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2
*
Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA;
Department of Community Health Nutrition/Infectious Disease Unit, Tufts University School of Medicine, Boston, MA;
**
Department of Biological Science, Tufts University School of Veterinary Medicine, North Grafton, MA; and
Department of Pathology, Sackler Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA
2To whom correspondence should be addressed. E-mail: smeydani{at}hnrc.tufts.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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-tocopheryl acetate/kg diet) or a vitamin E-supplemented diet (500 mg dl--tocopheryl acetate/kg diet) for 16 wk. After 6 wk of dietary supplementation, young and old mice were injected with saline or AOM weekly for 5 wk to receive the same total dose of AOM (2.2 mg) and killed 10 wk after the first AOM injection. Vitamin E supplementation had no effect on the number of AOM-induced ACF in young or old mice. In addition, vitamin E supplementation did not have an effect on splenocyte interferon-
, interluekin-6 and tumor necrosis factor- levels, natural killer cell killing activity or colonic cell proliferation in young or old mice. Thus, -tocopherol does not seem to affect the initiation and early promotion stages of AOM-induced colon carcinogenesis in young or old mice. Whether vitamin E supplementation might be effective in reducing AOM-induced colon tumors is unclear.
KEY WORDS: • vitamin E • colon cancer • aberrant crypt foci • mice
Colorectal cancer is the second leading cause of death among cancers in the United States. Because epidemiologic and experimental studies suggest that colon cancer is strongly influenced by dietary factors (1
–4
), there is considerable interest in using alterations in the diet to decrease the risk for colon cancer. However, the role of vitamin E in the etiology and prevention of colon cancer especially in the aged is not clear. In a recent study (5
), we showed that the age of mice influences susceptibility to azoxymethane (AOM)3 -induced aberrant crypt foci (ACF), a surrogate biomarker of colon cancer.
Free radicals have been shown to play a role in colon cancer (6
,7
). Thus, vitamin E, the body’s primary lipid-soluble defense against free radicals and reactive oxygen molecules, might inhibit the process of lipid peroxidation and reduce the formation of mutagenic peroxidation products in the colon. Because oxidative stress is increased with aging, vitamin E supplementation may produce a greater decrease in susceptibility to colon cancer in the aged. The role of the immune system in controlling tumor development has been reported from animal experiments and clinical observations. Interferon (IFN)- has been shown to have an antitumor effect, whereas interleukin (IL)-6 was demonstrated to have a tumor-stimulating effect in certain types of cancer, including colorectal cancer (8
–13
). IFN- also activates natural killer (NK) cells, which exhibit cytotoxic activity against virus-infected cells and tumor cells (14
,15
). Age-dependent deterioration of the immune system is believed to contribute to the high incidence of morbidity and mortality from cancer and infection in the aged. Vitamin E supplementation has been reported to increase NK cell activity and IFN- production in influenza-infected old mice (16
,17
). Furthermore, vitamin E supplementation improved T cell-mediated functions in aged mice and humans (18
,19
). Thus, vitamin E supplementation might reduce the risk for colon cancer by increasing the immune response in the aged. In addition, vitamin E has been shown to have an antiproliferative property in cancer cell lines (20
,21
). Therefore, the present study was designed to investigate the effect of vitamin E supplementation on AOM-induced colonic ACF formation in young and old mice.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Specific pathogen-free young (3 mo) and old (19–21 mo) male C57BL/6JNIA mice consumed a custom pelleted diet containing either 30 mg dl--tocopheryl acetate/kg diet (control diet: Teklad 01149 from Harlan Teklad, Madison, WI) or 500 mg dl--tocopheryl acetate/kg diet (vitamin E diet: Teklad 01148 from Harlan Teklad) ad libitum. The level of vitamin E in control and vitamin E diet was confirmed by Covance Laboratories (Madison, WI). These diets are modifications of TD 99370 (NIH-31) (Harlan Teklad Technical Manual). Our previous work (16
,17
,22
) showed that 30 and 500 mg dl--tocopheryl acetate/kg diet represent basal and supplemental levels of vitamin E, respectively. Furthermore, the 500 mg dl--tocopheryl acetate/kg diet has been shown to enhance the immune response and reduce PGE2 production in old mice (19
,22
). Thus, we used these doses of vitamin E in this study. All mice were individually housed in suspended, solid bottom filtered polycarbonate cages with nitrocellulose bedding and maintained at a constant temperature (23°C) with a 12-h light:dark cycle. Body weights were recorded weekly. All handling and animal conditions were approved by the Animal Care and Use Committee of the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University. AOM was purchased from Sigma Chemical (St. Louis, MO) and dissolved in a fresh 9 g/L saline solution 1 h before injection.
