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Departments of Genetics and Medical Genetics, University of Wisconsin-Madison, Madison, WI, 53706 and * California Animal Health and Food Safety Laboratory System, Toxicology Laboratory, University of California, Davis, CA 95616
2To whom correspondence should be addressed. E-mail: taprolla{at}facstaff.wisc.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • gene expression • selenium • selenoprotein • oxidative stress • mice
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–3
). Various Se compounds of natural and synthetic origin have also been shown to inhibit tumor development in animal studies in a wide range of dosages (4
). Although most animal studies have employed pharmacologic doses of Se (>2 mg/kg) in cancer chemoprevention (4
), Se deficiency has also been shown to enhance mammary (5
) and UVB-induced skin carcinogenesis (6
). A recent double-blind, randomized cancer prevention trial in humans involving physiologic doses (0.2 mg) of Se demonstrated a remarkable reduction in incidence of lung, prostate and intestinal cancers (7
). These observations suggest that Se may be one of the most powerful cancer chemopreventive agents in the human diet. Several hypotheses have been proposed to account for the Se-mediated inhibition of tumorigenesis. As a constituent of selenoproteins, Se has an enzymatic role as an antioxidant (8
). Studies have also demonstrated stimulation of apoptosis and enhanced carcinogen detoxification after Se supplementation at pharmacologic doses (9
–12
). However, despite decades of research in the mechanisms of action of Se, there is currently no consensus on how this remarkable micronutrient prevents tumorigenesis. Possibly, low Se status associated with decreased dietary Se intake and supplementation with pharmacologic doses of Se affect tumor susceptibility by distinct mechanisms.
To gain a better understanding of the effect of Se deficiency, we used Affymetrix high density oligonucleotide arrays representing 6347 murine genes to determine the transcriptional profile associated with low Se status in the intestines of C57Bl/6J mice. Our observations demonstrate that under such conditions, low Se status can induce multiple transcriptional pathways suggestive of oxidative stress, DNA damage and alterations in cell-cycle progression, providing a framework for understanding the multiple roles of Se in human health (13
).
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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C57BL/6J mice were originally provided by Dr. W. Dove, from the colony at the McArdle Laboratory (University of Wisconsin-Madison) and were raised from birth in our animal facility. Guidelines for the ethical care and treatment of animals from the Animal Care and Use Committee at the University of Wisconsin-Madison were strictly followed. Mice were housed in groups of three in microisolator cages under fluorescent lighting on a 12-h cycle. Tap water was available continuously during the experiment and was replaced weekly. Diets were stored in the dark at 4°C and fresh diet was added to feeders twice weekly. Diets were randomly allocated and were consumed ad libitum by weanling (3-wk-old) mice. Mice were fed either the Se-deficient diet (Table 1
) containing <0.01 mg/kg of Se or a high Se diet that represents the Se-deficient diet supplemented with 1.0 mg/kg of Se as seleno-L-methionine (Sigma Chemical, St. Louis, MO). The Se composition of diets was determined by chemical analysis to be <0.01 mg/kg and 0.97 mg/kg in the Se-deficient and high Se diet diets, respectively. The Se-deficient diet contained no added Se and 
15 g/100 g total fat (Table 1)
. Mice in our study were deficient only in Se and received adequate doses of vitamins and other trace minerals.
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Glutathione peroxidase (GPX)3
activities in tissue homogenates were determined by the indirect, coupled test procedure (14
). Briefly, the oxidized glutathione (GSSG) produced from GPX enzyme activity was immediately reduced by NADPH and glutathione reductase. Therefore, the rate of NADPH consumption was monitored as a measurement for the rate of GSSG formation during the GPX reaction. The final concentrations of the reagents in the reaction mixture were 50 mmol/L potassium phosphate, pH 7.0, 1 mmol/L EDTA, 1 mmol/L NaN3, 0.15 mmol/L NADPH, 4 U glutathione reductase, 1 mmol/L glutathione (GSH), and 0.15 mmol/L H2O2 at 25°C. The rate of decrease in absorption of NADPH at 340 nm was followed, and the GPX activity was defined as nmol of NADPH consumption per min per mg of tissue protein at 1 mmol/L GSH. GPX activity was calculated using a mmol/L extinction coefficient for NADPH of 6.22. One enzyme unit (U) was defined as 1 nmol of reduced glutathione oxidized per minute. Tissue protein was determined by the Bradford method (15
).
