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,2
* Department of Biological Sciences and
College of Veterinary Medicine, Mississippi State University, Mississippi State, MS 39762 and
R & D Office, Health Care Division Product Development Department, Otsuka Pharmaceutical Co., Ltd., 31–13 3-Chome Saigawa Otsu, Shiga 520-0002 Japan
2To whom correspondence should be addressed. E-mail: rkb1{at}ra.msstate.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • polychlorinated biphenyls • fiber • retinol
Diets supplemented with nondigestible carbohydrates alter the populations and metabolic characteristics of the gastrointestinal tract (GIT)2 bacteria (1–5), and have been associated with various health benefits, including immunomodulation (6,7) and enhanced resistance to enteric and systemic health challenges (6). Moreover, diets supplemented with fiber that can be fermented by the GIT bacteria can increase the size of the small intestine and its capacity to absorb water-soluble nutrients (8–15). These benefits have led to the marketing of fiber, and particularly fermentable forms, as dietary supplements.
Few studies have examined whether dietary fiber supplementation has detrimental consequences. For example, there is justifiable concern that some fiber supplements may reduce the availability of lipid-soluble nutrients, and similar concern about nonabsorbable fat substitutes (16). Also, the larger and increased absorptive capacities of the GIT of some mammals fed diets with nondigestible oligosaccharides (NDO) can be predicted to increase the absorption and accumulation of contaminants and toxins present in the environment and in foods. However, dietary supplementation with several types of soluble and insoluble fiber does not increase tissue accumulation of contaminants and may lower it (17,18). Instead, dietary fiber increases fecal excretion of contaminants (19–21). Apparently, the contaminants are adsorbed onto the dietary fiber and to bacteria, which increase in density when some forms of fiber are added to the diet, and this increases fecal elimination.
In a previous study (17), we reported that dietary supplementation with various types of fiber increased fecal excretion of mirex and methylmercury, but did not reduce small intestinal absorption and accumulation of the lipid-soluble vitamin, retinol. Interestingly, accumulation of retinol was lower when mice were exposed to methylmercury, compared with mirex. The present study measured accumulation and excretion of polychlorinated biphenyls (PCB) and retinol during a 2-wk exposure period in mice that were fed diets with types of fiber that varied in solubility and fermentability. Polychlorinated biphenyls are chemically stable and lipophilic; they are widely dispersed in terrestrial and aquatic ecosystems, accumulate in numerous tissues and can be secreted in breast milk (22–24). The health consequences of PCB exposure include neurological disorders, carcinogenic and teratogenic effects and diminished reproductive and immunological functions (22–24). The study used Arochlor 1254, a commercially available mixture of PCB, and retinol, a lipid-soluble nutrient that was tested to determine whether various amounts and types of fiber affect accumulation and elimination.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The mice were randomly assigned by cage to two control and six experimental diets (six cages per diet) that were based on the AIN 76A formulation with 0 or 100 g/kg of fiber added to the dry diet (17). One control diet contained a form of cellulose (solkafloc) that is poorly fermented by the GIT bacteria. The second control diet was prepared without fiber (fiber-free). In each of the six experimental diets, the cellulose was replaced with one of six varieties of fiber. Of these, four are highly fermentable [4G-ß-D-galactosylsucrose (lactosucrose; Ensuiko Sugar Refining, Yokohama, Japan), polydextrose (Danisco Culter Japan, Tokyo, Japan), indigestible dextrin (Fibersol 2; Matsutani Chemical Industry, Itami, Japan), soybean polysaccharide (Soyafiber-S-RA100; Fuji Oil, Osaka, Japan)]. The remaining two fibers [rice bran (Toryou Sangyou, Tokyo, Japan) and chitosan (Kimitsu Chemical Industries, Tokyo, Japan)] are less fermentable.
