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© 2005 The American Society for Nutritional Sciences J. Nutr. 135:283-286, February 2005

Nutrition and Cancer

Dietary Vitamin E Does Not Inhibit the Promotion of Liver Carcinogenesis by Polychlorinated Biphenyls in Rats1,2

Howard P. Glauert*,{dagger},**,3, Zijing Lu*,{dagger}, Amita Kumar*, R. Petruta Bunaciu*, Sandip Patel*, Job C. Tharappel*, Divinia N. Stemm{dagger}, Hans-Joachim Lehmler{dagger},4, Eun Y. Lee{dagger},{ddagger}, Larry W. Robertson*,{dagger},4 and Brett T. Spear*,{dagger},{ddagger},{dagger}{dagger}

* Graduate Center for Nutritional Sciences, {dagger} Graduate Center for Toxicology, ** Department of Nutrition and Food Science, {ddagger} Department of Pathology and Laboratory Medicine, and {dagger}{dagger} Department of Microbiology, Immunology, and Molecular Genetics, University of Kentucky, Lexington, KY 40506

3To whom correspondence should be addressed. E-mail: hglauert{at}uky.edu.


   ABSTRACT
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 ABSTRACT
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 
In this study, the effect of dietary vitamin E on the hepatic tumor-promoting activity of PCB-77 and PCB-153 in female Sprague-Dawley rats (175–200 g) was investigated. One week after diethylnitrosamine injection, rats were fed purified diets containing 10, 50, or 250 mg/kg vitamin E in the form of {alpha}-tocopheryl acetate. Starting 1 wk later, we injected rats i.p. with vehicle (corn oil) or PCB-77 or PCB-153 (300 µmol/kg) every 14 d for 4 injections. All rats were killed 10 d after the last PCB injection. The number and volume of placental glutathione S-transferase (PGST)–positive foci were increased by PCB-77 but not by PCB-153. Vitamin E did not affect the induction of PGST-positive foci. PCB-77, but not PCB-153, increased hepatic NF-{kappa}B activity. In conclusion, dietary vitamin E supplementation does not protect against the induction of altered hepatic focal lesions by PCBs.

KEY WORDS: • polychlorinated biphenyls • vitamin E • altered hepatic foci • NF-{kappa}B

Polychlorinated biphenyls (PCBs)5 are persistent environmental contaminants that bioaccumulate in the food chain, thus posing a health hazard to animals and humans (1,2). Coplanar PCBs are congeners that are substituted in both para and at least 2 meta positions but not in any of the ortho positions; they therefore may form a more coplanar configuration and bind strongly to the Ah receptor. In contrast, PCBs with chlorine substitutes in 2 ortho positions are noncoplanar and have low affinity for the Ah receptor; they activate the constitutive androstane receptor and induce cytochrome P450 2B1/2 (3). Previous studies showed that PCB mixtures or individual congeners can act as tumor promoters (1,4), but the exact mechanisms are still unclear.

The formation of reactive oxygen species is one mechanism by which chemicals may promote hepatic tumors. Several studies have shown that PCBs can cause oxidative damage, in the form of lipid peroxidation, modulation of antioxidant status and antioxidant enzymes, and oxidative DNA damage (4–7). Oxidative stress caused by tumor promoters can alter gene expression. For example, the transcription factor NF-{kappa}B was shown to be activated by PCBs (8,9). Vitamin E, the major lipophilic chain-breaking antioxidant, is thought to be chemopreventive in both the initiation and the promotion stages.

In this study, the effect of dietary {alpha}-tocopheryl acetate on PCB-induced hepatic focal lesion growth in diethylnitrosamine (DEN)-initiated Sprague-Dawley rats was investigated. The PCBs used in this study were 3,3',4,4'-tetrachlorobiphenyl (PCB-77), a coplanar PCB, and 2,2'4,4',5,5'-hexachlorobiphenyl (PCB-153), a noncoplanar PCB. Rats were fed purified diets containing different levels of {alpha}-tocopheryl acetate (10, 50, or 250 mg/kg diet); the 50 mg/kg diet represents the adequate level, with the other 2 diets containing low or excessive levels. Rats were then administered 4 doses of corn oil, PCB-77, or PCB-153 after a 150 mg/kg dose of DEN. This initiation-promotion model was chosen because we previously used it to study the promoting activities of PCBs and their modification by diet (9,10). The hepatic DNA binding activity of NF-{kappa}B and the levels of proteins in the NF-{kappa}B activation pathway were also determined.


