The trace element selenium (Se) is capable of exerting multiple actions on endocrine systems by modifying the expression of at least 30 selenoproteins, many of which have clearly defined functions. Well-characterized selenoenzymes are the families of glutathione peroxidases (GPXs), thioredoxin reductases (TRs) and iodothyronine deiodinases (Ds). These selenoenzymes are capable of modifying cell function by acting as antioxidants and modifying redox status and thyroid hormone metabolism. Se is also involved in cell growth, apoptosis and modifying the action of cell signalling systems and transcription factors. During thyroid hormone synthesis GPX1, GPX3 and TR1 are up-regulated, providing the thyrocytes with considerable protection from peroxidative damage. Thyroidal D1 in rats and both D1 and D2 in humans are also up-regulated to increase the production of bioactive 3,5,3′-tri-iodothyronine (T3). In the basal state, GPX3 is secreted into the follicular lumen where it may down-regulate thyroid hormone synthesis by decreasing hydrogen peroxide concentrations. The deiodinases are present in most tissues and provide a mechanism whereby individual tissues may control their exposure to T3. Se is also able to modify the immune response in patients with autoimmune thyroiditis. Low sperm production and poor sperm quality are consistent features of Se-deficient animals. The pivotal link between Se, sperm quality and male fertility is GPX4 since the enzyme is essential to allow the production of the correct architecture of the midpiece of spermatozoa. Se also has insulin-mimetic properties, an effect that is probably brought about by stimulating the tyrosine kinases involved in the insulin signalling cascade. Furthermore, in the diabetic rat, Se not only restores glycaemic control but it also prevents or alleviates the adverse effects that diabetes has on cardiac, renal and platelet function.
The biological roles ascribed to selenium (Se) include the prevention of cancer (Combs & Lu 2001) cardiovascular disease (Rayman 2002, Beckett et al. 2004) and viral mutation (Beck 2001). In addition the trace element is essential for optimal endocrine and immune function and moderating the inflammatory response (McKenzie et al. 2002b, Arthur et al. 2003).
These biological actions are mediated in most cases through the expression of at least 30 selenoproteins coded by 25 selenoprotein genes in humans (Kryukov et al. 2003). The importance of Se to endocrine systems is highlighted by the fact that many endocrine tissues have evolved mechanisms to maintain relatively high concentrations of Se even when there is severe dietary deficiency. This review will focus on the various mechanisms by which Se may modify thyroid function, fertility and glucose homeostasis.
The current recommended dietary intake of Se in humans is between 55 and 75 μg per day (Rayman 2000). These amounts are based on the Se intake that maximally induces the activity of glutathione peroxidase (GPX) in plasma or erythrocytes. The anticancer properties of Se operate at intakes of the order of 200 μg/day, suggesting that a re-appraisal of dietary Se intake may be useful. Many areas of the globe including the UK have Se intakes that are significantly below the current recommended intake, leading to sub-maximal expression of GPX and other selenoproteins in blood and tissues (Brown et al. 2000, Rayman 2002).
The selenoproteins incorporate Se co-translationally as a selenocysteine residue that is fully ionized at physiological pH and acts as a very effcient redox catalyst. Of the up to 30 selenoproteins that have been characterized or identified bioinformatically (Table 1), six are GPXs, three are iodothyronine deiodinases (Ds) and three are thioredoxin reductases (TRs; Kryukov et al. 2003). Selenoprotein P is quantitatively the major selenoprotein in plasma and has both antioxidant and transport roles (Burk et al. 2003, Hill et al. 2003, Mostert et al. 2003). Thus Se can influence at least three broad areas of cell biochemistry, namely antioxidant function, redox status and thyroid hormone metabolism.
The TRs, with thioredoxin as a substrate and NADPH as a cofactor, form a powerful dithiol–disulphide oxidoreductase system that regulates the cellular redox state of cells and may also protect against oxidative stress (Holmgren 2001, Kryukov et al. 2003). The system is also involved in many diverse cellular functions including cell signalling, regulation of cell growth and inhibition of apoptosis (Saitoh et al. 1998, Rundlof & Arner 2004). A range of diseases in humans are suspected to be related to the activity of TR and the enzyme has become a major target for the development of therapeutic drugs (Becker et al. 2000, Gromer et al. 2004).
At least six mammalian GPX isoenzymes have been described (Table 1). Cytosolic enzyme (GPX1) is expressed by all cells types in mammals. Extracellular GPX (GPX3) is a secreted glycoprotein that is the second most abundant selenoprotein in plasma while phospholipid hydroperoxide GPX (GPX4) can specifically reduce phospholipid hydroperoxides (Imai & Nakagawa 2003) and may be involved in moderating apoptotic cell death (Nomura et al. 2001) and sperm maturation.