Experimental procedures.
After 6 wk of dietary supplementation, mice (n = 124) were randomly assigned to six groups: 1) young mice fed the control diet and injected with saline (n = 8); 2) old mice fed the control diet and injected with saline (n = 9); 3) young mice fed the control diet and injected with 15 mg AOM/kg body for the first injection and 12 mg AOM/kg body for injections 2–5 (n = 26); 4) old mice fed the control diet and injected with the same amount of AOM (mg) as the young mice injected with 15/12 mg AOM/kg body (n = 27); 5) young mice fed the vitamin E diet and injected with 15/12 mg AOM/kg body (n = 26); and 6) old mice fed the vitamin E diet and injected with the same amount of AOM (mg) as the young mice injected with 15/12 mg AOM/kg body (n = 28) (see statistical analysis for sample size calculation). A few mice died after the first injection; thus we reduced the AOM doses for injections performed in wk 2–5 as described above. Mice were injected with saline or AOM weekly for 5 wk. The total dose of AOM was calculated by summarizing each week’s injection dose. The total dose of AOM injected to all young and old groups was the same (2.2 mg). Ten weeks after the first AOM injection, mice in all groups were killed by CO2 asphyxiation. Colon, blood, and spleen were collected.
Tissue preparation.
Blood was drawn by cardiac puncture and the plasma was separated and stored at -80°C for later analysis of vitamin E levels. Colons were removed, slit open longitudinally, and rinsed in cold normal saline for quantification of ACF and immunostaining for proliferating cellular nuclear antigen (PCNA). The spleens were processed as previously described (17
) and used for measurement of IFN-, IL-6, and tumor necrosis factor (TNF)- productions as well as NK cell killing activity.
Vitamin E assessment.
Plasma -tocopherol levels were assessed by HPLC using electrochemical detector (23
).
Quantification of ACF.
The colon was fixed flat between two pieces of filter paper in 70% ethanol. After fixation, the colon was placed in a Petri dish containing a solution of 0.2% methylene blue dissolved in 70% ethanol for 1 min. It was then placed with the mucosal side up on a microscope slide and viewed with a light microscope. ACF were distinguished from the surrounding normal crypts by the increased crypt size, darker staining, enlarged pericryptal zone and increased thickness of the epithelial cell lining as previously described (24
). The number of ACF per colon, their shape and the location of each focus were recorded without knowledge of group status. After quantification of ACF, the dye was removed and the colon was embedded in paraffin. Serial longitudinal sections were made onto microscope slides for hematoxylin and eosin staining as well as immunostaining.
Measurement of immune response.
IFN-, IL-6, and TNF- determination.
Splenocytes were cultured at 5 x 105 cells/well in the presence of concanavalin A (5 mg/L; Sigma Chemical) for IFN- production or lipopolysaccharide (10 mg/L; Sigma Chemical) for IL-6 and TNF- production in 24-well culture plates for 24 h. IFN-, IL-6 and TNF- levels were measured by using ELISA, according to the manufacturer’s instructions.
Determination of NK cell killing activity.