Tissue Se analysis.
Total Se was analyzed by inductively coupled argon plasma (ICP) atomic emission using hydride generation (16
) (Model ACCURIS ICP; Fison Instruments, Dearborn, MI).\E Tissue (1 g) was digested for 3 h at 330°C in a mixture of 1.0 mL concentrated sulfuric acid, 3.0 mL concentrated nitric acid, and 1.0 mL concentrated perchloric acid to convert all Se species to selenate. The selenate was reduced to selenite with 5 mol/L hydrochloric acid at 95°C. The selenite was quantitatively reduced to hydrogen selenide by acidic (10 mol/L HCl) sodium borohydride and then determined by ICP atomic emission at 196.090 nm. The method detection limit for a 1-g sample is 0.005 mg/kg. For acceptance of data, the recovery rates had to fall within a range of 80–120% of the certified value. A spiked sample was prepared using 0.100 mL of 10 mg/kg Se in 1 g of tissue, and spike recovery was within 80–120% for acceptability. In addition, acceptable drift was no more than ± 10% over the entire analytical run, and reslope drift correction was no more than ± 5% of the slope of the original calibration curve.
Tissue preparation and high density oligonucleotide array hybridizations.
Weanling C57BL/6J male mice (21 d of age) were fed either a Se-deficient diet containing Se at <0.01 mg/kg or a high Se diet containing 1.0 mg/kg Se as seleno-L-methionine. Mice were killed at 111 d of age by cervical dislocation after avertin anesthesia. The intestine was flushed twice with saline solution and the small intestine was measured and divided in three equal segments. A 3-cm region of the middle segment of the small intestine corresponding to the jejunum (300 mg of tissue) was cut and rinsed again with physiological saline to completely remove contents, flash frozen in liquid nitrogen and stored at -80°C. We analyzed mRNA from each mouse independently. Total RNA was extracted from frozen tissue using the guanidinium isothiocyanate method using TRIZOL (Life Technologies, Grand Island, NY), and poly(A) RNA was purified using an oligo-dT-linked Oligotex resin (Qiagen, Valencia, CA). Poly(A) RNA (1 µg) was converted into double-stranded cDNA using a Superscript Choice System (Life Technologies) and used to synthesize biotin-labeled cRNA using a T7 Megascript kit (Ambion, Austin, TX). Biotin-labeled cRNA was purified using a RNeasy affinity column (Qiagen) and hybridized to the Affymetrix Mu6500 GeneChip (Affymetrix, Santa Clara, CA) as described (17
). After hybridization, the gene chips were washed and stained in a fluidic station (Model 800101; Affymetrix). The gene chips were read at a resolution of 6 µm using a Hewlett-Packard GeneArray Scanner (Model 900154; Affymetrix). Data collected from two scanned images were used for the analysis.
Data analysis.
Detailed protocols for data analysis of Affymetrix microarrays and extensive documentation of the sensitivity and quantitative aspects of the method have been described (18
). The Affymetrix GeneChip MU6500 (Affymetrix) set was derived from selected genes and expressed sequence tags (EST) from the August 15, 1996 release of GenBank. Briefly, each gene is represented by the use of 20 perfectly matched (PM) and mismatched (MM) control probes. The MM probes act as specificity controls that allow the direct subtraction of both background and cross-hybridization signals. The number of instances in which the PM hybridization signal is larger than the MM signal is computed along with the average of the logarithm of the PM:MM ratio (after background subtraction) for each probe set. These values are used to make a matrix-based decision concerning the presence or absence of an RNA molecule. All calculations are performed by Affymetrix software. To determine the quantitative RNA abundance, the average of the differences representing PM minus MM for each gene-specific probe family is calculated, after discarding the maximum, the minimum and any outliers beyond 3 SD. To make comparisons between data-sets, the average intensity differences for each gene are normalized to the total fluorescence intensity of the array. This is similar to the concept of normalizing signal to a reference mRNA, such a ß-actin in a typical Northern blot. To calculate fold changes (FC) between data sets (after normalization) obtained from mice in the Se-deficient diet (d) vs. mice in the high Se diet (a), the following formulas are used by the software:
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where SId is the average signal intensity from a gene-specific probe family from a mouse in the Se-deficient diet and SIa is that from a mouse in the high Se diet. Alternatively, if the Qfactor, a measure of the nonspecific fluorescence intensity background, is larger, the smallest of either SIa or SId, the FC is calculated as:
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The Qfactor is automatically calculated for different regions of the microarray and therefore minimizes the calculation of spurious FC. Averages of pairwise comparisons are made between study groups, each composed of three mice using Excel software. As an example, each tissue from Se-deficient mice (n = 3) is compared with high Se mice (n = 3), generating a total of nine pairwise comparisons.