The mice were fed the control and experimental diets for 8 wk before a 2-wk exposure period to allow the GIT and the resident bacteria to adapt. Water was available ad libitum throughout the 1-wk acclimation, 8-wk adaptation, and 2-wk exposure periods. Food consumption by all mice in each cage was measured for the first 2 wk of the adaptation period. Because the mice ate slightly more of the two control diets and the experimental diet with lactosucrose, we minimized treatment differences due to variation in food consumption by adding 3 g/d of food per mouse to each cage every 2 to 3 d. The body mass of each mouse was recorded every 2 wk.
Exposure to Arochlor 1254 and retinol. After the 8-wk adaptation period, the mice in each cage were transferred to a metabolic cage. During the next 2 wk the mice continued to consume the same diet and each morning (0800 to 0830) were fed peanut butter (0.4 g/mouse) containing Arochlor1254 and retinol. During the 2-wk period the mice were fed Arochlor (Chem Service, West Chester, PA) at a dosage (5.9 mmol/mouse) estimated to be 5% of the reported mean lethal dose. This level of exposure was considered to be nontoxic and did not cause any obvious abnormalities. The 2-wk dosage of retinol (all-trans; Sigma Chemical, St. Louis, MO) was 175 nmol/mouse, which doubled the amount in the diet (25). Accumulation of Arochlor 1254 and retinol was quantified by adding 9.9 kBq of 14C Arochlor 1254 (8.9 nmol; Perkin-Elmer Life Sciences, Boston, MA) and 9.9 kBq of 3H retinol (0.019 nmol; Perkin-Elmer Life Sciences) to each g of peanut butter.
Collection of tissue samples. Feces and urine were separately collected daily (0730 to 0800) from each metabolic cage. Whole blood samples (30 to 40 µL) were obtained from each mouse in heparinized capillary tubes by saphenous vein puncture (26) at 0800 to 0900 on d 1, 3, and 7 of the 2-wk exposure period. The mass of the feces and the volume of the urine and blood samples were recorded, and all samples were stored at -20°C until analyzsis.
After the 2-wk exposure period, the mice were killed by CO2 asphyxiation at 0800 to 1200. The food was removed from the cages 5 to 8 h earlier so the mice were in a postabsorptive state. Following a protocol described previously (17), seven solid tissues (liver, gall bladder, small and large intestine, mesentery, brain and kidney) and the contents of large intestine were collected from each mouse and the mass of each sample was recorded. Another blood sample was obtained from the abdominal vena cava. The collected tissue samples, contents of the large intestine, and blood samples were stored at -20°C until analysis. The seven solid tissues were selected to investigate how dietary fiber affects concentrations of Arochlor 1254 and retinol in tissues associated with the absorption (small and large intestine), accumulation (brain and mesentery), metabolism (liver) and excretion (kidney and gall bladder) of environmental contaminants.
Measurement of radioactivity in collected samples. Three protocols were used to measure the amount of radioactivity determined by liquid scintillation counting (Tri-Carb 2100TR; Perkin-Elmer Analytical Instruments, Shelton, CT) associated with the collected samples and the peanut butter vehicle. Samples (50 to 100 mg) from the small and large intestine, mesentery and brain and the intact gall bladder with its contents were solubilized (Solvable; Perkin-Elmer Life Sciences), and scintillant (Ultima gold; Perkin-Elmer Life Sciences) was added. The urine samples (200 µL) were directly added to the scintillant.
The solubilization procedure was not effective for measuring the accumulation of radioactivity in the liver and kidney tissue, the contents of the large intestine, the blood samples and the labeled peanut butter. Therefore, these samples were oxidized (Model 307; Perkin-Elmer Analytical Instruments). The 14C Arochlor 1254 was recovered in a combination of Carbosorb E and Permafluor E (Perkin-Elmer Life Sciences), and the 3H retinol was separately recovered in Monophase S (Perkin-Elmer Life Sciences). Measurements of radioactivity in samples of intestine, mesentery and brain that were analyzed by both solubilization and oxidation differed by < 5 to 8%.