NK cell killing activity of splenocytes was determined in a 4-h chromium release assay against YAC-1 target cells as previously described (25
). Target cells were labeled by incubating 1 mL of YAC-1 cell suspension (5 x 109 cells/L) with 100 µCi (3.7 x 106 Bq) of Na251CrO4 (Perkin Elmer Life Sciences, Boston, MA) for 90 min at 37°C. A labeled YAC-1 cell suspension (100 µL; 1 x 108 cells/L) was added to 96-well plates containing 100 µL of varying amounts of effector cells in triplicate so that the target cell-to-effector cell (T:E) ratios were 1:100, 1:50, 1:25 and 1:10. Target cells were added in triplicate to 100 µL of media to determine nonspecific release (NSR). Plates were centrifuged for 2 min at 80 x g and incubated at 37°C for 3 h in 5% CO2. After 3 h incubation, 100 µL of 5% Triton-X-100 (Sigma) was added to wells for total release (TR) in plates, plates were incubated again at 37°C for 1 h in 5% CO2. At the end of the incubation, plates were centrifuged at 400 x g for 1 min and 100 µL of supernatant was collected and counted with a gamma counter. The percentage of killing was calculated by the following formula: % killing = [Sample counts per minute (cpm) - NSR cpm]/(TR cpm -NSR cpm) x 100.
Measurement of colonic cell proliferation.
PCNA staining was performed using the avidin and biotinylated horse-radish peroxidase macromolecular complex (ABC) system (Vectastain, Burlingame, CA). Tissue sections were deparaffinized, and incubated with 3% H2O2 for 30 min. They were incubated with normal horse serum at room temperature (RT) for 30 min and incubated overnight at 4°C with anti-PCNA mouse monoclonal Ab (PC-10, Dako, Carpinteria, CA). This was followed by incubation with biotinylated horse anti-mouse immunoglobulin G at RT for 45 min and then with ABC reagent (Vectastain) for 30 min. Each step was performed after washing with PBS. Peroxidase activity was visualized by treatment with liquid diaminobenzidine tetrahydrochloride (DAB) (Sigma) for 2 min. Cells were counterstained with Mayer’s hematoxylin (Sigma). To determine the PCNA labeling index (LI), 8–20 open U-shaped crypts were identified and the number of PCNA positive and negative epithelial cells per crypt were counted by an observer who was unaware of group status on two separate occasions; the mean of the two determinations was calculated. The PCNA LI was calculated by the following formula: PCNA LI = (number of positive epithelial cells per crypt/total number of epithelial cells per crypt) x 100.
Statistical analysis.
With the variability observed in our preliminary experiments and the use of the assumption that vitamin E would induce a 30% difference in ACF formation, our power calculation using the formula: n = 16 x (SD/difference in mean)2 + 1 indicated that n = 26 would be required to detect age and vitamin E-induced differences with 80% power at P < 0.05. For old mice, the attrition rate was also considered.
Data concerning plasma vitamin E levels, immune response and cell proliferation were analyzed by two-way ANOVA for effects of age and treatment. For treatment, there were two contrasts, i.e., effect of vitamin E and effect of AOM. Data concerning ACF formation were analyzed by two-way ANOVA for the effect of age and vitamin E in mice treated with AOM only. No ACF were found in mice treated with saline and they were not included in the analysis of ACF data. Individual comparisons were by Tukey’s honestly significant difference post-hoc test using Systat 9 statistical software (Systat, Evanston, IL). Student’s paired t test was used to test for difference in body weights before and after AOM injection. Log transformation was performed for data that were not normally distributed before statistical analysis. Data are reported as means ± SEM. Significance was set at P < 0.05.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
There were significant effects of AOM and diet (P < 0.001), but no significant effect of age on plasma vitamin E levels (Fig. 1
). Young and old mice fed the vitamin E diet had higher plasma vitamin E levels than those fed the control diet after 16 wk of dietary supplementation (P = 0.002). Young and old mice fed the control diet and treated with AOM had lower plasma vitamin E levels than those fed the control diet and treated with saline (P = 0.002). However, there was no difference in the degree of this AOM-induced reduction in plasma vitamin E levels between young and old mice.