Thyroid hormone deiodinases
Three iodothyroinine deiodinases (D1, D2 and D3) have been identified. All are integral membrane proteins of 29–33 kDa, sharing 50% sequence identity. Each has a selenocysteine residue at the active centre that confers the high catalytic activity of the enzymes. The deiodinases have differing substrate specificities and tissue distribution (Bianco et al. 2002). The enzymes can catalyse the removal of iodine from the 5 or 5′ positions of iodothyronine substrates and in doing so have an important regulatory role in the activation and inactivation of the thyroid hormones in all tissues (Fig. 1).
Recently details of the protein structure of the deiodinases has become available. The extra-membrane portion of the deiodinases belongs to the thioredoxin-fold superfamily, a superfamily that also includes the GPXs. Furthermore, a large deiodinase region embedded in the thioredoxin fold shares strong similarities with the active site of iduronidase, a member of the clan GH-A-fold glycoside hydrolases. The substrates for the deiodinases (iodothyronines such as thyroxine (T4), reverse tri-iodothyronine (rT3) and 3,5,3′-tri-iodothyronine (T3)) and substrates for the iduronidase (sulphated α-l-iduronic acid) are structurally similar, having O-linked hexagonal rings substituted with bulky groups lying ortho to the linker. It would thus appear that the deiodinases have iduronidase-like sequences embedded in the selenocyteine-containing thioredoxin fold that are critical for iodothyronine binding. The predicted protein structure of the deiodinases together with site-directed mutagenesis experiments have allowed the elucidation of some of the critical amino acids that are responsible for the differences in substrate specificity and enzyme kinetics observed between D1, D2 and D3 (Callebaut et al. 2003).
The deiodinases show marked tissue- and time-specific expression during the foetal period and may be important regulators of this maturation process by modifying the supply of T3 to T3-responsive genes (Hume et al. 2001, Kester et al. 2004). However, the ontogeny of the deiodinases and their tissue distribution is quite different in rats than humans, thus data obtained from rat models cannot always be appropriately applied to humans.
Regulation of selenoprotein expression
The predominant control of selenoprotein expression is Se supply with a strict hierarchy of selenoprotein expression when Se supply is limited. Endocrine tissues are well adapted to maintaining selenoprotein expression in Se deficiency and within any single tissue the expression of the deiodinases, GPX4 and TRs is maintained at the expense of GPX1, which is quickly lost (Behne et al. 1988, Bermano et al. 1995, 1996, Crosley et al. 2003). Oxidative stress induces TR1 and GPX (Sun et al. 1999) and isothiocyanates such as sulforaphane induce TR1 (Zhang et al. 2003). Activation of second-messenger pathways also modifies the expression of specific selenoproteins in a tissue-specific manner (Beech et al. 1995, Howie et al. 1995, 1998, Anema et al. 1999).
Se and thyroid function
The thyroid contains more Se per gram of tissue than any other organ (Dickson & Tomlinson 1967) and Se, like iodine, is essential for normal thyroid function and thyroid hormone homeostasis. Labelling cultured human thyrocytes with [75Se]selenite reveals numerous selenoproteins with TRs and GPXs predominating (Fig. 2).
Thyroid hormone synthesis
Synthesis of thyroid hormone requires iodination of tyrosyl residues on thyroglobulin which is stored in the lumen of the thyroid follicle. This iodination is catalysed by thyroid peroxidase (TPO) and requires the generation of high H2O2 concentrations which are potentially harmful to the thyrocyte. The generation of H2O2 appears to be the rate-limiting step in thyroid hormone synthesis and is regulated through the action of thyroid-stimulating hormone (TSH) via a complex network of interacting, second-messenger systems (Corvilain et al. 1991, 1994, Raspe et al. 1991, Kimura et al. 1995). The iodination of thyroglobulin and generation of H2O2 takes place on the luminal surface of the apical membrane of the thyrocyte (Fig. 3). This organization allows the H2O2 formed on the surface of the thryocyte to be made readily available for uses iodination reactions, while any harmful H2O2 that diffuses into the thryocyte can be degraded by the intracellular GPX, TR and catalase systems (Ekholm & Bjorkman 1997).