The levels of radioactivity per mmol of Arochlor 1254 and retinol were calculated from the samples of peanut butter, which had known concentrations of Arochlor 1254 and retinol, and were used to quantify the concentrations of Arochlor 1254 and retinol in the blood, solid tissue, urine and feces. Concentrations in the tissues were expressed as nmol/g and in the blood as nmol/L. Total organ accumulations were calculated by multiplying tissue specific accumulation times organ mass. Excretion [nmol/(d · mouse)] was calculated as the product of fecal (nmol/g) and urine (nmol/mL) activity times total fecal mass [g/(d · mouse)] and urine volume [mL/(d · mouse)]. The total amount of retinol and Arochlor 1254 in the large intestine (nmol/mouse) was calculated as the product of the retinol and Arochlor concentrations in the contents (nmol/g) times the mass of the large-intestine contents (g/mouse).
Statistics. The values presented in the tables are means ± SEM. One-way ANOVA was used to test the effects of the various diets on accumulation of retinol and Arochlor 1254 in individual tissues, feces and urine. When a significant dietary effect was detected, Duncan’s multiple range test was used to identify differences among the diet groups. Two-way ANOVA was used to test the effects of time and diet on concentrations of PCB and retinol in whole blood, and to test for the effect of tissue type on accumulation of retinol and PCB. For all tests, values of P < 0.05 were considered significant. The analyses were performed using SAS Version 8.0 statistical software (SAS Institute, Cary, NC).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Food consumption, body mass, organ and tissue weights and intestinal dimensions. The amount of food available to the mice in each cage was limited, and consumption of the 8 diets ranged from 14.25 to 14.95 g/(5 mice · d) during the 10-wk period. The food intake of individual mice was not measured.
Initial body mass did not vary among the diet groups (25 to 27 g; data not shown). Despite similar levels of food consumption, at the end of the 10-wk period, mice fed the fiber-free diet weighed more than those fed the diets with cellulose, polydextrose, indigestible dextrin and soy polysaccharides (P < 0.05), and mice fed the chitosan diet weighed the least (Table 1; P < 0.05).
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The large-intestine length in mice fed the diets with experimental fiber was greater than in mice fed the control diets without fiber and with cellulose (P < 0.05). Mice fed the diets with chitosan and lactosucrose had the greatest large-intestine mass, whereas large-intestine mass was lowest in mice fed the fiber-free, cellulose and rice bran diets, with intermediate values in mice fed the polydextrose, indigestible dextrin and soy polysaccharide diets.
The mass of the liver and mesentery varied among diet groups (P < 0.05) in a manner consistent with total body mass. Consequently, the relative liver mass (liver mass/body mass) was 0.044 ± 0.001 for all diet groups, except for the higher values in mice fed the chitosan diet (0.049 ± 0.001; P < 0.05). Normalizing mesentery mass to body mass yielded the same pattern.
The mass of the gall bladder, kidney and brain did not vary among treatments (Table 1).
The percentage of total body mass represented by the seven tissues was 15% in mice fed the chitosan diet, which was higher (P < 0.05) than in mice fed the rice bran, cellulose and polydextrose diets (12%) or the fiber-free, soy polysaccharide, lactosucrose and indigestible dextrin diets (13%).
Mass of large-intestine contents and feces and volume of urine. The mass of the large-intestine contents was greater in mice fed the polydextrose diet than in mice fed the other diets (Table 2). However, during the 2 wk period mice fed the chitosan diet produced the greatest total mass of feces among all the diet groups (P < 0.05). The mice fed the rice bran diet produced lower total fecal mass compared with mice fed the cellulose diet (P < 0.05), but greater fecal mass compared with mice fed the diets with fermentable fiber (lactosucrose, polydextrose, indigestible dextrin and soy polysaccharides; P < 0.05). Mice fed the fiber-free diet produced the lowest total fecal mass among all the diet groups (P < 0.05). Total urine volume for the 2-wk collection period did not vary among the diet groups.
