Endocrine-disrupting compounds (EDCs) are synthetic or natural compounds that interfere with endogenous endocrine action. The frequent use of chemicals with endocrine active properties in household products and contamination of soil, water, and food sources by persistent chemical pollutants result in ubiquitous exposures. Wildlife observations and animal toxicological studies reveal adverse effects of EDCs on reproductive health. In humans, a growing number of epidemiological studies report an association with altered pubertal timing and progression. While these data are primarily reported in females, this review will focus on the small number of studies performed in males that report an association of polychlorinated biphenyls with earlier sexual maturity rating and confirm subtle effects of lead, dioxins, and endosulfan on delaying pubertal onset and progression in boys. Recent studies have also demonstrated that EDC exposure may affect pubertal testosterone production without having a noticeable effect on sexual maturity rating. A limitation to understand the effects of EDCs in humans is the potential for confounding due to the long temporal lag from early-life exposures to adult outcomes. The complex interplay of multiple environmental exposures over time also complicates the interpretation of human studies. These studies have identified critical windows of vulnerability during development when exposures to EDCs alter critical pathways and affect postnatal reproductive health. Contemporaneous exposures can also disrupt the hypothalamic–pituitary–gonadal axis. This paper will review the normal process of puberty in males and summarize human data that suggest potential perturbations in pubertal onset and tempo with early-life exposures to EDCs.
William Zawatski and Mary M Lee
C. Y. Lee and D. M. Henricks
Untreated serum exhibited two forms of insulin-like growth factor-I (IGF-I)-binding protein complexes during gel chromatography: one of M r 150 000 and the other of M r 40 000–45 000. The majority of the immunoreactive IGF-I was associated with the M r 150 000 complex. Following acid-ethanol extraction of serum, the binding activity at M r 150 000 disappeared and a reduced binding activity appeared in the albumin size range. Acid incubation of serum was slightly less effective than acid-ethanol extraction in reducing the binding activity. Acid-ethanol-extracted or acid-incubated serum were parallel to IGF-I standard in the dose–response displacement of iodinated IGF-I. Gel filtration of serum with 1 mol acetic acid/l almost completely separated IGF-I and the binding proteins. Binding-protein fractions from gel filtration interfered with the immunoreactivity of IGF-I with its antibodies, causing a non-parallel displacement curve in the radioimmunoassay (RIA). Serum IGF-I could be isolated as a single peak by high performance C18 reverse-phase liquid chromatography (HPLC). The concentrations of IGF-I measured in bovine sera by RIA were similar between acid gel filtration and HPLC; the concentrations by acid-ethanol extraction and acid incubation being about 30% smaller than those measured with former methods. The lower concentration of IGF-I measured in bovine serum with acid-ethanol extraction or acid incubation appears to be due to interference of IGF-binding proteins not removed by either treatment.
Journal of Endocrinology (1990) 127, 139–148
H M Kronenberg, K Lee, B Lanske and G V Segre
Parathyroid hormone (PTH) controls calcium homeostasis through its actions on kidney and bone to raise blood calcium. Calcium, in turn, suppresses PTH secretion from the parathyroid gland. This negative feed-back loop (Fig. 1) serves to maintain the constancy of blood calcium from minute to minute. The receptor that mediates the actions of PTH is a G-protein-linked receptor that also mediates actions of parathyroid hormone related protein (PTHrP). The normal functions of PTHrP are still incompletely understood, but are likely to include predominantly paracrine actions (Broadus & Stewart 1994). PTHrP is synthesized by many tissues from the earliest stages of development and throughout life, although the blood levels of PTHrP are usually quite low. PTH/PTHrP receptors are often found near the sites of synthesis of PTHrP, and PTHrP has been shown to act on tissues in which PTHrP is synthesized.
How one receptor can mediate the calcium homeostatic
V. W. K. LEE and D. M. DE KRETSER
Changes in levels of LH and FSH in the circulation were examined during repeated blood sampling in untreated rats and gonadectomized male and female rats treated with oestrogen, progesterone and thyroxine. Blood depletion induced a significant increase in levels of LH in steroid-treated rats but the increase was abolished when the depleted blood volume was replaced with egg albumen. The rise in LH was less dramatic in male than in female animals. In untreated rats, levels of LH either decreased or did not change with repeated phlebotomy. In contrast, the levels of FSH either did not alter or were lowered in all situations.
