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U.S. Department of Agriculture, ARS, Grand Forks Human Nutrition Research Center, Grand Forks, ND 58203;
* U.S. Department of Agriculture, ARS, Animal Manure & Byproducts Laboratory, Beltsville, MD 20705-2350;
IWMI-SEA Regional Office, Kasetsart University, Bangkok 10903, Thailand; and
** Department of Pathology, University of Western Ontario, London, ON N6A 5C1, Canada
3To whom correspondence should be addressed. E-mail: preeves{at}gfhnrc.ars.usda.gov.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • cadmium • metallothionein • MT-null mice • rats • rice
Cadmium (Cd) is a toxic element found in most types of food; an amount < 10 µg/kg is not considered a health risk. However, some foods are natural bioaccumulators of Cd; if the growing conditions are favorable, the concentrations in the edible portion might exceed 1000 µg/kg. These foods include rice, durum wheat, sunflower kernels (SFK),4 flax seeds, and shellfish. Thus, Cd acquired from these sources in large amounts might become a health risk, especially if these foods constitute significant portions of the diet.
Dietary Cd intake is usually considered the main pathway in determining the body burden of Cd. However, numerous factors other than concentration affect the rate of intestinal absorption of Cd, organ retention, and body burden. One of these factors is the interaction between Cd and other mineral nutrients in the intestinal lumen and at the site of absorption. Cd is highly interactive with high concentrations of dietary zinc (Zn), iron (Fe), and/or calcium (Ca), which reduce the rate of Cd absorption from various food sources when fed to animals or humans (1–8). Conversely, low nutritional status of Fe and Ca enhances Cd absorption (9–13).
Recent studies demonstrated that the rates of absorption and whole-body retention of food Cd from SFK or rice increased 7–10 times in animals marginally deficient in Fe and Ca. When marginal Zn deficiency was added, the increase in Cd absorption was even greater (14,15). Using 109Cd-labeled foods, it was observed that marginal intakes of Zn, Fe, and/or Ca reduced the transit time of Cd through the gut of rats by decreasing its turnover rate (16). Cd concentration in the duodenum was 10 times higher in rats fed the marginal diets than in those fed the adequate diets.
Because high Cd intakes induce intestinal metallothionein (MT), which binds Cd, an increase in MT is considered a likely storage form of Cd. Thus, one of the objectives of the current research was to determine whether intestinal MT induction played a role in duodenal Cd accumulation in rats that consume Cd at concentrations commonly found in food in association with marginally adequate levels of Zn, Fe, and Ca.
In past experiments, the Cd content of rice used in the diet of test animals was increased by adding CdSO4 to the cooking water. When the cooked rice was dried, it contained Cd at concentrations similar to that found in rice grown in paddies contaminated with Zn and Cd (15). It was unclear; however, whether Cd added to rice in this manner was as available for absorption as the Cd in rice produced in Cd-contaminated areas. To test this hypothesis, high-Cd rice grown in Zn/Cd contaminated paddies was obtained from an isolated and geographically unique location in Northwestern Thailand (17), and compared with rice enhanced with Cd during the cooking process.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Experiment 1. A mouse model without functional MT-1,2 genes (MT-null) was used. Breeding pairs of wild-type (WT; 129S1/SvImJ) and MT-null mice (129S7/SvEvBrd-Mt1tm1Bri Mt2tm1Bri/J) were obtained from an inbred colony at the Department of Pathology, University of Western Ontario, London, Canada, and shipped to our laboratory in Grand Forks, ND. The parents originated from Jackson Laboratory, Bar Harbor, ME, from a strain originally developed by Masters et al. (19). The experiment was a 3-factor design with genotype (MT-null and WT), sex, and dietary treatment (adequate Zn, Fe, and Ca and marginal Zn, Fe, and Ca) as the factors. The diets were similar to those described elsewhere by Reeves and Chaney (16).
