Involvement of copper in female reproduction - CiteSeerX

Vol. 7, No. 3

193 REVIEW

Involvement of copper in female reproduction Anna Michaluk1 and Kazimierz Kochman The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Jabłonna, Poland Received: 1 June 2007; accepted:10 October 2007 SUMMARY Copper (Cu) is one of the essential trace metals which are necessary in maintaining the functioning of living organisms. The current knowledge on the role of copper in animal reproduction is presented in the article. Our studies have shown that complexes of copper (Cu2+) with gonadotropin-releasing hormone (GnRH) are even more effective in the release of LH than native GnRH. Moreover, Cu-GnRH is more potent in inducing in vivo release of FSH than LH. Copper complexes with GnRH interact with GnRH receptors (GnRHR) and modulate intracellular signaling in the gonadotrope cells of the anterior pituitary. Copper plays also a significant role in maintaining normal fetus development in mammals. Reproductive Biology 2007 7 3: 193-205. Key words: copper, GnRH, Cu-GnRH, hypothalamus, anterior pituitary, fetus

INTRODUCTION Copper (Cu) is an important trace element necessary for living organisms to function normally. It exists in three oxidation states: cuprous (Cu+), Corresponding author: The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna n. Warsaw, Poland; e-mail: [email protected] 1

Copyright © 2007 by the Society for Biology of Reproduction

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Copper and female reproduction

cupric (Cu2+) and cuprum (Cu0). In biological systems, copper primarily exists as Cu2+. The ability of copper to easily accept and also donate electrons explains its essential role in oxidation-reduction (redox) reactions [53]. It is also a critical functional component of a number of enzymes known as cuproenzymes. Copper affects the activity of cuproenzymes both as a cofactor and as an allosteric component. The most important cuproenzymes are: 1/ cytochrome c oxidase, a terminal enzyme of the electron transport system which reduces oxygen and generates a trans-membrane proton gradient during respiration; [17]; 2/ superoxide dismutase which catalyzes dismutation of superoxide anion [58]; 3/ ceruloplasmin which catalyzes the oxidation of ferrous ions, Fe2+ to ferric ions, Fe3+ [14, 41, 69]; 4/ protein-lysine-6-oxidases e.g. lysyl oxidase which participate in cross-linking of elastin and collagen fibres [23, 54, 55]; 5/ dopamine-β-monooxygenase which catalyzes the conversion of dopamine to noradrenaline [26, 40]; and 6/ peptide-α-amidating monooxygenase which is responsible for amidation at carboxy-terminal amino acid in hypothalamic and pituitary hormones [46, 48, 49]. Copper easily reacts with both individual amino acids and proteins containing histidine and cysteine. Complexes of Cu2+ with amino acids or peptides are able to bind to DNA forming Cu- aminoacid-DNA complexes which in consequence leads to constant change of the structure and biochemical properties of DNA. Cellular copper concentration may influence the synthesis rate of proteins by enhancing or inhibiting the transcription of specific genes. Modulation of transcription [47] is exerted by copper’s influence on the properties of the transcription factors. Copper is also necessary for red blood cell formation, and normal iron and lipid metabolism [28, 51]. Reduced copper availability during the development of the central nervous system can cause damage to it [16]. However, excess copper is highly toxic and can lead to oxidative damage of proteins, lipids and nucleic acids. Two human recessive disorders are now known; the X-linked Menkes syndrome which leads to abnormal sequestration of copper [36] in the intesine and kidney [37, 38, 63] and the autosomal recessive Wilson disease [67] characterized by the toxic accumulation of copper in the liver and brain [70]. Mosaic mutant mice [39, 56, 57] which exhibit symptoms similar to humans with Menkes disease in clinical phenotype and biochemical

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abnormalities, are a good animal model to study the disease [21, 50, 68]. Further research on copper cellular transport and metabolism may bring new possibilities for treatment and prevention of the disease. In 1936, Fevold et al. [20] first discovered that ovulation could be induced by intravenous injection of copper salts. Since then other researchers have found that systematic administration of copper salt to female rabbits [25, 59, 60, 61] and ewes [43] leads to ovulation through its action at the level of the hypothalamus. Copper ions have been shown to stimulate both basal and GnRH-stimulated LH release from pituitary cells of immature female rats in vitro [24]. Copper is also an extremely potent releaser of GnRH from isolated hypothalamic granules [9], which supports the hypothesis that copper influences GnRH neurons and copper action only occurs in GnRH granules. In contrast, Kozłowski et al. did not observe any ovulatory effect of copper salts in rats [33]. The paper summarizes the role of copper in several aspects of mammalian reproduction. Biosynthesis and realease of GnRH Neurohormone GnRH is a key factor in the stimulation of biosynthesis and release of the gonadotropins from the anterior pituitary. It is synthesized in GnRH neurons whose cell bodies are predominantly located within the preoptic area of the hypothalamus. A prohormone molecule synthesized on the neuronal ribosomes is further processed to produce a biologically active decapeptide form of GnRH [29]. The most important parts of this process are: 1/ shortening the peptide chain; 2/ amidation of glycine at position 10 of the peptide sequence; and 3/ cyclization of glutamine at position 1 to pyro-glutamic acid. Peptydylglycine α–amidating monooxygenase (PAM) catalyzes the reaction of α-amidation of C-terminal peptidyl-glycine. Consequently, inactive peptides and protein hormones are transformed into their bioactive forms both in the hypothalamus and pituitary [46, 48]. The PAM is largely localized to the trans-Golgi network region (TGN) and is also one of the few membrane proteins associated with peptide-containing secretory granules (fig. 1).