Pearson correlation coefficients were calculated between individual mice in the same diet groups. No correlation coefficient between two individual mice in the same diet group was < 0.92. Specific intragroup correlation coefficients were as follows: sd1/sd2 = 0.97; sd1/sd3 = 0.96; sd2/sd3 = 0.94; sh1/sh2 = 0.98; sh1/sh3 = 0.92; sh2/sh3 = 0.93 (sd, Se-deficient group; sh, high Se group fed 1.0 mg/kg Se). Supplementary information, including a complete list of genes displaying increased (19
) or decreased (20
) gene expression, including average signal intensity, is available. Data from mice fed the two diets were compared by Students’s t test.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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To determine the effect of the Se-deficient (<0.01 mg/kg) and high Se (1.0 mg/kg) diets (Table 1)
on Se status, we determined GPX activity in liver, kidney and intestine in mice at 111 d of age (Table 2
). Compared with mice fed the high Se diet (1.0 mg/kg), those receiving the Se-deficient diet had significantly lower GPX activity in all organs tested (Table 2)
. There was a 90% reduction of activity in liver (P < 0.0001), an 81% reduction of activity in kidney (P < 0.0013) and a 45% reduction of activity in intestine (P < 0.0008). Se levels (Table 2)
were 96% lower in liver Se (P < 0.0002) and 83% lower in kidney (P < 0.0007).
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We examined the gene expression profile associated with Se status using C57BL/6J mice. A comparison of the small intestine from mice fed the Se-deficient diet or the high Se diet revealed that Se status was associated with alterations in specific mRNA levels, which may reflect changes in gene expression, mRNA stability or both. Of the 6347 genes surveyed in the DNA microarray, only 48 (0.8%) displayed a greater than twofold decrease in expression in response to low Se status, whereas 84 (1.3%) displayed a greater than twofold increase in expression. Functional classes were assigned to genes displaying the largest alterations in expression.
Genes that displayed a greater than twofold increase in expression in low Se diet—fed mice were consistent with a state of DNA damage, genetic instability and oxidative stress (Table 3
). These included alterations in expression of the cell cycle arrest/DNA damage inducible genes GADD34, GADD45ß, GADD
and XP-E, as well as the molecular chaperones HSP27 and HSP40 (21
). Also induced were the mitogen- and stress-activated protein kinase AMPK, and metallothionein-I, a free radical scavenger implicated in oxidative damage protection (22
). MDM2, an oncogene, which functions mainly to modulate p53 tumor suppressor activity by increasing its susceptibility to proteolysis (23
) and is induced directly by p53 under conditions of stress (24
), was also induced by low Se status.
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. These include genes involved in cell cycle control, such as M-phase inducer phosphatase 2, G2/mitotic-specific cyclin B2, cyclin-dependent kinase 1, cyclin-dependent kinase inhibitor, serine/threonine protein phosphatase 2A, protein-tyrosine-phosphatase IA-2 and a dual specificity protein phosphatase PAC-1 (25
,26
). We also observed the concomitant induction of signal transducers and activators of transcription (STAT), including STAT3 and STAT5A proteins, which are involved in STAT signaling and oncogenesis by stimulating cell proliferation and preventing apoptosis (27
).
Additionally, low Se status resulted in changes in the expression of genes that participate in angiogenesis and tumor metastasis, such as keratin, arachidonate 12-LOX and PIGPEN (28
). We also observed the parallel induction of vascular endothelial growth factor (VEGF) and the tyrosine-protein kinase receptor RSE, both of which play important roles in vasculogenesis and angiogenesis (29
). Genes involved in cell adhesion and attachment, which are required for tumor growth and invasion, were also induced by Se deficiency, including laminin ß-chain 1 and plakoglobin (30
). Our observations are in agreement with a recent report that low Se status induces metastasis of melanoma cells in mice and increases the production of VEGF in rat mammary carcinomas (31
,32
).