The mice, (n = 55; 25 WT and 30 MT-null) were divided unevenly among the 8 treatment groups. As the pups were born, they were assigned to treatment groups by sex. For unknown reasons, there was a dearth of males born to the WT pairs, which left small numbers of mice in these groups. The mice were housed in plastic cages with paper bedding (Alphi-dri Paper Squares, Certified Grade; Shepherd Specialty Papers) and had free access to the test diets and to deionized water at all times.
After the mice had consumed their respective diets for 5 wk, each was anesthetized i.p. with a 1.37:1 mixture of ketamine: xylazine [1µL/g body weight (BW)] [Ketamine HCl (Ketaset), Fort Dodge Animal Health; Xylazine (Xyla-Ject), Phoenix Scientific], and blood (
1.0 mL) was collected from the abdominal vein until the mouse died. About 3 cm of the upper small intestine (duodenum) was removed and the lumen was rinsed thoroughly with 5 mL of ice-cold saline (8.5 g/L NaCl in deionized water). Total liver and both kidneys were removed and stored, along with the duodenum, at –20°C until analyzed for Cd, Zn, Fe, and Ca contents.
Experiment 2. The experimental design consisted of 5 different diet groups, each further subdivided into 2 treatment groups (Table 1): adequate or marginal with respect to Zn, Fe, and Ca. The experiment began with 80 female rats [SAS:VAF (SD), Charles River/Sasco], 8/group, at 3 wk of age. The rats were housed individually in stainless steel cages with wire-mesh bottoms. The rats had free access to powdered diet and deionized distilled water. Room temperature and relative humidity were 22°C and 50%, respectively. Descriptions of the diet formulations are given below and in Table 2.
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Each rat that received a dose of 109Cd was anesthetized i.p. with a 1.37:1 mixture of ketamine: xylazine (1 µL/g BW), and blood (10 mL) was collected from the abdominal aorta until the rat died. Subsequently, 20 cm of the upper small intestine was isolated and the mucosal layer was removed as outlined by Reeves and Chaney (15). Total liver, both kidneys, and spleen were removed and stored, along with the mucosa, at –20°C until analyzed for mineral contents. Nonlabeled rats were killed according to the methods outlined above and similar tissues were removed for analysis. The duodenal mucosa of these rats was removed for the determination of MT (20).
Rice processing. The rice with a naturally high Cd content was obtained from Thailand. In November 2001, as part of the collaborative research program between the International Water Management Institute and the Thai Department of Agriculture, rice grain samples (Variety HM105) were collected at harvest from an isolated and geophysically unique Cd/Zn cocontaminated site in Mae Sot District, Tak Province, Thailand. The study site receives irrigation sourced from Mae Tao Creek whose headwaters are within an actively mined Zn mineralized area. In total, 432 preselected fields from within 11 Farmer Field Groups were sampled. For each field, as a function of field size, 6 panicles from 20 to 30 randomly selected rice plants were collected and made into a composite. Concurrent soil samples (0–30 cm depth) were digested with aqua regia (21) and assayed. They contained Cd and Zn concentrations ranging from 0.5 to 218.2 mg/kg and 100 to 7919 mg/kg, respectively. Rice grain samples (digested in 2:1 HNO3:HClO4) ranged from <0.05 to 7.7 mg Cd/kg. Approximately 85% of the rice grain samples contained Cd at concentrations exceeding the Codex Committee on Food Additives and Contaminants draft provisional Maximum Level for Cd in rice grain of 0.2 mg Cd/kg (22). It is important to note that these rice grain Cd concentrations are not indicative of Thai rice grain as a whole as reported by Pongsakul and Attajarusit (23) and Zarcinas et al. (24).
The agricultural practice in the study area is to composite the harvested rice into a single bulk sample before threshing. To simulate this, for each field sampled, a subsample representing 10% of the total sample mass was taken and combined to form a bulk sample for each Farmer Field Group. These bulk samples were subsequently oven dried at 65°C for 72 h and stored for 1 y before polishing. Polishing was done by the Research and Product Development Department of the Institute of Food Research and Product Development, Kasetsart University, Thailand. The polished rice was air-shipped to the laboratory in Grand Forks, ND, for use in this study.
