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Institute for Experimental Endocrinology, Charité-Universitaetsmedizin Berlin, D-10117 Berlin, Germany
Address all correspondence and requests for reprints to: Dr. Lutz Schomburg, Institut fuer Experimentelle Endokrinologie, Charité-Universitaetsmedizin Berlin, Charitéplatz 1, D-10117 Berlin, Germany. E-mail: lutz.schomburg{at}charite.de.
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Abstract |
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Introduction |
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Se deficiency predisposes to a variety of major human pathologies including cancer, infertility, and autoimmune and infectious diseases (3, 11). There are only few data on the influence of gender on selenoprotein expression and Se metabolism in humans and the reports mainly focus on reproductive issues (12). Still, striking sex-associated differences in incidence rates and responsiveness to treatment are observed in the aforementioned conditions, especially in autoimmune diseases (13) and life expectancy (14). Regarding autoimmune thyroid diseases, a 5- to 10-fold higher susceptibility is known for women, compared with men (15). Se supplementation has been shown to significantly reduce antibody load in thyroid-specific autoimmune diseases (16, 17). Unfortunately, influence of gender could not be addressed in these studies because of the limiting number of treated male patients. A large prospective Se supplementation study, the so-called Se and Vitamin E Cancer Prevention Trial, has just been initiated in the United States (18). Unfortunately again, we will not be able to deduce gender-specific aspects of Se function because only men are enrolled, and the primary end point will be the analysis of prostate cancer development. Yet prospective human studies have indicated that the chemopreventive potential of Se is in general higher in men than women, whereas the underlying sex-specific differences in Se metabolism or Se-dependent molecular effects are not identified (19). For these data and other epidemiological and animal experimental findings, Se has even been denoted as the XY nutraceutical (12).
It is the action of selenoproteins that is believed to mediate most biological functions and described health effects of Se within the mammalian organism. Recently transgenic mouse models have been established for the analysis of the physiological role of individual selenoproteins in development, health and disease (20). Unfortunately, data from wild-type and transgenic mice are often presented irrespective of sex.
We realized that phenotypes of selenoprotein P (SePP) knockout mice display clear sex-specific differences and male individuals are affected more severely by Se-dependent deficiency symptoms (21, 22). Ataxia, infertility, episodic seizures, and weight loss had a clear sex bias for males (23, 24). Therefore, we decided to compare Se concentrations and selenoprotein expression in male and female mice to elucidate whether sex-specific differences exist that might underlie the sex-specific phenotype. To analyze the role of sex steroids directly, groups of male and female mice were castrated. Because current data on sex-specific expression of selenoproteins appear inconsistent, we speculated that the observed differences might be dependent on the Se supply.
Indeed, the Se status of the animals turned out to represent a major modifier of the tissue- and sex-specific dimorphisms. Moreover, differences on the mRNA level did not translate linearly into altered selenoprotein activities indicating additional posttranscriptional regulatory mechanisms that modify selenoprotein expression in a sex-specific way. Together these findings help to explain some of the conflicting results on this issue and highlight the need for sex-specific analyses of Se metabolism and Se-dependent health effects.
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Materials and Methods |
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[32P]dCTP was from Hartmann Analytic (Braunschweig, Germany), and [125I]rT3 was from NEN Life Science Products DuPont/PerkinElmer (Koeln, Germany).