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Figure 1. Scheme of intracellular route of GnRH maturation. TGN: trans-Golgi network; PAM: peptidylglycine α–amidating monooxygenase.

The amidation reaction proceeds in a two-step reaction and is catalyzed by two enzymes: peptidylglycine-α-hydroxylating-monooxygenase (PHM) and peptidylglycine-α-hydroxyglycine α-amidating lyase (PAL) which together form PAM. The first step of the amidation is catalyzed by PHM whereas the second step is catalyzed by PAL. The PHM contains two copper ions that cycle through cupric (Cu2+) and cuprous (Cu+) oxidation states. Such structure suggests that the PHM reaction precedes the activation of substrate by copper–bound oxygen spaces. Enzyme PAM also contains one zinc atom which can connect with PAL. The activity of the latter can be abolished by such chelating agents as silver (Ag) and EDTA and restituted by additional molar excess of divalent metals (fig. 2). The activity of PAM depends on molecular oxygen, ascorbate and copper. Reduced concentration of PAM and ascorbate can make αamidation the limiting step in the synthesis of bioactive peptide. Copper plays an essential role in amidation of GnRH and cannot be substituted by other divalent metals [49]. Copper is also important for dopamine β–monooxygenase (DBM) activity which catalyzes hydroxylation of dopamine to noradrenaline, an essential neurotransmitters involved in GnRH release. Purifed enzyme contains one atom of copper per DBM subunit; it does not form a strong bond with the protein and can be removed by chelating agents. Its activity can


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Figure 2. GnRH prohormone amidation reaction crucial for maturation and physiological activity of the GnRH decapeptide. PHM: peptidylglycine-α-hydroxylating-monooxygenase; PAL: peptidylglycine-α-hydroxyglycine α-amidating lyase.

be completely recovered by a new addition of copper [49]. Requirements for noradrenaline synthesis are presented below. DOPAMINE

2Cu, O2, ascorbate, DBM

NORADRENALINE

The DBM catalyzes the transformation of dopamine to noradrenaline in a similar way to the action of PHM. Indeed, these two enzymes possess two copper atoms incorporated into their active centres which enables them to exhibit catalytic competence of the reduced copper both to form a radical intermediate and to transfer O2 to an activated aliphatic carbon in the enzyme molecule. The main steps are summarized as follows: 1/ two copper ions are reduced from Cu2+ to Cu+ by electron transfer from two ascorbates oxidized to semidehydroascorbates, 2/ molecular oxygen, not water oxygen, is incorporated into PHM or DBM product. Copper participates in the modulation of these different neurotransmiter systems. It was shown that copper ions could also modulate the activity of the glutamate receptor as well as inhibit voltage-gated calcium channels [65]. In that way it may influence the complex neural transmission network leading to the release GnRH from the median eminence nerve endings.

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In a series of experiments Barnea et al. [1] have shown the importance of copper in maintaining the stability of hypothalamic GnRH-containing granules and suggested the mechanism of GnRH release both from isolated granules and granules from hypothalamic explants [12]. Incubation of isolated GnRH granules with Cu-ATP and Mg-ATP revealed that CuATP not only stimulated GnRH release independently on KCl but also was more effective than Mg-ATP. It seems that Cu-ATP and Mg-ATP may act through different mechanisms with respect to GnRH release [9] and secretory granules may be the site of the copper action. The complexes of copper with amino acids such as histidine and cysteine significantly stimulated GnRH release from isolated granules, and the complex of Cu-His was the most potent [1]. GnRH release was also shown to be temperature-dependent and was inhibited by an addition of dithiothreitol (DTT). The authors suggest that copper binds to peptide or protein and oxidizes thiol groups in the GnRH granules leading to a change in membrane permeability and subsequently inducing the release of GnRH [52]. Characteristics of this release are: ligand and metal specificity, the involvement of a limited number of copper interactive sites, and a lack of dependence on extracellular calcium [10]. Moreover, chloride transport is also essential for Cu-His stimulated release of GnRH [11]. Chelated copper stimulated GnRH release also from median eminence (ME) explants [11, 12]. Copper significantly augmented GnRH-releasing activity of prostaglandin E2 (PGE2; [4, 7]) It was shown that copper could markedly amplify PGE2 stimulation of GnRH release from median eminence explants [3] and this process depends on extracellular calcium [5]. A similar ligand specificity was observed in copper stimulation of GnRH release both from ME explants and isolated granules [6]. Besides copper involvement in the maturation of GnRH prohormone to active peptide, GnRH release from secretory granules, biosynthesis of noradrenaline, and intracellular metabolism of neurons containing GnRH, this trace metal participates also in cellular respiration, the defense against excess of free radicals, and the metabolism of intracellular iron.