GPX3 as a potential regulator of thyroidal hormone production
The thyrocyte is capable of synthesizing and secreting GPX3 in a controlled manner. In basal conditions, cultured human thyrocytes secrete GPX3 and this secretion is prevented by the co-addition of the calcium ionophore A23187 and phobol ester (PMA), known stimulators of production (Howie et al. 1995). This raises the H2O2 intriguing possibility that GPX3 may provide an additional mechanism for controlling thyroid hormone synthesis through regulating the concentration of H2O2 in the follicular lumen. Thus when increased thyroid hormone production is signalled through the TSH receptor, increased synthesis of H2O2 at the apical membrane is accompanied by impaired secretion of GPX3 and thus diminished degradation of the peroxide. These concurrent changes would have the effect of amplifying the concentration of H2O2 available for iodination of thyroglobulin. When thyroid hormone synthesis is not strongly signalled, thyroid hormone production would be prevented both by diminished H2O2 synthesis and by active secretion of GPX3 across the apical membrane that would promote degradation of H2O2 produced in the basal state.
Se as an antioxidant in the thyroid
The thyrocyte is continually exposed to potentially toxic concentrations of H2O2 and lipid hydroperoxides. The cytotoxic effects of H2O2 on thyroid cells include caspase-3-dependent apoptosis that occurs at H2O2 concentrations that are insuffcient to induce necrosis. In Se deficiency the apoptotic response to H2O2 is increased (Demelash et al. 2004). When Se intake is adequate the intracellular GPX and TR systems protect the thyrocyte from these peroxides. Furthermore, in iodine deficiency or Grave’s disease, where hyperstimulation of the TSH receptor signals increased H2O2 production, activation of the calcium-phosphoinositol cascade stimulates GPX1 production and particularly TR1 (Fig. 2; Howie et al. 1998) thus providing an up-regulation of antioxidant protection (Fig. 3).
Se as a regulator of T3 production
The deiodinase D1 is the major isoform in liver, kidney, thyroid and pituitary. It can catalyse 5 or 5′-monodeiodination and thus can convert T4 to the inactive metabolite rT3 or the active isomer T3. The important physiological roles of D1 include providing an important source of plasma T3 and degrading rT3 and T3 sulphate.
There are species-specific differences in the expression of D2. In rats, D2 is predominantly expressed in brain, brown adipose tissue and pituitary with little or no expression being found in thyroid, skeletal muscle or heart. In humans, Northern blotting or activity measurements suggest that D2 expression occurs in thyroid, heart, brain, spinal cord, skeletal muscle, placenta, pituitary and keratinocytes and to some extent in kidney and pancreas. D2 can only perform 5′-deiodination reactions and the enzyme has a short half-life (<1 h), which is controlled by ubiquitination. Physiologically, D2 provides an intracellular source of T3 to specific tissues and, particularly in humans, it also appears to provide a significant source of plasma T3. Among its other physiological roles, D2 is critical for regulating brain development, TSH secretion in the pituitary and adaptive thermogenesis in brown adipose tissue. D3 is found in the plasma membrane of brain, placenta and foetal liver and performs only 5-monodeiodination (Fig. 1; Baqui et al. 2003). The biochemistry, cellular and molecular biology and physiological roles of the deiodinases have been reviewed extensively (St Germain 2001, Bianco et al. 2002).
In Se-suffcient rats, hepatic D1 provides an important source of circulating T3 yet in Se-deficient animals, when hepatic D1 expression falls to approximately 10% of that in Se-adequate animals, plasma T3 concentrations are largely maintained. The maintenance of plasma T3 in these Se-deficient animals arises from an adaptive response driven by a rise in TSH that in turn signals increased de novo synthesis of T3 on thyroglobulin and also increased expression of thyroidal D1 that promotes high rates of T4-to-T3 conversion (Beckett et al. 1987, Arthur et al. 1990). In humans, thyroidal D2 may also contibute to maintaining plasma T3 in Se deficiency. The paradoxical increase in thyroidal D1 found in Se-deficient rats is made possible because the gland retains adequate amounts of the trace element in dietary Se deficiency (Bermano et al., 1995). Not all animal species express thyroidal D1 and theoretically those lacking the enzyme may be less able to maintain plasma T3 concentrations in Se deficiency (Beech et al. 1993). Since D2 expression and T3 production are vital for regulating thermogenesis in brown adipose tissue, Se-deficient animals may show impaired production of D2 and uncoupling protein, with poor survival when subjected to a cold stress (Arthur et al. 1991).