P. M. Harris, B. W. McBride, M. P. Gurnsey, B. R. Sinclair and J. Lee
In vivo effects of local infusion of a variant of insulin-like growth factor-I (IGF-I), long-R3-IGF-I, into the skin were investigated using six conscious sheep with food available ad libitum. An artery and vein on the abdominal flank of each animal, as well as the saphenous artery, were catheterized so that infusion of isotopically labelled amino acids, with or without IGF-I, could be used to determine amino acid uptake by arteriovenous difference in combination with blood flow determined by dye dilution. Measurements were made on each animal prior to IGF-I infusion, at hourly intervals for the 4 h of IGF-I infusion into the skin artery, then 2 and 4 h after IGF-I infusion ceased. Numbers of cells replicating in the bulbs of wool follicles in the IGF-I-infused area and in the skin on the contralateral side of each animal were measured after labelling with 5-bromo-2′-deoxyuridine. IGF-I caused a significant increase in the skin blood flow (P<0·05), utilization of oxygen (P<0·05), uptake of cysteine (P<0·05) and phenylalanine (P<0·001), and the rate of utilization of cysteine (P<0·05) for protein synthesis. IGF-I increased amino acid uptake regardless of whether the skin was in negative or positive amino acid balance prior to infusion. During the recovery period amino acid utilization by skin returned towards preinfusion levels. No effects of IGF-I were found on replicating cell numbers in the bulbs of wool follicles.
Journal of Endocrinology (1993) 139, 463–472
A. M. Galzin, M. T. Eon, H. Esnaud, C. R. Lee, P. Pévet and S. Z. Langer
5-Methoxytryptamine is a potent agonist of presynaptic 5-hydroxytryptamine autoreceptors modulating serotonin release in the central nervous system. This methoxyindole can be synthesized in the pineal gland, but its presence in vivo is still controversial, probably because of rapid catabolism by monoamine oxidase. An improved high-pressure liquid chromatography method, with coulometric detection, has been developed for the simultaneous measurement of melatonin, 5-methoxytryptamine, 5-methoxytryptophol and 5-methoxyindolacetic acid. We have demonstrated a day–night rhythmicity in the amount of 5-methoxytryptamine in the pineal gland of golden hamsters (Mesocricetus auratus) maintained under a long photoperiod (14 h light: 10 h darkness) and pretreated with the monoamine oxidase inhibitor pargyline. Levels of 5-methoxytryptamine were highest at 16.30 h and lowest at 00.30 h. The rhythm for 5-methoxytryptamine appears to be the same as for serotonin (opposite in phase to that of melatonin). The identification of 5-methoxytryptamine has been confirmed by analysis with gas chromatography–mass spectrometry.
J. Endocr. (1988) 118, 389–397
C. M. H. Lee, F. R. Tekpetey, D. T. Armstrong and M. W. Khalil
We have previously suggested that in porcine granulosa cells, a putative intermediate, 5(10)-oestrene-3,17-dione is involved in 4-oestrene-3,17-dione (19-norandrostenedione; 19-norA) and 4-oestren-17β-ol-3-one (19-nortestosterone: 19-norT) formation from C19 aromatizable androgens. In this study, luteal cells prepared from porcine, bovine and rat corpora lutea by centrifugal elutriation were used as a source of 3β-hydroxysteroid dehydrogenase/isomerase in order to investigate the role of this enzyme in the biosynthesis of 19-norsteroids. Small porcine luteal cells made mainly 19-norT and large porcine luteal cells 19-norA from 5(10)-oestrene-3β,17β-diol, the reduced product of the putative intermediate 5(10)-oestrene-3,17-dione. However, neither small nor large cells metabolized androstenedione to 19-norsteroids. Serum and serum plus LH significantly stimulated formation of both 19-norA and 19-norT from 5(10)-oestrene-3β,17β-diol, compared with controls.
Inhibitors of the 3β-hydroxysteroid dehydrogenase/isomerase (trilostane and cyanoketone) significantly reduced formation of 19-norT in small porcine luteal cells and 19-norA in large porcine luteal cells, although they were effective at different concentrations in each cell type. In parallel incubations, formation of [4-14C]androstenedione from added [4-14C]dehydroepiandrosterone was also inhibited by cyanoketone in both small and large porcine luteal cells in a dose-dependent manner; however, trilostane (up to 100 μmol/l) did not inhibit androstenedione formation in large porcine luteal cells. In addition, the decrease in progesterone synthesis induced by trilostane and cyanoketone (100 μmol/l each) was accompanied by a parallel accumulation of pregnenolone in both cell types. These results suggest that 3β-hydroxysteroid dehydrogenase/isomerase, or a closely related enzyme, present in small and large porcine luteal cells can convert added 5(10)-3β-hydroxysteroids into 19-nor-4(5)-3-kestosteroids in vitro. In the porcine ovarian follicle, therefore, formation of 19-norA from androstenedione can be envisaged as a two-step enzymatic process: 19-demethylation of androstenedione to produce the putative intermediate 5(10)-oestrene-3,17-dione, and subsequent isomerization to 19-norA. In contrast to granulosa cells, porcine luteal cells synthesized 19-norA or 19-norT only when provided with the appropriate substrate. Unfractionated rat luteal cells also metabolized 5(10)-oestrene-3β,17β-diol to a mixture of 19-norA and 19-norT; conversion was inhibited by trilostane. In addition, small bovine luteal cells synthesized mainly 19-norT and formation was also inhibited by trilostane and cyanoketone.