   MATERIALS AND METHODS
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 ABSTRACT
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 LITERATURE CITED
 
    Chemicals. PCB-77 and PCB-153 were synthesized and characterized as described previously (11). Both compounds had a purity of >98% as determined by gas chromatography. Tocopherol-stripped corn oil was from Acros Organics. All dry constituents of the purified diet were from Teklad Test Diets. The anti-placental glutathione S-transferase (PGST) antibody was purchased from Novocastra Laboratories. The Vectastain staining kit was from Vector Laboratories. The DL-{alpha}-tocopheryl acetate and other chemicals were from Sigma Chemical.

    Experimental design. This study was approved by the University of Kentucky Institutional Animal Care and Use Committee. Eighty-one female Sprague-Dawley rats (175–200 g) were obtained from Harlan Sprague-Dawley and housed 3 rats per cage in a temperature- and light-controlled room. After 1 wk, the rats were initiated with DEN (150 mg/kg, p.o.). After a 1-wk recovery period, rats were divided into 3 groups (27 rats per group) and allowed ad libitum access to a purified diet similar to the AIN-93 diet (12).6 After 1 wk, rats received an i.p. injection of corn oil, PCB-77, or PCB-153 (300 µmol/kg). The rats received 3 other i.p. injections every 2 wk and were killed 10 d after the last injection (52 d after receiving the first PCB injection). Liver pieces were removed and fixed in 100 g/kg buffered formalin; the remaining liver was frozen in liquid nitrogen and stored at –80°C until time of assay. Liver pieces were homogenized in 1.15% KCl (w:v) with 0.1 mmol/L EDTA, pH 7.4, using an Ultra-Turrax homogenizer (Tekmar) The homogenate was immediately separated into aliquots and stored at –80°C to be used for vitamin E analysis. All tocopherols were extracted from liver homogenate with hexane and {alpha}-tocopherol was measured using fluorescence detection in an HPLC system as described by Twaroski et al. (13). All other tocopherols were below the detection limit.

    Electrophoretic mobility shift assay (EMSA). Nuclear extracts were prepared from frozen liver tissue by the method of Deryckere and Gannon (14) as modified by Calfee-Mason et al. (15). The NF-{kappa}B DNA binding activity was then determined by EMSA (15). After electrophoresis, the gel was dried under a vacuum and exposed overnight at –80°C to a phosphorimage screen. The radioactivity was counted with a phosphorimaging analysis system (Molecular Dynamics).

    Western blotting. Cytosols were prepared from frozen liver pieces and Western analyses were then performed on the cytosols, as described previously (15). All antibodies were purchased from Santa Cruz Biotechnology and included anti-I{kappa}B{alpha}, I{kappa}Bß, I{kappa}B kinase (IKK){alpha}/ß, IKK{gamma}, and the anti-rabbit HRP antibodies.

    PGST immunostaining. The tissues processed for paraffin sections were used for immunostaining with an anti-PGST antibody for labeling PGST-positive foci. The staining was carried out as described by Murdoch et al. (16), using a protocol provided by Vector Labs.

    Quantitation of altered hepatic foci. The number and volume of PGST-positive foci were measured using a computer digitizing system; the number of foci/cm3 (Saltykov method), foci/liver (Saltykov method), mean focal volume (Saltykov method), and volume fraction (Delesse method) were analyzed (17–19).

    Statistical analysis. Results were first analyzed by two-way ANOVA. Individual differences between means were determined using Bonferroni’s post hoc test. The results were reported as means ± SEM. Differences were considered significant at P ≤ 0.05.


   RESULTS
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 LITERATURE CITED
 
Body weights were significantly lower in rats treated with PCB-77 (data not shown). Absolute and relative (percentage of body weight) liver weights were significantly increased in rats treated with PCBs at all levels of dietary vitamin E (data not shown). Dietary vitamin E had no effect on the liver weights. The concentration of vitamin E in liver was increased by dietary vitamin E; additionally, PCB-77-treated rats fed the 250 mg/kg diet had a higher level of hepatic vitamin E than corn oil–treated rats fed the same diet (Fig. 1).