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Regulation of gonadotropin release A release of LH and FSH from the anterior pituitary is a consequence of GnRH binding with a specific receptor on the gonadotrope cell membrane. Calcium ions are crucial intracellular mediators in the gonadotropin release. Also the depolarization of the cell membrane in a manner dependent on calcium and potassium ions can result in LH release [64]. Hazum [24] found that cupric ions affect the pituitary resulting in a high release of LH through calcium dependent mechanisms. Copper ions modify the conformation of the GnRH receptor to the plasma membrane, and cause mobilization of ionic calcium, and expulsion of the content of the gonadotropin secretory granule to the extracellular space. Our recent work showed that copper and nickel salts [2] had no effect on LH release from the porcine pituitary cells in vitro while the Cu-GnRH complex exhibited a significant stimulatory effect [30, 42]. Moreover, the stimulatory effect of Cu-GnRH was more expressed than that of native GnRH. Cu-GnRH was able to evoke FSH release even more effectively than LH release [32]. The collected data indicate that Cu-GnRH is more effective than native GnRH in stimulation of LH secretion both in vivo [30, 31] and in vitro [42]. The Cu-GnRH was found to bind to the GnRH receptor with a higher affinity than native neurohormone [15, 31]. Interestingly, in porcine gonadotrophic cells, the copper-GnRH complexes induced signaling different than that of native GnRH, with no effect on IP3 accumulation but with a stimulatory action on cAMP synthesis [8, 32]. This data suggest that LH release in response to metal-GnRH complexes may be the result of cAMP production. On the other hand, the release of LH in response to GnRH does not require the production or involvement of cAMP [13] and/or cAMP does not have an intermediate role in GnRH-induced gonadotropin release [45]. To establish the potential physiological role of copper in female reproduction further research is necessary especially concerning the presence of Cu-GnRH complexes in the hypothalamus and its possible release into portal blood. Structural, spectroscopic and potentiometric studies showed that very stable GnRH copper complexes are formed below pH 9.5, predominant-

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ly in solutions of the physiological pH [22]. Nevertheless, spectroscopic analysis revealed that the binding mode of GnRH with copper did not change when pH was increased to above 9. According to nuclear magnetic resonance (NMR) spectroscopy study [15, 44], the copper-GnRH complex contained two domains and their reciprocal orientation was dependent on mobility of central glycine. This degree of freedom may help in accommodating this peptide at the receptor site. The role of copper in embryonic development and neonatal metabolism The fetus stores almost ten times more copper per unit of body mass than adult organism. Fetus is also fully dependent on the maternal copper supply and increased copper retention may be partly due to the decreased biliary copper excretion observed during pregnancy. It was shown that copper and ceruloplasmin (a copper-binding protein) concentrations rise significantly during pregnancy, and copper is accumulated mainly during the second and third trimester. At that time many body organs, systems and functions develop. Around 50% of accumulated copper is stored in the liver, primarily as metalothionein. The second site for copper accumulation in the fetus is the brain [62]. Several data revealed that copper uptake into the fetal compartment was dependent both on placental carrier–mediated copper transport from the ceruloplasmin as well as on albumin/ histidine bound copper [66]. Donley et al. [19] reported that in most mammalian offspring at birth, the liver concentration of copper was high, and the mammary gland actively transferred it to milk [19]. Moreover, ceruloplasmin was abundant in the blood plasma and also present in milk [19]. A plasma membrane protein, Ctr1 which binds copper and is present in all tissues of the organism is critically important in the transport of copper [34, 35]. It was shown that copper concentration in fetal liver is negatively correlated with the level of zinc available during pregnancy [27]. Also female rats fed a diet with low zinc during pregnancy and lactation exhibited elevated copper concentration in milk [27]. It was found that this increase was associated with the increased expression of Ctr1 [18]. Nevertheless, the precise mechanism(s) of this up-regulation of milk copper transport during zinc deficiency remains to be elucidated.


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CONCLUSIONS Copper is essential for the normal functioning of all living organisms as a crucial cofactor for enzymes involved in the development of nervous system, respiration and iron metabolism. Copper also plays an important role in female reproduction. It acts at the level of hypothalamus through the modulation of neural activity, modification of GnRH granules stability and modulation of neurohormone release. Our studies have shown that copper complexes with GnRH are more effective than native GnRH in the release of LH and FSH from the anterior pituitary in vivo. In addition, copper influences fetus development; its deficiency leads to different structural and biochemical abnormalities including skeletal defects or changes in cardiac ultrastructure.

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