In addition to 19-norA, an unknown metabolite, formed in low amounts by large porcine luteal cells, appears to be related to another steroid which accumulated at high inhibitor concentrations; it may represent 5(10)-oestrene-3,17-dione postulated as a putative intermediate formed during 19-norsteroid biosynthesis.
Journal of Endocrinology (1991) 129, 233–243
Shengyi Sun, Elissa W P Wong, Michelle W M Li, Will M Lee and C Yan Cheng
During spermatogenesis, spermiation takes place at the adluminal edge of the seminiferous epithelium at stage VIII of the epithelial cycle during which fully developed spermatids (i.e. spermatozoa) detach from the epithelium in adult rat testes. This event coincides with the migration of preleptotene/leptotene spermatocytes across the blood–testis barrier from the basal to the apical (or adluminal) compartment. At stage XIV of the epithelial cycle, Pachytene spermatocytes (diploid, 2n) differentiate into diplotene spermatocytes (tetraploid, 4n) in the apical compartment of the epithelium, which begin meiosis I to be followed by meiosis II to form spermatids (haploid, 1n) at stage XIV of the epithelial cycle. These spermatids, in turn, undergo extensive morphological changes and traverse the seminiferous epithelium until they differentiate into elongated spermatids. Thus, there are extensive changes at the Sertoli–Sertoli and Sertoli–germ cell interface via protein ‘coupling’ and ‘uncoupling’ between cell adhesion protein complexes, as well as changes in interactions between integral membrane proteins and their peripheral adaptors, regulatory protein kinases and phosphatases, and the cytoskeletal proteins. These precisely coordinated protein–protein interactions affect cell adhesion and cell movement. In this review, we focus on the 14-3-3 protein family, whose members have different binding partners in the seminiferous epithelium. Recent studies have illustrated that 14-3-3 affects protein–protein interactions in the seminiferous epithelium, and regulates cell adhesion possibly via its effects on intracellular protein trafficking and cell-polarity proteins. This review provides a summary on the latest findings regarding the role of 14-3-3 family of proteins and their potential implications on spermatogenesis. We also highlight research areas that deserve attentions by investigators.
WM Lee, M Diaz-Espineira, JA Mol, A Rijnberk and HS Kooistra
The pulsatile secretion patterns of GH were investigated in seven beagle bitches by collecting blood samples every 10 min for 6 h during euthyroidism and 1.5 years after induction of primary hypothyroidism. Hypothyroidism was induced by surgical removal of the thyroid gland and subsequent destruction of any remnant thyroid tissue by oral administration of sodium [(131)I]iodide. Some of the physical changes observed in the dogs with primary hypothyroidism mimicked those of acromegaly. During both euthyroidism and hypothyroidism GH was secreted in a pulsatile fashion. The mean (+/-s.e.m. ) basal plasma GH concentration was significantly higher (P=0.003) in the hypothyroid state (4.1+/-1.6 microg/l) than in the euthyroid state (1.2+/-0.4 microg/l). Likewise, the mean area under the curve (AUC) for GH above the zero-level during hypothyroidism (27.0+/-10.0 microg/lx6 h) was significantly higher (P=0.004) than that during euthyroidism (11.7+/-2.0 microg/l x 6 h). The mean AUC for GH above the baseline was significantly lower (P=0.008) during hypothyroidism (2.4+/-0.8 microg/l x 6 h) than during euthyroidism (4.5+/-1.8 microg/lx6 h), whereas there was no significant difference in GH pulse frequency. The mean plasma IGF-I level was significantly higher (P<0.01) in the hypothyroid state (169+/-45 microg/l) than in the euthyroid (97+/-15 microg/l). The results of this study demonstrate that primary hypothyroidism in dogs is associated with elevated basal GH secretion and less GH secreted in pulses. This elevated GH secretion has endocrine significance as illustrated by elevated plasma IGF-I levels and some physical changes mimicking acromegaly. It is discussed that the increased GH release in hypothyroid dogs may be the result of the absence of a response element for thyroid hormone within the canine pituitary GH gene and alterations in supra-pituitary regulation.
S. PORS NIELSEN, B. BUCHANAN-LEE, E. W. MATTHEWS, J. M. MOSELEY and C. C. WILLIAMS
Synthetic porcine calcitonin (α-calcitonin) and its methionine-sulphoxide derivative (β-calcitonin) were given by intravenous infusion to conscious male rats. α-Calcitonin inactivated by performic acid oxidation was used as a control.
Microgram doses of α-calcitonin produced a dose-dependent decrease in the renal excretion of magnesium. The effect was not due to a secondary release of parathyroid hormone since it was also seen in parathyroidectomized animals.
A marked increase in the renal excretion of inorganic phosphate, sodium and potassium preceded the change in magnesium excretion in parathyroidectomized rats. It is concluded that the phosphaturia and natriuresis previously described after administration of extracted calcitonin preparations are true effects of the hormone.
The effect of β-calcitonin was indistinguishable from that of α-calcitonin.