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Accumulation of Arochlor 1254. Concentrations of Arochlor 1254 varied among the diet groups in all tissues sampled, with the exception of the large intestine (Table 4). Total organ accumulation also varied among the groups (data not presented). Total small-intestine accumulation of Arochlor 1254 in mice fed the chitosan diet (53 ± 11 nmol/entire small intestine) exceeded that in mice fed the fiber-free (26 ± 6 nmol) and cellulose (21 ± 3 nmol) diets (P < 0.05). Mice fed the chitosan diet also had greater total accumulation of Arochlor 1254 in the liver, kidney, mesentery and brain compared with mice fed the cellulose diet (P < 0.05), whereas gall bladder accumulation was lower in the chitosan group (P < 0.05). Mice fed the rice bran diet had lower liver accumulation of Arochlor 1254 than mice fed the cellulose diet (P < 0.05). Mice fed the polydextrose diet had greater gall bladder accumulation of Arochlor 1254 than mice fed the fiber-free and cellulose diets (P < 0.05).
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Arochlor 1254 in the large-intestine contents, feces and urine. The amount of Arochlor 1254 in the large-intestine contents at the time of death was higher in mice fed the polydextrose diet compared with mice fed the cellulose and chitosan diets (Table 5; P < 0.05). Values were intermediate for the remaining diet groups.
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Urinary elimination of Arochlor 1254 was 
6.5% of fecal elimination among the groups, but was higher in mice fed the diets with polydextrose, indigestible dextrin and soy polysaccharides compared with that in mice fed the diets with cellulose, rice bran and chitosan (Table 5; P < 0.05). The sum of urinary and fecal elimination of Arochlor 1254 (total elimination) for mice fed the chitosan diet [151 ± 7 nmol/(d · mouse)] exceeded that for all other treatment groups (P < 0.05). Total elimination of Arochlor 1254 was higher in mice fed the indigestible dextrin diet than in mice fed the fiber-free diet (P < 0.05). Total elimination of Arochlor 1254 was lowest in mice fed the fiber-free and polydextrose diets [both 85 ± 4 nmol/(d · mouse)] compared with the other diet groups.
Retinol in the large-intestine contents, feces and urine. The dietary treatments did not affect retinol concentration in the large-intestine contents (nmol/mouse) or total 2-wk excretion in urine. Total fecal elimination of retinol was higher in mice fed the chitosan diet than in all other groups, which did not differ (Table 5; P < 0.05).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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The intestinal capacity to absorb nutrients, as well as contaminants, is dependent on a combination of the amount of intestinal absorptive tissue and the rates of carrier-mediated and carrier-independent absorption. Although a carrier-mediated process for PCB absorption has not been identified, 90 to 100% of an oral dose of PCB and related compounds is absorbed from the GIT (27–31). Because a high percentage of an oral PCB dose is absorbed in any case, it seemed unlikely that diet-induced changes in intestinal dimensions, such as the larger postgastric gut in mice fed the chitosan diet, would markedly alter absorptive capacity. Despite this, the combined total accumulation of Arochlor 1254 by the small and large intestine at the time of death (nmol/mouse) varied almost fourfold, from 15 ± 2 nmol for mice fed the rice bran diet to 57 ± 14 nmol for those fed the chitosan diet (P < 0.05).
In contrast to PCB, retinol absorption is at least partly mediated by a carrier-mediated process (32). Still, accumulation in the small intestine was independent of diet, as also reported by others (17). Interestingly, the fraction of the retinol dose that was administered during the 2-wk period and recovered in the small and large intestine combined (0.8%) was almost 1000-fold greater than the fraction of the Arochlor 1254 dose that was recovered in the small and large intestine (0.001%).