Sample collection and preparation of tissue homogenates
Mice (C57BL/6) were raised on regular lab chow (Altromin, Lage, Germany) containing on average 0.24 ppm Se or on a diet with reduced Se content (Se-poor diet C 1045; Altromin) that turned out to contain 0.07 ppm Se. The animals were maintained under automatically controlled 12-h light, 12-h dark cycles and constant temperature of 22 C. At the age of 5 wk, mice were anesthetized, the chest was opened, and blood was taken from the heart. Blood samples were stored on ice for 1 h and then centrifuged (4 C, 10,000 x g, 10 min). Collected serum and removed tissues were frozen in liquid nitrogen and stored for later analysis at –80 C. For enzymatic assays and Se determinations, tissues were pulverized under liquid nitrogen using a dismembrator (Braun, Melsungen, Germany). Aliquots of the tissue powders were homogenized on ice using a glass/Teflon homogenizer in about 5 volumes of buffer [(pH 7.0), containing 250 mM sucrose, 20 mM HEPES, and 1 mM EDTA]. Homogenates were centrifuged at 14,000 x g for 10 min, and supernatants were removed and stored until analysis. The pellets were resuspended in homogenization buffer containing additionally 1 mM dithiothreitol. Protein concentrations were measured by a modified Bradford assay using IgG as standard (Bio-Rad, Muenchen, Germany).
Gonadectomy
Groups of male mice were orchidectomized or sham-operated at the age of 6 wk. Female mice were ovariectomized at the age of 6 wk and 2 wk later, half of them received 200 ng 17-ß-estradiol (E2) sc to restore E2 levels by daily injections for 6 d [ovariectomized (ovx)+E2]. Castrations of both male and female mice were performed under isoflurane inhalation anesthesia with a 1 d postoperative analgetic treatment by paracetamol. The ovx control group received injections of vehicle (peanut oil; Sigma-Aldrich). Mice were killed at the age of 2 months as described above. Animal experiments were conducted in accordance with accepted standards of humane animal care and approved by the local authorities (LaGetSi, Berlin, Germany).
5'-Iodothyronine deiodinase assay
Assays for type 1 iodothyronine deiodinase (Dio1) were performed as described earlier (23). The resuspended pellet fractions were prepared for the activity assay in a reaction mixture containing 20 µg (liver) or 40 µg (kidney) protein. Dithiothreitol (10 mM) served as cofactor and [125I]rT3 was added as tracer (50,000 cpm/assay, specific activity: 25 TBq/mmol). Substrate concentration was 1.0 µM rT3, reaction volume was 100 µl, and reaction proceeded at 37 C for 1 h. Measurements were performed in triplicates. Conditions had been optimized such that final substrate deiodination was less than 15%. Released iodide was recorded, and background-corrected activity was calculated as described. [125I]rT3 was purified free from [125I] by chromatography using Sephadex LH-20 (Sigma-Aldrich) before use.
GPx assay
GPx activities were determined from serum or the supernatants of the tissue homogenates by a coupled enzymatic assay as described earlier (21). Reduced nicotinamide adenine dinucleotide phosphate (NADPH) consumption by glutathione reductase was recorded at 340 nm as a measure of the rate of oxidized glutathione formation in the GPx reaction. GPx activity was determined in a buffer containing 20 mM potassium phosphate (pH 7.0), 0.6 mM EDTA, 0.15 mM NADPH, 4 U glutathione reductase (Sigma-Aldrich), 2 mM glutathione, and 0.1 mM t-butylhydroperoxide. Activity was expressed as amount of NADPH consumed per time and microliter of serum or milligram of protein. Nonspecific NADPH oxidation was determined by inhibiting Se-dependent GPx activity with 100 mM mercaptosuccinate before addition of the peroxide substrate and subtracted from the raw data to obtain the Se-dependent GPx activities.
Northern blot analysis and real-time PCR
Total RNA was isolated from pulverized liver and kidney tissues using peqGOLD TriFast (PEQLAB, Erlangen, Germany) according to the manufacturers’ instructions. Aliquots (20 µg of total RNA) were size fractionated in denaturing formaldehyde/agarose gels, capillary transferred onto nylon membranes (Nytran NY 12 N; Schleicher & Schuell, Dassel, Germany), and analyzed under high-stringency conditions as described earlier (21). cDNA fragments for probe synthesis were amplified by PCR, subcloned into pGEM-T vectors, verified by sequence, isolated, and randomly labeled with [32P]dCTP. After hybridization and extensive washings at 60 C, Northern results were quantified by analysis with a phosphor imager (Cyclone storage phosphor system; Packard BioScience, Dreieich, Germany). The signals obtained for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA were used to calculate relative expression levels. Ubiquitin B signals served as a second independent control.