Low-Cd polished rice (Variety Kokuho Rose, unenriched, US#1 extra fancy, medium grain, grown in the San Joaquin Valley of California) was obtained from Nomura. All rice was cooked and processed according to the methods of Reeves and Chaney (16), except that the cooked rice was oven-dried at 60°C instead of lyophilized. By analysis, the low-Cd rice contained 12.2 ± 3.3 µg Cd/kg, 10.8 ± 0.2 mg Zn/kg, 2.3 ± 0.1 mg Fe/kg, and 45.0 ± 0.8 mg Ca/kg of edible grain. In contrast, the high-Cd rice contained 1390 ± 30 µg Cd/kg, 18.8 ± 0.1 mg Zn/kg, 2.6 ± 0.1 mg Fe/kg, and 39.2 ± 0.6 mg Ca/kg. To obtain reasonable but higher than normal amounts of Cd in the low-Cd rice, enough CdSO4 was incorporated into the cooking water to obtain 600 µg Cd/kg of cooked, dried, ground rice for Expt. 1 and 280 µg Cd/kg for Expt. 2.
Sunflower kernel processing. Raw SFK were obtained from Heartland Mills and processed according to the methods in Reeves and Chaney (14). By analysis, SFK contained 557 ± 16 µg Cd/kg, 51.3 ± 6.7 mg Zn/kg, 53.6 ± 3.0 mg Fe/kg, and 975 ± 27 mg Ca/kg of edible kernel.
Diet.
The compositions of the diets for Expt. 1 were similar to those used by Reeves and Chaney (15), and contained 240 µg Cd/kg. Diets for Expt. 2 are shown in Table 2, and were based on the AIN-93G-EGG diet formulation by Reeves (25). The compositions of the mineral supplements were based on the contributions of minerals from the dietary ingredients (25). Zn, Fe, and Ca in the marginal diets were supplied partially by the rice; however, even at 40% of the diet, the rice did not supply enough of any of the 3 minerals to obtain the desired marginal amount. Thus, extra minerals were added as Zn carbonate, ferrous sulfate, and Ca carbonate to bring them to the required marginal level. In the adequate diet, the concentrations of Zn, Fe, and Ca were adjusted by adding more of the mineral salts to obtain the concentrations found in the AIN-93G diet (26). The analyzed concentration of each mineral is shown in Table 1 for each diet. The marginal values represent 30, 30, and 50% of the requirements of Zn, Fe, and Ca, respectively, for growing rats as recommended in the standard experimental diet for laboratory rodents, AIN-93G (26).
Diet labeling with 109Cd for Expt. 2.
It was not possible to label the rice and SFK endogenously with 109Cd; therefore, an exogenous labeling procedure was used, which was similar to that outlined by Reeves and Chaney (16). The dried material was thoroughly mixed and aliquots were analyzed for 109Cd to ensure equal distribution of the label in the dried diet. One gram of diet labeled with 3 µCi of 109Cd was then fed to each rat by dispensing it into an acid-washed glass food container.
Sample analysis. The procedures used to prepare and analyze tissue samples for mineral content were similar to those outlined by Reeves and Chaney (14). To ensure adequate quality control, samples of bovine liver with certified concentrations of minerals were analyzed with each batch of tissues [Cd, 500 ± 30 µg/kg; Zn, 127 ± 16 mg/kg; Fe, 184 ± 15 mg/kg; Ca, 116 ± 4 mg/kg (NIST)]. Assayed values were within the accepted ranges: Cd, 515 ± 14 µg/kg; Zn, 124 ± 13 mg/kg; Fe, 190 ± 21 mg/kg; and Ca, 122 ± 6 mg/kg (mean ± SD, n = 6).