Solutes with high lipophilicity are typically carried in the blood by binding proteins. Notable is the direct relationship between the serum concentration of retinol and that of retinol-binding protein (33). It is possible that this study found no dietary effects on the accumulation of retinol in the blood because the various treatments did not differ in serum concentration of retinol-binding protein or in other mechanisms that regulate the systemic availability of retinol. The lack of further increase in blood retinol concentrations after d 7 of exposure is consistent with a limited concentration of binding proteins. In contrast, PCB concentrations in whole blood continued to increase in all diet groups during the 14-d exposure period. It is of particular importance that the blood concentrations at the time of death were lower in mice fed the diets with water-insoluble and poorly fermented fibers (cellulose, rice bran and chitosan) compared with those in mice fed the diets with fermentable fiber (lactosucrose, polydextrose, soy polysaccharides and indigestible dextrin).
Because PCB is lipophilic, tissues with a high percentage of fat routinely accumulate higher concentrations (34–36). This is consistent with the greater magnitude of Arochlor 1254 accumulation in the mesentery, gall bladder and liver in the present study, compared with the kidney and intestinal tissues (P < 0.05). However, the relationship between tissue lipid content and PCB accumulation is not universal, as is evident from the lower levels of Arochlor 1254 in the brain of mice in the present study, and of PCB and other contaminants in the brain in other species of mammals (37,38). Apparently, the blood-brain barrier can restrict the accumulation of PCB by the central nervous system.
Although the percentage of total body mass represented by the seven tissues studied ranged from 12 to 15%, these tissues accumulated only 5.5 to 7.5% of the administered dose after correcting for fecal and urinary losses. Evidently, the remaining tissues accumulated proportionally more of the Arochlor 1254. Based on the distribution of PCB in rats (35,36), the majority of the administered Arochlor 1254 dose that was not recovered (56 to 73%) would have accumulated in adipose tissue, skin, and muscle. Interestingly, despite accumulating more Arochlor in five of the seven tissues studied, the apparent total body retention of Arochlor 1254 [100(total dosage-dosage recovered in feces and urine)/total dosage] in mice fed the chitosan diet (64 ± 2%) was lower (P < 0.05) than in mice fed the fiber-free diet (80 ± 1%), the cellulose diet (78 ± 1%) or the other experimental fiber diets (77–79 ± 1%).
Accumulation of retinol by the seven tissues (28 to 35% of the administered dose) was higher than for Arochlor 1254, due largely to the high level of accumulation in the liver, and also varied among diet groups. The patterns of the estimated retention of retinol differed from those of Arochlor 1254. Specifically, the total retention of retinol in mice fed the chitosan diet (70 ± 3%) was lower (P < 0.05) compared with that in mice fed the polydextrose (80 ± 2%), indigestible dextrin (79 ± 1%) and cellulose (78 ± 2%) diets. Values for the other experimental groups were intermediate and did not differ from those for the chitosan group.
The high levels of Arochlor 1254 measured in the gall bladder suggest enterohepatic recycling of PCB. This speculation agrees with the presence of the mercapturic acid pathway in rats (39), and is corroborated by the hepatic and intestinal xenobiotic metabolism of PCB (40). Although not directly examined, the differences in accumulation of Arochlor 1254 in the liver, gall bladder, small intestine and kidney among the diet groups suggest that the amount and type of fiber can influence the metabolism, recycling and elimination of PCB. The present study did not determine whether radioactivity detected in the tissues was associated with Arochlor 1254 or a metabolite.