Transcript levels for two transacting factors involved in selenoprotein translation, i.e. SBP2 and EFSEC, and for two pituitary hormones subject to feedback regulation by steroid hormones, i.e. prolactin (PRL) and GH, were determined by real-time PCR. cDNA synthesis were performed from 1 µg total RNA per sample using random hexamer primers and a first-strand cDNA synthesis kit (Fermentas GmbH, St. Leon-Rot, Germany). Specific transcript levels were determined via quantitative real-time PCR (I-Cycler; Bio-Rad) in duplicate using the ABsolute QPCR SYBR Green mix (ABgene House, Surrey, UK). Differences were calculated after normalization to GAPDH transcript levels. Oligonucleotides were synthesized by Invitrogen (Karlsruhe, Germany), and cycling conditions were optimized such that efficiency of amplification was 1.85–2.0 times/cycle determined by serial dilution of a control template mix. Specificity of amplified products was verified by 3% agarose gel electrophoresis at the end of each run. Cycling conditions were identical for the transcripts determined (40 cycles of 30 sec at 95 C, 45 sec at 56 C, and 30 sec at 72 C). Threshold cycle numbers (CT) and primer sequences for SBP2 and EFSEC are listed (see Table 2
). For GH and PRL, primer pairs 5'-CTGGCTGCTGACACCTACAA/5'-TGGGATGGTCTCTGAGAAGC and 5'-ATCAATGACTGCCCCACTTC/5'-ATTCCAGGAGTGCACCAAAC were used, respectively.
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, and IL-1ß (Linco Research) were conducted according to the manufacturer’s instructions.
Fluorometric Se determination
The determination of Se was essentially performed as described (21). For analysis of serum Se parameters, 50 µl serum were used and measured directly or after a trichloroacetic acid (TCA)-mediated precipitation step of serum proteins as similarly described earlier (25). Tissue Se concentrations were determined from the homogenates prepared for enzyme activity measurements. A commercially available pooled human serum standard (Sero AS, Billingstad, Norway) along with Se atomic absorption standard solutions (1000 µg/ml; Sigma) were used to validate the method.
Statistical analysis
One-way ANOVA calculations followed by Bonferroni’s post hoc probability test were used to compare differences between female and male mice. Data are expressed as mean ± SD. Statistical significance was defined as P < 0.05 (*), P < 0.01 (**), or P < 0.001 (***).
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Results |
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). Total Se concentrations were within the normal range for mice on regular Se-replete diet. Upon separation of serum proteins from soluble serum constituents by TCA-mediated precipitation, again no significant sex-specific differences were observed in the Se contents of the pellet fractions (Fig. 1B). In contrast to these more general parameters, a significant influence of sex was detectable for extracellular GPx3 activity, which was higher in female compared with male serum (5.6 ± 1.1 vs. 4.2 ± 0.8 nmol/µl·min) (Fig. 1C).
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). Liver represents the tissue mainly responsible for synthesis and secretion of SePP into plasma (26, 27). We measured a 1.3-fold higher SePP mRNA level in livers of female compared with male mice (Fig. 2A). Surprisingly, in kidney the transcript levels of SePP were inversely different among the sexes and females displayed only 31% of male renal SePP mRNA concentrations (Fig. 2B). Therefore, this sexual dimorphic expression pattern does not simply result from differences in plasma sex hormone levels. Plasma GPx3 is mainly derived from kidney. Renal GPx3 mRNA levels did not differ between male and female mice (Fig. 2B) despite the sex-specific difference of GPx3 activity in serum (Fig. 1C
). In comparison, no influence of sex was observed for the mRNA levels of the main intracellular GPx isoform, i.e. the ubiquitously expressed cytosolic GPx1 in liver or kidney (Fig. 2, A and B). Because GPx1 expression is known to be mainly controlled by intracellular Se levels, this finding nicely correlates with the comparable Se concentrations in both tissues (Fig. 2C). Accordingly, enzymatic activity of GPx1 was similar in kidney (female: 1312 ± 301 vs. male: 979 ± 207 nmol/mg·min; n = 5–6) and liver (female: 1174 ± 271 vs. male: 948 ± 230 nmol/mg·min; n = 5–6). Transcript levels of ubiquitin B appeared sex specifically different in liver and kidney; therefore, GAPDH was chosen as standard to calculate relative mRNA expression levels in these analyses.