Se and iodine deficiency
In humans, attention has focused on how Se status may modify the effects of iodine deficiency and the pathogenesis of endemic myxoedematous cretinism (reviewed by Corvilain et al. 1993, Arthur et al. 1999, Rundlof & Arner 2004), a condition associated with severe hypothyroidism, thyroid involution and stunted growth. Some epidemiological studies have suggested that the increased generation of H2O2 caused by the high TSH associated with iodine deficiency, together with a loss of thyroidal selenoperoxidase activity due to concurrent Se deficiency, produces the marked thyroid atrophy found in myxoedematous cretinism. In contrast, if Se supply is adequate thyroid destruction may be prevented due to the maintenance of thyroidal GPX and TR. The importance of Se in protecting the thyroid from oxidative damage is supported by rodent experiments (Contempre et al. 1995). These animal studies suggest also that myxoedematous cretinism may also result from a Se-deficiency-induced disturbance in the inflammatory response (Contempre et al. 1996). More recent reports have failed to provide convincing support for this hypothesis and the possible roles of other additional factors such as dietary thiocyanates must again be considered (Moreno-Reyes et al. 1998).
Se and autoimmune thyroid disease
The links between Se deficiency, altered immune function and inflammation have prompted studies in humans to examine if Se supplementation can modify auto-antibody production in patients with chronic autoimmune thyroiditis. Double-blind, randomized, placebo-controlled trials using daily Se supplements of 200 μg selenite produced a significant decline in TPO antibody (TPOAb) concentration accompanied in some patients by an improved ultrasound echogenicity of the thyroid (Gartner et al. 2002, Gartner & Gasnier 2003). This effect of Se on TPOAb concentration has been demonstrated both in an area of Germany with marginal dietary iodine and Se intakes (Gartner et al. 2002) and in an area around Athens where iodine and Se intakes were close to requirement (Duntas et al. 2003). In these studies Se supplements had no significant effect on the concentration of thyroglobulin antibodies or the concentration of TSH or thyroid hormone concentrations. The mechanism by which Se exerts effects on TPOAb production is likely to be due to the ability of high doses of Se to modify the inflammatory and immune responses (reviewed in (McKenzie et al. 2002a, 2002b). Further work is required to examine what long-term clinical benefits Se supplementation may have when given to patients with autoimmune thryoiditis. It would be important to determine if Se supplementation could modify the course of Graves’ disease since there is one report of Se supplements decreasing the titre of TSH receptor antibodies in such patients (Vrca et al. 2004).
Se and fertility
Se and fertility in males
The testes contain high concentrations of Se and work with selenoprotein P-knockout mice indicates that Se is essential for testicular function (Hill et al. 2003). Low sperm production and poor sperm quality including impaired motility with flagella defects localized primarily to the midpiece have been a consistent feature in Se-deficient animals (Watanabe & Endo 1991, Behne et al. 1996) but it is only relatively recently that an explanation for this phenomenon has been recognized and studies extended to humans (Maiorino et al. 1999, Flohe et al. 2001, Foresta et al. 2002, Maiorino & Ursini 2002).
GPX4 provides the pivotal link between Se, sperm quality and male fertility since GPX4 is essential to allow the production of the correct architecture of the midpiece of spermatozoa. In testes GPX4 is present as three isoforms that are derived from the same gene and are found in the cytosol, mitochondria and nucleus. The nuclear form differs from the other forms in having an arginine-rich N-terminus (Puglisi et al. 2003, Tramer et al. 2004a, 2004b). In the developing spermatozoa GPX4 probably provides protection from harmful reactive oxygen species but during sperm maturation the selenoenzyme takes on a structural role. In the midpiece of mature sperm GPX4 is a major component present as a polymeric form with no enzymic activity. Thus during sperm development GPX4 first appears in pachytene spermatocyte stages VII–X and its expression gradually increases through the stages of round spermatids with peak levels being found in elongating spermatids. As the spermatozoa mature there is a marked redox switch that is accompanied by an almost complete loss of glutathione. As this occurs reduction of peroxides catalysed by GPX4 in the spermatozoa utilizes protein thiols as an alternative donor substrate to glutathione. This results in GPX4 forming covalent cross-links with itself and other proteins that ultimately build up as a keratin-like material. This material is largely incorporated into the helix of mitochondria in the midpiece of spermatozoa that ultimately forms up to 50% of the capsule material.