|
As described earlier (5
) and summarized here, both young and old mice injected with AOM had significantly lower body weight after 5 wk of AOM injection (weights before AOM injection were 34.2 ± 0.6 and 40.5 ± 1.2 g in young and old mice, respectively, and weights after AOM injection were 32.5 ± 0.5 and 31.9 ± 0.8 g in young and old mice, respectively, P < 0.01). The magnitude of the weight loss was greater in the old mice than in the young mice (P < 0.001). Vitamin E supplementation did not affect this AOM-induced weight loss in young or old mice (data not shown).
There was a significant overall effect of age (P < 0.001), but no significant effect of vitamin E or an age and vitamin E diet interaction on ACF formation (Fig. 2
). As shown before (5
), young mice had significantly more ACF than old mice (P < 0.001).
|
There were significant effects of age (P < 0.001) and AOM (P = 0.011), but no effect of the vitamin E diet on IFN- production by splenocytes (Table 1
). Young and old mice treated with AOM had significantly higher IFN- production compared with those treated with saline (P < 0.03). Old mice had significantly higher levels of IFN- than young mice (P < 0.001). However, there was no effect of vitamin E supplementation on IFN- production in young or old mice.
|
. Young and old mice injected with AOM had higher IL-6 levels than those injected with saline (P < 0.001). Old mice had higher IL-6 levels than young mice (P < 0.001). However, splenocyte IL-6 levels were not affected by vitamin E supplementation in young or old mice. There were no significant effects of age, AOM or vitamin E diet on TNF- production by splenocytes (data not shown).
There were significant effects of age (P < 0.001) and AOM (P = 0.001), but no effect of the vitamin E diet on NK cell killing activity (Table 1)
. There was a significantly higher NK cell killing activity in young and old mice injected with AOM than in those injected with saline (P < 0.03). Young mice had a significantly higher NK cell killing activity compared with old mice (P < 0.001). However, there was no significant difference in NK cell killing activity between mice fed the control diet and the vitamin E diet in young or old mice.
PCNA LI was used to determine colonic cell proliferation. There was a significant effect of AOM (P < 0.001), but no effect of age or the vitamin E diet on PCNA LI (Table 1)
. Young and old mice treated with AOM had significantly higher PCNA LI compared with those treated with saline (P < 0.01). However, there was no difference in PCNA LI between young and old mice in saline or AOM-injected groups. Vitamin E supplementation had no effect on PCNA LI in young or old mice.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Although this is the first study to investigate the effect of vitamin E supplementation on ACF, a biomarker of colon cancer, in aged mice, the effect of vitamin E supplementation on colon cancer was investigated previously in young animals (26
–31
). Cook et al. (26
) showed that mice fed a high vitamin E (600 mg/kg diet) diet had fewer colorectal tumors and carcinomas than those fed a low vitamin E diet (10 mg/kg diet) after treatment with 1,2-dimethylhydrazine (DMH). Sumiyoshi et al. (27
) also showed that vitamin E supplementation (100 mg/kg diet) reduced the incidence of DMH-induced colon cancer in rats compared with low vitamin E supplementation (<5 mg/kg diet). On the contrary, Toth et al. (28
) reported that vitamin E supplementation increased colonic tumorigenesis in DMH-treated mice. The other studies (29
–31
) reported no effect of vitamin E supplementation on carcinogen-induced colon ACF formation or tumors in rats or mice, which is in agreement with our observation in this study, i.e., there is no effect of vitamin E supplementation on ACF formation in young mice. In addition, vitamin E supplementation does not affect ACF formation in old mice. There is a considerable discrepancy in the literature concerning the effect of vitamin E in animal models of colon cancer. Perhaps part of the explanation lies in the different end points used in various studies. Studies that used surrogate biomarkers indicative of early stages in colonic carcinogenesis, such as the ACF in our study, tend to be negative, whereas at least two animal studies that have used tumor formation as the primary end point have observed a preventive effect of vitamin E (26
,27
). Thus, vitamin E may have a positive effect on the later, but not the early, stages of colonic carcinogenesis. Recent work demonstrating vitamin E inhibition of neoplasm-associated angiogenesis (32
) might explain its inhibitory effects on the growth of tumors.