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, A and B). Successful gonadectomy and E2 replacement were verified by determining pituitary GH and PRL mRNA concentrations. Using GAPDH mRNA as standard, GH mRNA was reduced in the castrated males (to 50% of sham-operated littermates, P < 0.001, n = 6) and females (to 57%, compared with E2-substituted littermates, P < 0.01, n = 5), respectively. At the same time, PRL mRNA increased strongly on E2 supplementation (by a factor of 36.7, P < 0.001, n = 5). Because postsurgical stress and inflammatory cytokines are known to modify selenoprotein expression, we tested serum concentrations of IL-6, TNF, and IL-1ß in all mice at the time of analysis. Values from the experimental groups were within control range (IL-6: 4.1 ± 1.3 to 10.0 ± 8.1 pg/ml; TNF: 3.4 ± 0.2 to 4.8 ± 0.7 pg/ml; IL-1ß: 3.3 ± 0.4 to 5.3 ± 2.1 pg/ml), indicating full recovery from the surgeries.
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). These alterations diminished the significant sex-specific difference for SePP mRNA in kidney as described above (Fig. 2B) and argue for a positive effect of androgens on renal SePP expression. Furthermore, an influence of sex was elicited on GPx3 activity in plasma (Fig. 3D). Orchidectomy caused a significant decrease of renal GPx3 mRNA levels and serum GPx3 activity to about 70% of control values. Ovariectomy, on the other hand, had only a marginal impact on GPx3 activity (Fig. 3D). In comparison, no alterations of GPx1 transcript or protein levels in liver or kidney were detected after orchidectomy or ovariectomy (Fig. 3B, 3C).
Liver and kidney display a peculiar sexual dimorphism of Dio1 expression
Dio1 is mainly expressed in liver, kidney, pituitary, and thyroid gland and has been described by us and others (28, 29, 30, 31, 32) to be differentially expressed in tissues of male and female rats. As expected, hepatic Dio1 activity was 2.8-fold higher in male mice, compared with female littermates (49.9 ± 13.5 vs. 17.5 ± 3.7 pmol/mg/min) (Fig. 4A). Hepatic Dio1 transcript levels were not similarly different between the sexes. Surprisingly, males expressed lower (by 30%) hepatic Dio1 mRNA levels, compared with female mice. Contrary to liver, female mice displayed a 1.8-fold higher Dio1 activity in kidney (Fig. 4A). This difference was in correlation with clearly higher renal Dio1 mRNA concentrations in females, compared with male mice (2.6-fold). Thus, in liver but not in kidney, there was an obvious discrepancy between Dio1 transcript levels and enzymatic activity indicating sex-specific regulation of hepatic Dio1 expression at the posttranscriptional level.
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). In comparison, ovariectomy induced an increase of hepatic Dio1 activity in females that could be partly reversed by E2 treatment (Fig. 4B). These effects were not paralleled by respective changes on the Dio1 mRNA level in liver with or without E2 treatment. E2 therefore appeared to mainly impact onto posttranscriptional regulation of hepatic Dio1 expression.
In kidney, gonadectomy modulated the above-mentioned sex-specific difference of Dio1 activity and transcript concentration in both sexes. In male mice, orchidectomy increased renal Dio1 activities to female values (Fig. 4C). Interestingly, the ovariectomized female mice displayed significantly lower Dio1 transcripts than their littermates after E2 treatment, but Dio1 enzymatic activities remained unaffected (Fig. 4C).