Statistical analysis. The data in Expt. 1 were analyzed by 3-way ANOVA using the StatView (Version 5.0) computer program (SAS Institute). In Expt. 2, data were analyzed by 2-way ANOVA using the Proc Mixed procedure in SAS. For many variables, the group variances were not homogeneous, but differed greatly between the groups fed marginal or adequate diets. For these variables, rather than using a single pooled variance estimate, 2 variance estimates were calculated: 1 for the 5 marginal groups and 1 for the 5 adequate groups. When the interaction term between diet components and mineral status was significant (P < 0.05), Bonferroni contrasts were used. Contrasts were limited to the comparisons of interest, i.e., between the means of the 5 dietary treatments within each level of dietary minerals (adequate or marginal) and between the level of dietary minerals for each of the 5 components.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Kidney Cd concentration was 2–4 times higher in mice consuming diets with marginal mineral content compared with those consuming minerals at adequate levels (Table 3). There was no effect of genotype or sex on kidney Cd concentration. There was no treatment effect on the concentration of kidney Zn; however, both kidney Fe and Ca were lower (P < 0.024 and P < 0.050, respectively) in male mice than in female mice (Table 3).
Experiment 2. Regardless of the type of diet, there was more (P < 0.001) 109Cd in the bodies of rats consuming diets with marginal Zn, Fe, and Ca than in those consuming diets with adequate minerals (Fig. 2). The amount of label entering the body from rice was higher (P < 0.05) than the amount from SFK. Rats fed the AIN-93G-EGG diet with or without added Cd had more 109Cd in their bodies than rats fed SFK, but values did not differ from those in rats fed rice.
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50% of the dose. Even after 7 d, the effect of dietary mineral content remained, although it was reduced in magnitude, 90 vs. 80% (P < 0.001); however, there were differences among diet types. At d 3, the difference in fecal excretion between rats fed SFK diets with adequate minerals and those fed SFK diets with marginal minerals was 80 vs. 66%, respectively, compared with 80 vs. 50% in the rice-fed groups.
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25–40% of that in rats fed the other diets. The concentration of Cd in the mucosa of rats fed the AIN-93G-EGG with no added Cd was very low (Fig. 5).
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Although dietary Ca concentrations did not differ between rats following the marginal and adequate regimens, dietary components affected the mucosal concentration of this mineral. Rats fed rice diets had much more duodenal Ca than rats fed SFK or the AIN-93G-EGG diets. The concentration of Ca in the mucosa of rats fed marginal Ca in rice or AIN-93G-EGG diets was lower than in those fed adequate Ca, but there was little effect on mucosal Ca in rats fed SFK (Table 4). The concentration of MT in the duodenal mucosa of rats was not affected by feeding a marginal supply of minerals (Table 4), even though mucosal Cd was elevated by marginal mineral status (Fig. 5). Diet composition affected (P < 0.036) mucosal MT in that rats fed the natural rice diets tended to have less mucosal MT than those fed the AIN-93G-EGG diets alone.
The concentrations of liver Zn and Ca were not affected by marginal mineral status; however, liver Fe was reduced (P < 0.001) considerably in rats with marginal status (Table 4). There was a significant interaction (P < 0.002) between mineral status and diet components, which showed that the difference in liver Fe between rats with marginal and adequate mineral status was much greater in those fed rice and AIN-93G-EGG than in those fed SFK. Although kidney Zn was higher (P < 0.001) in rats fed the AIN-93G-EGG diet than any other diet, the differences were very small (Table 4). Kidney Fe was lower (P < 0.001) in rats fed the marginal mineral diets; however, dietary components had no effect. The concentration of kidney Ca was not affected by mineral status or diet components.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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It was shown that Cd and Fe use the same enterocyte apical membrane transporter, divalent metal transporter-1, to transport Cd into cells; thus, the 2 minerals compete with each other for uptake (29,30). When dietary Fe intake is low relative to Cd, enterocyte uptake of Cd would be favored. Similarly, it was suggested that Cd and Ca use the same Ca channel in the liver (31); however, Lecoeur et al. (32) blocked the Ca channels of an intestinal epithelial cell model, HT-29, with verapamil, and no effect on Cd uptake occurred. In addition, Hoadley and Johnson (33) concluded that the 2 elements did not share a common carrier in rat intestine. Excess dietary Zn also was shown to reduce Cd absorption (34,35); perhaps these 2 minerals also act through specific and common transporters.