The type of vitamin E used in this study was -tocopherol. Other types of tocopherol such as -tocopherol might lower the risk for colon cancer because it is secreted preferentially into the intestine and fecal materials via the bile, whereas -tocopherol is secreted preferentially into plasma (7
). In addition, Cooney et al. (33
) reported that -tocopherol in fecal materials might be particularly effective in preventing DNA damage caused by reactive nitrogen oxide species in the epithelial cell lining of the colon by either reducing NO2 production or reacting with it to form a nonnitrosating agent. Nitrosating agents can deaminate DNA bases and cause mutations, and they are generated when -tocopherol reacts with NO2 (33
).
Young and old mice injected with AOM had significantly higher splenocyte IFN- and IL-6 levels, NK cell killing activity and PCNA LI compared with those injected with saline. However, there was no significant effect of AOM on splenocyte TNF- production. In addition, AOM injection significantly reduced plasma -tocopherol levels in mice fed the control diet. The plasma -tocopherol level does not seem to be related to ACF formation. Even though young and old mice fed the vitamin E diet had higher plasma -tocopherol levels, the ACF formation in response to AOM was not different from that seen in mice fed the control diet. It is not clear how AOM injection reduced plasma -tocopherol levels; this might reflect mobilization of vitamin E to other tissues such as the colon, which might be exposed to higher oxidative stress after AOM injection. Vitamin E might also be used to maintain the reduced form of other antioxidants that might have been oxidized during that process.
Vitamin E supplementation did not affect splenocyte IFN-, IL-6 and TNF- productions, NK cell killing activity or PCNA LI in this study, which was consistent with its lack of effect on ACF formation. In other models, however, we and others (16
,17
,34
) reported enhancement in splenocyte IFN- and IL-6 productions as well as NK cell killing activity after vitamin E supplementation. Hayek et al. (16
) and Han et al. (17
) showed that vitamin E supplementation decreased lung virus titers by significantly increasing NK cell activity and IFN- production in old mice infected with influenza. In the same study (17
), Han et al. also showed that old mice fed the vitamin E-supplemented diet had significantly lower TNF- production compared with those fed the control diet. Wang et al. (34
) showed that vitamin E supplementation restored IFN- production and NK cell activity that were suppressed by retrovirus infection and normalized the IL-6 level that was increased by retrovirus infection in the murine AIDS model. This discrepancy might reflect specific interactions between vitamin E and different pathogens.
In summary, this is the first study to elucidate the effect of vitamin E supplementation on AOM-induced ACF formation in both young and old mice. The findings indicate that vitamin E supplementation does not have an effect on ACF formation or on contributing factors to colon cancer such as IFN-, TNF- and IL-6 production, NK cell killing activity and colonic cell proliferation in young or old mice. Future studies are required to determine whether other tocopherols such as -tocopherol might alter AOM-induced colonic ACF formation, and whether -tocopherol supplementation is similarly ineffective at later stages of colon carcinogenesis.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: ABC, avidin and biotinylated horse-radish peroxidase macromolecular complex; ACF, aberrant crypt foci; AOM, azoxymethane; cpm, counts per minute; DMH, 1,2-dimethyhydrazine; IFN, interferon; IL, interleukin; LI, labeling index; NK, natural killer; NSR, nonspecific release; PCNA, proliferating cellular nuclear antigen; RT, room temperature; TNF, tumor necrosis factor; TR, total release.
Manuscript received 26 August 2002. Initial review completed 23 September 2002. Revision accepted 20 November 2002.
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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