Se status is a major determinant of the sexually dimorphic expression of hepatic Dio1
In general, Se availability represents a major factor controlling selenoprotein expression. Different tissues retain Se to a variable degree in Se deficiency, and within these tissues there are preferentially supplied selenoproteins and others that are barely synthesized if the trace element is limiting (35). Because liver and kidney do not belong to the privileged tissues and GPx3 ranks low in the hierarchy of selenoproteins (36), we wondered whether the observed sex-specific differences were dependent on dietary Se supply. Accordingly, groups of male and female mice were raised on Se-poor diets containing only 0.07 ppm Se, compared with 0.24 ppm Se of regular chow. Thereby Se status was profoundly altered and serum Se concentrations dropped by almost 1 order of magnitude (Fig. 5A), compared with regularly fed mice (Fig. 1A). Serum GPx3 activity responded to the limited nutritional Se supply and decreased in parallel in both sexes (Fig. 5A) thereby diminishing the sex-specific difference observed before (Fig. 1C). On the regular diet, a strong sexual dimorphism was noted for hepatic Dio1 expression, and females contained more Dio1 transcripts but expressed less protein in liver under Se-replete conditions (Fig. 4A). In Se deficiency, Dio1 mRNA concentrations remained higher in female compared with male livers, but hepatic Dio1 enzymatic activities were disproportional reduced, i.e. by 2-fold in females and 5.6-fold in males (Fig. 5B). These differentially pronounced reductions leveled out the sexual dimorphic expression of hepatic Dio1 that was observed on regular diet (compare Figs. 4A and 5B). Thus, the sex-specific difference in the expression of hepatic Dio1 is not a constant condition but depends strongly on the Se status of the individual mice. In kidney, Dio1 activities decreased on Se-poor diet in both sexes, but in contrast to liver, the gap between the sexes widened (Fig. 5C). Renal Dio1 transcript levels and renal Dio1 activity became 4 to 5 times lower in males, compared with females, under such Se-deficient conditions (Table 1).
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). Threshold cycle numbers (CT values) and relative transcript concentrations after normalization to GAPDH signals were similar for SBP2 and EFSEC in male and female livers, indicating comparable expression of these central transacting factors for selenoprotein biosynthesis. Thus, these two most promising candidates appear not to be responsible for the sexual dimorphism observed. |
Discussion |
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). Such a discordant regulation of selenoprotein mRNA levels and resulting enzymatic activities has been observed before with respect to different tissues during Se deficiency (40). Now we have to realize that also between the sexes there are additional differences in either translational efficiency or protein stability that regulate expression of certain selenoproteins in a discordant way. Because these posttranscriptional regulatory mechanisms appear to be strongly influenced by the Se status (41), they might be responsible to maintain expression of critically important selenoproteins during Se deficiency by sex-specific routes. As a net result, differences between the sexes might disappear for important selenoproteins in central tissues, whereas at other sites a discordant expression of the same selenoprotein might remain or even intensify as exemplified by Dio1 in liver and kidney. In general, serum Se levels were comparable between male and female mice. This finding is well in agreement with earlier reports and is similarly observed in adult rats (42). There is a wealth of data on serum Se in humans, and generally men display slightly higher Se serum concentrations than women (43, 44, 45). Here the different nutritional habits are likely responsible for this effect. In mice, we observed a slightly higher GPx3 activity in serum from females, compared with males, whereas no such difference or even an inverse relationship has been reported from studies in rats (42, 46). In humans, there is in general a similar sex-specific difference with higher serum GPx3 activity in females than males (47, 48). These findings and the tendencies we observed after E2 treatment of ovariectomized mice are in accordance with recent studies that have demonstrated that ovariectomy reduces GPx3 activity and E2 treatment is able to abolish this effect (49). Similarly, a positive correlation of endogenous E2 and serum GPx3 activity has been observed in young women (50). Yet whether these modulatory effects of sex steroids are direct or via regulation of the transcription factors dominantly involved in GPx3 expression remains to be analyzed.