Many human subjects who have infertility due to low sperm count and poor sperm quality have marked decreases in polymerized GPX4 in their sperm. The loss in GPX4 is particularly marked in oligoasthenozoospermic specimens (Foresta et al., 2002). It is unlikely that dietary Se deficiency alone could be the cause since in most patients other pathologies causing infertility could be identified. However, one study performed in Scotland (where Se intakes are below requirements at only 30–40 μg/day) showed the sperm quality and fertility of the patients improved after Se supplementation (Scott et al. 1998). Further research is clearly required to determine the association between male fertility in humans and the range of Se intakes that are seen throughout the world.
Information regarding the importance of Se in female reproduction is sparse; however, experiments in rodents suggests that Se deficiency has no significant effect on female reproduction even in sixth-generation animals (Bates et al. 2000). In humans a significant depletion of Se in follicular fluid of women with unexplained fertility has been described (Paszkowski et al. 1995). A decrease in the concentration of serum Se occurs throughout normal pregnancy but women with first-trimester miscarriages have significantly lower serum Se concentrations than women in the first trimester whose pregnancies went to term (Barrington et al. 1996). In vitro studies using bovine granulosa cells obtained from different-sized follicles found that Se significantly stimulated the proliferation of cells from small follicles and augmented the stimulatory effects of gonadotrophins in the same cells. Se also enhanced oestradiol production (Basini & Tamanini 2000). The relevance of these observations to humans is not known.
Se and diabetes
Se has insulin-mimetic properties in vitro and in vivo. Insulin-stimulated glucose metabolism is impaired in adipocytes isolated from Se-deficient rats (Souness et al. 1983). An insulin-like effect of Se in cultured rat adipocytes include stimulating glucose transport, phosphodiesterase activity and ribosomal S6 protein phosphorylation (Ezaki 1990). When administered to streptozotocin-diabetic rats, Se restores glycaemic control and modifies the activity of a range of enzymes involved in hepatic glycolysis and gluconeogenesis. These changes are not linked to changes in insulin levels (McNeill et al. 1991, Ghosh et al. 1994, Becker et al. 1996, Battell et al. 1998, Mukherjee et al. 1998, Ghose et al. 2001). In animal models, Se also prevents or alleviates the adverse effects that diabetes has on cardiac (Battell et al. 1998, Ayaz et al. 2002, 2004), renal and platelet function (Douillet et al. 1996a, 1996b). We are unaware of any publications describing Se-supplementation trials in diabetic humans. Se may exert these insulin-like effects on glucose metabolism by stimulating the tyrosine kinases involved in the distal signalling of the insulin signalling cascade (Pillay & Makgoba 1992, Stapleton et al. 1997, Hei et al. 1998, McKenzie et al. 2002a).
The role of Se in the aetiology of several diseases and the impact that Se status has on several endocrine systems has now been established. The multiple roles that selenoproteins play in cell signalling systems and in modifying the immune response, cell growth and cell survival suggest that there are more roles waiting to be discovered for Se in endocrine systems. Se may also have a role in treating malignancies that are responsive to endocrine manipulation. For example Se is effective at reducing the risk of prostatic cancer possibly by inhibiting tumour cell growth via down-regulation of androgen receptor expression (Dong et al. 2003, Dong et al. 2004).
Mammalian selenoproteins and their functions
|Glutathione peroxidases (GPXs)|
|GPX1||Antioxidant in cell cytosol; Selenium store?|
|GPX2||Antioxidant in GI tract|
|GPX3||Antioxidant in extracellular space and plasma|
|GPX4||Membrane antioxidant; structural protein in sperm; apoptosis?|
|Thioredoxin reductase (TRs)||Multiple roles including dithiol-disulphide oxoreductase Detoxifies peroxides, reduces thioredoxin (control of cell growth); maintains redox state of transcription factors|
|TR1||Mainly cystosolic, ubiquitous|
|TR2||Expressed by testes|
|Type D1 and D2||Converts thyroxine (T4) to bioactive 3,5,3′-tri-iodothyronine (T3)|
|Type D1 and D3||Converts thyroxine (T4) to bioinactive 3′, 3′, 5′ reverse T3|
|Selenoprotein P||Selenium-transport protein. Antioxidant on endothelium|
|Selenoprotein W||Antioxidant in cardiac and skeletal muscle?|
|Selenophosphate synthetase (SPS2)||Synthesis of selenophosphate for selenoprotein synthesis.|
|15 kDa Selenoprotein (Sep 15)||Protects against cancer?|
|H, I, K, M, N, O, R, S, T, V||Role largely unknown|
J R A’s lab is funded by the Scottish Executive Environment and Rural Affairs Department (SEERAD). The authors declare that there is no conflict of interest that would prejudice the impartiality of this scientific work.
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