Decreased expression of genes encoding selenoproteins, xenobiotic and lipid metabolism in Se deficiency.
Se deficiency downregulated the mRNA levels of the Se-dependent enzymes glutathione peroxidase (GPX1) and Type 1 iodothyronine deiodinase (ID-1) (Table 4
) by 3.0- and 2.4-fold, respectively (corresponding to 66 and 59% reductions in mRNA levels). GPX1 is an important enzyme in cellular antioxidant defense systems, detoxifying peroxides and hydroperoxides, and its expression is controlled at the mRNA level by dietary Se (33
). These observations are in agreement with reports that GPX1 mRNA levels can decrease to <10% of original levels in Se-deficient rat liver (34
), that Se regulation of GPX1 mRNA requires a functional selenocysteine insertion sequence in the 3'-UTR that functions to stabilize the transcript (35
) and that feeding a Se-deficient diet to rats leads to a 50% reduction in ID-1 mRNA levels in liver (35
). Genes involved in the cellular detoxification of both xenobiotic and endobiotic compounds accounted for 8% of the genes decreased in Se-deficient mice, including genes that encode the phase I detoxification enzymes cytochrome P450 3A1, 2B9 and the phase II enzymes epoxide hydrolase and a glutathione S-transferase-µ homolog. Other Se-dependent genes that were represented in the DNA chip and expressed in the intestine, but which did not display reduced mRNA levels as a result of low Se status, were selenoprotein-P, phospholipid hydroperoxide glutathione peroxidase (GPX4), plasma glutathione peroxidase (GPX2) and a poorly characterized Se-binding liver protein (SLP-56) that has been shown to be expressed in multiple tissues (36
).
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, especially in lipid transport, including apolipoprotein (apo)AI, AIV, CII, CIII, APOBEC-1, nonspecific lipid-transfer protein and fatty acid binding protein. The apoAI-Clll-AIV gene cluster is modulated by both gene- and cluster-specific cis-acting elements (37
). Apo-Al is the major determinant of the capacity of HDL particles to promote cholesterol efflux and is associated with the inhibition of atherosclerosis (38
). |
DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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–3
), dietary supplementation with modest doses of Se in humans inhibits cancer development at multiple sites (7
) and Se deficiency enhances tumorigenesis in at least some tissues in rodents (5
,6
). In fact, previous studies suggested that there are at least two roles for Se in cancer chemoprevention, i.e., overt Se deficiency promotes tumorigenesis in the presence of high fat (5
), whereas pharmacologic levels of Se (>2mg/kg diet) protect against tumorigenesis relative to Se-adequate levels (4
).
In the current study, mice receiving the Se-deficient diet displayed both GPX activity and tissue Se concentrations that were consistent with a state of Se deficiency, as previously reported in mice fed Se-deficient torula yeast diets (39
–41
). Interestingly, liver GPX activity decreased to only 9% of the level found in mice fed high Se (Table 2)
, whereas liver GPX activity was reported to decrease to 1% of Se- adequate levels in mice fed comparable Se-deficient diets (42
). Thus, tissue GPX activities suggest that these mice may not have been as deficient as those in some other animal studies. In contrast, mice receiving the high Se levels had elevated liver Se levels compared with a previous study that reported tissue levels in mice receiving 0.5 mg/kg of Se as sodium selenite (39
). The elevated Se tissue levels in the mice receiving the high Se diet in our study may have been due to the fact that selenomethionine is incorporated nonspecifically into protein and is therefore deposited nonspecifically in tissues at pharmacologic levels of dietary Se (42
). In Americans, the daily Se intake was recently estimated to be 108 µg Se/d, whereas daily Chinese Se intakes associated with overt deficiency disease are <20 µg/d (43
), and recent European daily Se intakes ranged from 28 to 67 µg Se/d (13
). The amount of dietary Se required to reach plateau levels of plasma GPX activity has been estimated to be between 40 and 70 µg Se/d (43
,44
). Therefore, a large fraction of the human population may consume levels of Se that are below the levels that result in plateau levels of activity of Se-dependent enzymes.