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  		FIGURE 1 Effect of vitamin E and PCBs on hepatic {alpha}-tocopherol concentrations in rats. Tocopherols were extracted from liver homogenate with hexane and measured using fluorescence detection in an HPLC system. Values represent means ± SEM; n = 7–10. *Different from similarly treated rats fed low (10 mg/kg) vitamin E (P < 0.05). {dagger}Different from corn oil–treated controls fed the same level of vitamin E (P < 0.05).

 
The number and volume of altered hepatic foci were quantified using PGST as an immunohistochemical marker. The numbers of PGST-positive foci per cubic centimeter and per liver were increased by PCB-77 at all dietary levels of vitamin E. The total focal volume as a percentage of liver volume was increased by PCB-77 in rats fed the 10 (P < 0.1) or 250 (P < 0.05) mg/kg diets but the mean focal volume was not affected (Table 1). The number and volume of foci were not significantly affected by either PCB-153 administration or dietary vitamin E.


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  		TABLE 1 Effect of vitamin E and PCBs on the induction of PGST-positive foci in the livers of rats1

 
The DNA binding activity of NF-{kappa}B was measured with EMSA. In rats treated with PCB-77, there was an increase (P < 0.05) in the DNA binding activity of NF-{kappa}B compared to controls (Fig. 2). In rats treated with PCB-77 or PCB-153, the DNA binding activity of NF-{kappa}B did not differ from corn oil–treated controls. Dietary vitamin E had no effect on the DNA binding activity of NF-{kappa}B in the corn oil– or PCB-153–treated groups. The specificity of the NF-{kappa}B band on the EMSA was demonstrated using cold competition and supershift analyses (data not shown).



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  		FIGURE 2 Effect of vitamin E and PCBs on the hepatic DNA binding activity of NF-{kappa}B in rats. A. Relative NF-{kappa}B DNA binding activity was measured by EMSA using a radiolabeled probe for NF-{kappa}B (Promega) with hepatic nuclear extracts from rats. Nuclear extracts were prepared from frozen liver tissue. Each lane contains extract from a single animal (5 µg). B. Quantitation of the NF-{kappa}B band as determined by subtracting background counts from the total counts in each NF-{kappa}B band. Values are means ± SEM; n = 3–4. *Different from corn oil–treated controls fed the same level of vitamin E (P < 0.05).

 
The levels of the IKK and I{kappa}B proteins were measured by Western blotting (Fig. 3). There were no differences in the IKK{alpha}, IKKß, and IKK{gamma} proteins due to PCB treatment but the high level of vitamin E tended to decrease I{kappa}B{alpha} and I{kappa}Bß protein levels qualitatively.



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  		FIGURE 3 Protein levels of cytosolic I{kappa}Bs and IKKs in rats treated with vitamin E and PCBs. Each line contains an equal amount of protein (50 µg) obtained from cytosol from 3 rats in the same group.

 

   DISCUSSION
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
LITERATURE CITED
 
In this study, we tested the hypothesis that oxidative stress induced by PCBs may contribute to their tumor promoting activities and therefore that the dietary supplementation of vitamin E would reduce formation of the PCB-induced altered hepatic focal lesions. The number and volume of PGST-positive foci were generally increased by PCB-77 at all of 3 levels of dietary vitamin E, but dietary vitamin E supplementation did not show a protective effect on the growth of PGST-positive foci.

The hepatic concentration of {alpha}-tocopherol was affected by dietary {alpha}-tocopherol level, and the level of {alpha}-tocopherol was increased by PCBs, with the highest increase in rats treated with PCB-77. This increase in hepatic {alpha}-tocopherol after PCB administration was reported earlier (13,20,21) and is proposed to be the result of acceleration of {alpha}-tocopherol absorption in the presence of PCBs (21). In our study, pathological examination showed that PCB administration caused fatty liver, with the most severe effect in rats treated with PCB-77, which suggested that the increase of {alpha}-tocopherol in liver could also be due to the accumulation of fat in the liver.

