and H. S. Wang

ABSTRACT

Two hundred Chinese primigravidae had 50 g 3-h oral glucose tolerance tests (OGTTs) twice in pregnancy; between 20 and 24 weeks and between 30 and 34 weeks of gestation. In 149 women, a single sample was taken for insulin-like growth factor-binding protein-1 (IGFBP-1) measurement 0, 1, 2 or 3 h after the glucose load at both visits; in 55 women IGFBP-1 levels were estimated in all four OGTT samples. Fetal growth was assessed by ultrasound performed at the first and second visit and, if possible, at term, and by anthropometry of the neonate. Cord serum IGFBP-1 was measured in 144 of the babies. Mothers who developed gestational diabetes were excluded.

Maternal levels of IGFBP-1 were inversely related to glucose levels at 0, 1 and 2 h in the third trimester of pregnancy. IGFBP-1 measured at 1 h in an OGTT increased between the second and third trimester. There was an inverse correlation between maternal IGFBP-1 measured in the second trimester and all fetal measurements at that time, and with most neonatal measurements and birthweight. Levels of IGFBP-1 in the third trimester were inversely correlated to neonatal abdominal circumference, skinfold thickness and birthweight. Cord blood IGFBP-1 was inversely related to growth of abdominal circumference. The strongest inverse relationship was between IGFBP-1 and maternal weight. Fasting glucose in the second trimester was positively correlated to fetal subcutaneous fat and growth of abdominal circumference. In the third trimester it was related to fetal abdominal circumference, the growth of abdominal circumference, birthweight and neonatal skinfold thickness. In a multiple regression analysis, both glucose and IGFBP-1 were shown to be determinants of birthweight. It is concluded that IGFBP-1 levels are related to glucose tolerance in pregnancy, and that both IGFBP-1 and glucose have a role in determining birthweight.

Journal of Endocrinology (1993) 136, 319–325

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H. S. Wang, J. Lim, J. English, L. Irvine, and T. Chard

ABSTRACT

Serum levels of insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-1 (IGFBP-1) have been determined by radioimmunoassay in the maternal circulation (n = 91) and in the umbilical artery (n = 56) and vein (n = 90) of man. In both the umbilical artery and vein, the concentration of serum IGF-I showed an inverse correlation with birthweight (P < 0·005 and P < 0·001 respectively); the mean serum IGF-I levels in the small-for-gestational-age (SGA) group were significantly higher than those in average-for-gestational-age (AGA) neonates (P <0·01 and P < 0·001 respectively). However, maternal serum IGF-I showed no association with birthweight and there was no significant difference between the SGA and AGA groups. These observations imply that the production of IGF-I in the maternal and fetal compartments is independent and that there is unlikely to be transfer of IGF-I across the placenta. Serum IGFBP-1 levels in both maternal and umbilical cord blood (artery and vein) showed an inverse relation to birthweight (P <0·001, P<0·005 and P<0·001 respectively). Increased IGFBP-1 levels in the umbilical artery and vein were observed in the SGA group. These findings suggest that IGFBP-1 might inhibit the action of IGF-I in both the maternal and the fetal compartments and that the rise in IGFBP-1 could be a primary factor in retardation of fetal growth. Alternatively, circulating IGF-I and IGFBP-1 levels may only be a secondary reflection of local tissue events involved in fetal growth.

Journal of Endocrinology (1991) 129, 459–464

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H Wang, E Isaksson, B Von Schoultz, JM Cline, and L Sahlin

The effects of oestrogen are mediated by two specific intracellular receptors, oestrogen receptors (ER) alpha and beta, which function as ligand-activated transcriptional regulators. Ovariectomized macaques (Macaca fascicularis) were used to study the regulation of ERalpha and ERbeta in the endometrium by immunohistochemistry and in situ hybridization after long-term hormone treatment. Animals were treated continuously for 35 Months with either conjugated equine oestrogen (CEE), medroxyprogesterone acetate (MPA), combined CEE/MPA, or tamoxifen (TAM). Treatment with CEE/MPA down-regulated ERalpha in the superficial glands. In the superficial stroma the ERalpha level was lower in the CEE/MPA group than in the CEE and MPA groups. ERbeta immunostaining was faint with minor variation in response to treatment, but increased in the superficial stroma after MPA treatment. The ratio of ERbeta/ERalpha increased in superficial stroma and gland after CEE/MPA treatment, and also in stroma after MPA and TAM. Cystic endometrial hyperplasia was observed in TAM-treated animals, in combination with a high level of ERalpha protein expression. The present data show that long-term hormone treatment affects the ERalpha and ERbeta protein levels in the endometrium. The balance between ERalpha and ERbeta seems to be important for the proliferative response to oestrogen.

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H Tokuda, K Hirade, X Wang, Y Oiso, and O Kozawa

We previously reported that basic fibroblast growth factor (FGF-2) activates p44/p42 mitogen-activated protein (MAP) kinase resulting in the stimulation of vascular endothelial growth factor (VEGF) release in osteoblast-like MC3T3-E1 cells and that FGF-2-activated p38 MAP kinase negatively regulates VEGF release. In the present study, we investigated the involvement of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) in FGF-2-induced VEGF release in these cells. FGF-2 markedly induced the phosphorylation of SAPK/JNK. SP600125, an inhibitor of SAPK/JNK, markedly reduced the FGF-2-induced VEGF release. SP600125 suppressed the FGF-2-induced phosphorylation of SAPK/JNK without affecting the phosphorylation of p44/p42 MAP kinase or p38 MAP kinase induced by FGF-2. PD98059, an inhibitor of upstream kinase of p44/p42 MAP kinase, or SB203580, an inhibitor of p38 MAP kinase, failed to affect the FGF-2-induced phosphorylation of SAPK/JNK. A combination of SP600125 and SB203580 suppressed the FGF-2-stimulated VEGF release in an additive manner. These results strongly suggest that FGF-2 activates SAPK/JNK in osteoblasts, and that SAPK/JNK plays a part in FGF-2-induced VEGF release.