It has been suggested that pharmacologic doses of Se influence tumorigenesis through the metabolism of Se, which leads to the formation of monomethylated forms of Se (4
), whereas suboptimal intakes of Se in the human population lead to reduced enzymatic activity of selenoproteins in multiple tissues (45
). Because the Se-dependent enzymes, GPX, thioredoxin reductase, phospholipid hydroperoxide glutathione peroxidase, gastrointestinal glutathione peroxidase and selenoprotein P, function as antioxidants (46
), it is plausible that low Se status is associated with some forms of oxidative stress. Indeed, symptoms of Se deficiency such as hepatic necrosis and muscular dystrophy are severely aggravated by a simultaneous deficiency of vitamin E, an inhibitor of lipid peroxidation (47
,48
). However, the link between specific Se-dependent enzymes and oxidative stress remains unclear because GPX1-deficient mice are healthy under normal conditions and are actually protected against -irradiation–induced DNA damage (49
). Additionally, simultaneous deficiency in both Se and Vitamin E, but not Se deficiency alone, leads to elevated levels of tissue and plasma F2-isoprostanes, a marker of lipid peroxidation (50
).
DNA damage in the intestine of Se-deficient mice consuming a high fat diet is supported by our observation that low Se status resulted in the induction of the DNA-damage inducible genes GADD34 and GADD45 (51
) (Table 3)
. Interestingly, peroxynitrite, a strong oxidant, has recently been shown to induce the expression of both GADD34 and GADD45 in human neuroblastoma cells (52
). Other oxidative stress– and DNA damage–inducible transcripts induced by low Se status include metallothionein-I, a free radical scavenger implicated in oxidative damage protection (22
) and XP-E, a DNA repair protein. Importantly, we note that the link between the observed changes in gene expression and oxidative stress, cell cycle alterations and DNA damage can be definitively established only through biochemical analysis of the tissues under study. Interestingly, a previous study established that after Se deficiency, loss of GPX activity is rapid in mice, followed by a slower, concerted increase in the activity of several enzymes involved in drug detoxification, including GSH transferases and reductases (40
). We did not observe the upregulation in expression of any gene involved in drug detoxification in the intestine of Se-deficient mice. The previously observed effect may be liver specific, or is mediated at the protein level, as opposed to increases in mRNA abundance.
The data presented here provide the first global assessment of gene expression patterns in response to a nutritional deficiency in mammals. Importantly, the observed effects may be limited to the chemical form of Se used in our study, seleno-L-methionine, and may not reflect the events that follow supplementation with pharmacologic doses of Se as used in many experimental studies in rodents. We also note that the reported alterations in gene expression might well require both overt Se deficiency and a high fat diet because only in rats that were fed a diet high in polyunsaturated fat did Se deprivation result in a marked enhancement of mammary tumorigenesis (5
). Additionally, the gene expression profile of Se deficiency in the intestine is complex and reflects multiple cell types, such as those found in the intestinal epithelium, muscularis and lymphatic nodules (53
). Although several animal models of cancer and human clinical trials indicate that Se is inversely associated with risk of cancer, the mechanism of action of this trace element is unknown. Here we show that the suboptimal intake of a single micronutrient can have complex effects on several pathways related to tumorigenesis, a finding that suggests that the mechanisms of Se-mediated cancer prevention may be multiple. Clearly, identifying optimal intakes of Se in the human population is likely to have a broad effect in human health.
Taken as a whole, our results suggest that in mice of low Se status fed high dietary fat, there is an induction of a stress response at the transcriptional level (Table 5
). This response may be due to oxidative stress, DNA damage or both, and could be related to a reduction in the activity of selenoproteins and detoxification enzymes. The gene expression profile also suggests that other responses to the low Se status may be the induction of genes involved in cell cycle regulation and oncogenesis (54
), a finding that may be linked to the previous observation that oxidative stress is associated with cellular proliferation (55
). Importantly, our observations suggest a link between genetic instability, oxidative stress and oncogene activation at the transcriptional level, resulting from suboptimal intake of a single micronutrient.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: apo, apolipoprotein; EST, expressed sequence tag; FC, fold change; GPX, glutathione peroxidase; GSH, glutathione; GSSG, oxidized glutathione; ICP, inductively coupled plasma; ID-1, Type 1 iodothyronine deiodinase; MM, mismatched; PM, perfectly matched; STAT, signal transducers and activators of transcription; VEGF, vascular endothelial growth factor.
Manuscript received February 21, 2001. Initial review completed March 19, 2001. Revision accepted September 5, 2001.
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LITERATURE CITED |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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