The transcription factor NF-{kappa}B was hypothesized to be important in tumor development (22) and in the tumor-promoting activity of PCBs (9). NF-{kappa}B may be involved in tumor promotion because of its role in the regulation of the cell cycle and apoptosis (22,23). The hepatic DNA binding activity of NF-{kappa}B was increased 1.5- to 2.5-fold by PCB-77, but not by PCB-153. In a previous study using the same initiation-promotion protocol, NF-{kappa}B was activated more than 4-fold by both PCB-77 and PCB-153 (9). The discrepancy between the 2 studies could be due to the different type of diets used. The level of antioxidants or the activity of the antioxidants could be different; in the present study, the vitamin mixture and the {alpha}-tocopheryl acetate were ordered fresh and the prepared purified diet was stored at –80°C until the day of use, whereas the unrefined diet used in the previous study was stored at room temperature until use. The fat source could also be a factor; corn oil was shown to activate NF-{kappa}B in Kupffer cells (24,25), although corn oil as vehicle did not affect hepatic NF-{kappa}B activation in a 2-d study (26). The long-term effect of dietary corn oil on hepatic NF-{kappa}B activity is still unknown. The purified diet used in our study contained solely corn oil stripped of vitamin E, whereas the fat sources in the unpurified diet used in the previous study (Purina Laboratory Diet No. 5001) were corn oil, soybean oil, fish oils, and some animal fat. Finally, the nonnutritive chemicals in unrefined diets could be activators or coactivators of NF-{kappa}B. Thus, NF-{kappa}B seems to be sensitive to dietary factors when animals are exposed to xenobiotics.

In summary, there was no protective effect of dietary vitamin E supplementation on the induction of altered hepatic focal lesions by PCBs in the present study. However, vitamin E slightly inhibited NF-{kappa}B activation and this effect was not associated with the induction of altered foci. The molecular mechanisms by which vitamin E exerts its effects will need to be determined for a complete understanding of how vitamin E may influence hepatic carcinogenesis.


   ACKNOWLEDGMENTS
 
We are grateful to Karen Calfee-Mason and Michelle L. Twaroski for their assistance with animal treatment and tissue collection.


   FOOTNOTES
 
1 This research was supported by NIEHS (ES07380) and the Kentucky Agricultural Experiment Station. Z. Lu was supported by the Training Core of the Superfund Basic Research Program (ES07380), by a Kentucky Opportunity Fellowship from the Graduate School of the University of Kentucky, and by a Dissertation Enhancement Award from the Graduate School of the University of Kentucky. Back

2 Presented in part at the Society of Toxicology Annual Meeting, San Francisco, CA, 2001 [Lu, Z., Lee, E. Y., Robertson, L. W., Spear, B. T. & Glauert, H. P. (2001) Effect of dietary vitamin E on the promotion of altered hepatic foci by 3,3',4,4'-tetrachlorobiphenyl (PCB-77) and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB-153) in rats initiated with diethylnitrosamine. Toxicol. Sci. 60: 161]. Back

4 Present address: University of Iowa, Department of Occupational and Environmental Health, 100 Oakdale Campus No. 219 IREH, Iowa City, IA 52242-5000. Back

5 Abbreviations used: DEN, diethylnitrosamine; EMSA, electrophoretic mobility shift assay; IKK, I{kappa}B kinase; NF-{kappa}B, nuclear factor-{kappa}B; PCB, polychlorinated biphenyl; PCB-77, 3,3',4,4'-tetrachlorobiphenyl; PCB-153, 2,2',4,4',5,5'-hexachlorobiphenyl; PGST, placental glutathione S-transferase. Back

6 The composition of the purified diet was as follows (g/kg): casein (vitamin free), 140; corn starch, 465.7; dextrose monohydrate, 255; cellulose fiber, 50; corn oil (tocopherol stripped), 40; AIN-93 mineral mix, 35; L-cystine, 1.8; choline bitartrate 2.5; AIN-93 vitamin mix without vitamin E, 10; and 10, 50, or 250 mg/kg vitamin E (as DL-{alpha}-tocopheryl acetate). Back

Manuscript received 21 November 2003. Initial review completed 3 January 2004. Revision accepted 26 August 2004.


   LITERATURE CITED
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 ABSTRACT
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 LITERATURE CITED
 

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5. Srinivasan, A., Lehmler, H. J., Robertson, L. W. & Ludewig, G. (2001) Production of DNA strand breaks in vitro and reactive oxygen species in vitro and in HL-60 cells by PCB metabolites. Toxicol. Sci. 60:92-102.[Abstract/Free Full Text]

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