Because the major part of an oral dose of PCB is absorbed, most of the 20 to 33% of the administered dose of Arochlor 1254 that was recovered in the urine, feces, and large-intestine contents at the time of death would have been eliminated from the body after absorption. The 16-fold higher fecal than urinary elimination of Arochlor 1254 is consistent with reports that rats excrete 80% of a dose of 3,3',4,4'–tetrachlorobiphenyl in the feces within 3 to 5 d (41,42). Moreover, because there is low basal-to-apical movement of PCB through the epithelial cells (43), the majority of the Arochlor 1254 and other PCB recovered in feces was probably recycled in the bile. The higher fecal excretion of Arochlor 1254 in mice fed the diets with poorly fermentable fiber, compared with that in mice fed diets with fermented fiber, corroborates reports on rats fed rice bran and exposed to PCB (21). One explanation is that Arochlor 1254, other PCB and other contaminants are adsorbed onto poorly fermented dietary fiber, and this enhances fecal elimination. A similar mechanism of elimination has been proposed for the increased fecal excretion of PCB when human subjects ingest the nonabsorbable lipid substitute Olestra (16). Moreover, GIT transit is influenced by fiber content (20), and poorly fermented fiber sources that reduce residence time, such as chitosan, would lower in vivo absorption of environmental contaminants (17,44). In contrast, bacterial metabolism of fermentable fiber would release adsorbed contaminants, decreasing fecal excretion and increasing intestinal absorption and recycling. This expectation is consistent with the higher concentrations of Arochlor 1254 in the blood and gall bladder of mice fed the lactosucrose, polydextrose, indigestible dextrin and soy polysaccharide diets.
The accumulation, recycling, disposal and toxicity of drugs and environmental contaminants (18,45–48) are dependent on a combination of xenobiotic transformation enzymes associated with the GIT mucosa, liver (49) and extra-GIT tissues (50) and export transporters, such as P-glycoproteins, in the intestine and kidney (51). Polychlorinated biphenyls are substrates for the oxidative reactions of phase I enzymes, and they upregulate xenobiotic metabolism in mice (23,44,52,53). Subsequent conjugation of the phase I products during phase II metabolism confers water solubility and increases excretion in the bile and urine (22). Although the magnitude of urinary excretion of Arochlor 1254 was lower than that of fecal excretion, as also reported by others (42), the effect of various types of fiber on urinary excretion was opposite to that on fecal excretion. Specifically, urinary excretion in mice fed the diets with fermentable fiber [6.5 ± 0.2 nmol/(d · mouse); mean for 14 d for lactosucrose, polydextrose, indigestible dextrin and soy polysaccharides] was higher (P < 0.0001) compared with that in mice fed the diets with poorly fermented fiber [5.5 ± 0.2 nmol/(d · mouse); mean for 14 d for cellulose, rice bran and chitosan]. These findings suggest an interaction among type of fiber, xenobiotic metabolism and the magnitude and route of PCB elimination.
The present study did not investigate the populations and metabolic characteristics of the GIT bacteria. However, the resident bacteria can play an important role in xenobiotic metabolism (54), and can influence intestinal dimensions and mucosal functions (55–57) and enterohepatic recycling of PCB and related compounds (58). Therefore, changes in bacterial densities and metabolism caused by diets with different amounts and types of fiber (1–5) can be predicted to alter the availability, accumulation, and elimination of PCB and other environmental contaminants.
The present findings, in conjunction with other reports, indicate that the amount and type of dietary fiber can influence the absorption, metabolism, distribution, accumulation and elimination of PCB, but do not affect accumulation and elimination of retinol. None of the types of fiber used in the present study lowered the accumulation of Arochlor 1254 relative to the fiber-free and cellulose control diets. Still, the results suggest that combinations of soluble and insoluble fiber may promote excretion by adsorption, enhancing xenobiotic transformations by the host and the bacteria resident in the GIT, and increase elimination in the feces. Further information is needed to identify specific fiber combinations and amounts that will most effectively reduce the toxicity and enhance the urinary and fecal excretion of PCB and other environmental contaminants.
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FOOTNOTES |
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3 Abbreviations used: GIT, gastrointestinal tract; LD50, median lethal dose; NDO nondigestible oligosaccharides; PCB, polychlorinated biphenyls.
Manuscript received 27 May 2003. Initial review completed 15 July 2003. Revision accepted 3 October 2003.
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