The Se transport and storage protein SePP accounts for the main fraction of Se in rodent and human blood (51). We and others have demonstrated before that SePP in serum is mainly derived from liver (26, 27). Because male and female mice display also similar Se concentration in liver, it is surprising that the higher hepatic SePP mRNA levels found in female mice do not cause correspondingly elevated serum Se levels via increased SePP synthesis and secretion. Interestingly, this unequal hepatic SePP expression is paralleled by an even more drastic difference in the kidneys in which male mice displayed 3 times higher SePP mRNA levels. The physiological relevance of this sexual dimorphic SePP expression is unknown but does not seem to impact onto tissue Se content, which appeared equal in male and female kidneys and livers. This is in agreement with comparable GPx1 activities in these tissues. Upon orchidectomy, renal SePP mRNA decreased in male to female levels, indicating that androgens exert positive effects on SePP expression in kidney. Such positive regulation of SePP mRNA has also been described in human prostate cancer cells (52). Interestingly, this effect was tissue specific and not observed in liver in accordance with the unchanged plasma Se concentrations in the orchidectomized animals, which reflect mainly circulating SePP levels.
The influence of sex on the tissue-specific expression of Dio1 was most surprising and fascinating due to the discordant results obtained on the mRNA and activity levels of this selenoprotein. Dio1 activity was 3 times higher in livers of male mice but approximately 2 times lower in their kidneys, compared with age-matched female mice. A similar sex-specific difference has been observed before in rat liver but not kidney (33, 34). Because expression of Dio1 is not stringently controlled by protein turnover in contrast to Dio2 (53), we could explain this finding by assuming a reduced translational efficiency of selenoproteins in female livers. Substantial support for this idea is given by the aforementioned finding of comparable serum Se concentrations between the sexes despite those higher hepatic SePP mRNA levels in females. The results from the ovariectomized mice corroborate this explanation because hepatic Dio1 activity increased in the absence of E2 despite reduced mRNA levels. Thus, a more male-like pattern of efficient Dio1 expression from fewer Dio1 transcripts is observed in the ovariectomized females.
Taken together, we are left with a profound impact of sex on translational efficiency and/or protein stability that appears very pronounced for Dio1 but might also control the posttranscritpional expression of other selenoproteins. Such peculiar mechanisms are not completely unparalleled for homeostatic control mechanisms of other minerals or trace elements because again in liver, similar complex circuits are known from iron metabolism and ferritin and transferrin biosynthesis (54).
Currently several studies that use Se as adjuvant therapy have been started and in prospective trials such as in cancer prevention (18), treatment of burns or sepsis, in autoimmune diseases of the thyroid (16), or after HIV infection. Unfortunately, the importance of a sex-specific study design and a respective analysis of the data are not always recognized. Our data emphasize again that profound sex-specific differences in selenoprotein expression do exist and need to be taken into account before general conclusions can be drawn and suitable recommendations can be given. In the future, gender-specific Se supplementation regimen might be advantageous for an efficient response to treatment and successful prevention of Se-responsive diseases.
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Acknowledgments |
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Footnotes |
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Parts of these studies were presented as a poster presentation at the German Endocrine Society, Muenster, Germany, March 2005, and as an oral communication at the European Congress of Endocrinology, Glasgow, United Kingdom, April 2006.
All listed authors have nothing to disclose.
First Published Online September 7, 2006
Abbreviations: CT, Threshold cycle number; Dio1, type 1 iodothyronine deiodinase; EFSEC, Sec-specific elongation factor; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GPx, glutathione peroxidase; NADPH, reduced nicotinamide adenine dinucleotide phosphate; ovx, ovariectomized; PRL, prolactin; SBP2, selenocysteine insertion sequence-binding protein 2; Se, selenium; Sec, selenocysteine; SePP, selenoprotein P; TCA, trichloroacetic acid.
Received May 23, 2006.
Accepted for publication August 30, 2006.
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