Another important issue addressed in this study was whether endogenous Cd in rice is more or less available than Cd added to the rice during cooking. Cd in rice diets with endogenous Cd was 30% higher than that in rice diets containing exogenous Cd. Even so, rats fed endogenous rice-Cd and marginal minerals tended to have less Cd in the duodenum, liver, and kidney than those fed exogenous rice-Cd. However, when rats were fed adequate minerals, the trend was in the opposite direction. This suggests that Cd availability did not differ between the 2 forms. Thus, data gathered in previous studies in which extrinsically labeled rice was used likely were reasonably accurate (15,16).
The availability of endogenous Cd from 2 different food sources, rice and SFK, was compared in the current study. Rats were fed diets with 20% SFK and Cd concentrations similar to that in 40% rice diets. When a marginal mineral status was induced in each group, rats fed the rice diets accumulated as much as 4 times more Cd in their organs than rats fed SFK. Similar findings were noted in previous studies (14,15), but could not be substantiated until both food sources containing endogenous Cd were compared in side-by-side experiments. As discussed earlier (16), SFK supply much more endogenous Fe and Zn than rice; thus, under normal dietary conditions, foods with high endogenous concentrations of Cd antagonists as well as Cd would provide a natural resistance to Cd absorption. This is one way in which different diets and different foods can influence the bioavailability of dietary Cd.
It also was shown in the current study that Cd availability from SFK was <50% of that from rice. The reason of this difference is not apparent; however, as stated above, it is obvious that the organic matrices vary widely between the different food types, and each contributes different amounts of endogenous inhibitors of Cd absorption, specifically, Zn, Fe, Ca, and phytate. However, because each of these minerals was added to the diets to equalize the concentrations in both diets, it seems unlikely that the higher natural mineral composition of SFK could have been the cause.
Phytic acid is a metal-binding component occurring in plant foods in variable amounts, and its presence in rice and SFK might have contributed to this difference. Although phytic acid was not evaluated as part of this study, it is estimated that SFK contain 4.5 g/kg (36), and milled rice contains 1.5 g/kg (37). At 40% of the diet, rice would contribute 600 mg phytate/kg of diet, whereas SFK at 20% of the diet would contribute 900 mg phytate/kg of diet. Whether this 50% difference in dietary phytate was sufficient to reduce Cd absorption and tissue accumulation in rats fed SFK compared with those fed rice, remains to be determined.
In conclusion, the present experiments helped clarify the role of intestinal MT in Cd absorption at low dietary Cd concentrations, and emphasized the role of mild Fe, Zn, and Ca deficiencies in dietary Cd absorption by humans and animals. In most past studies dealing with the role of MT induction in Cd absorption, toxicologic doses of Cd rather than amounts commonly found in foods were used. By using MT-null and control mice fed adequate and marginal Fe, Zn, and Ca diets, the role of intestinal MT induction in Cd absorption was minimal. The marginal mineral status of the mice caused equally enhanced accumulations of Cd in the duodenal mucosa of both MT-null and control mice. Overall, the findings support our previous work that illustrated the overwhelming importance of nutritional deficiencies of Fe, Zn, and Ca, even mild ones, in the control of absorptiion and potential environmental risk of dietary Cd.
Additionally, in a direct comparison of the availability of endogenous and exogenous Cd in rice fed to rats that were marginally deficient with respect to Zn, Fe, and Ca, there was no difference between the 2 methods of enhancing the Cd concentration in the food source. When Cd absorption was compared between rice and SFK, both of which contained high endogenous Cd, Cd from rice was 3 times more likely to be absorbed than Cd from SFK. Together these findings add additional weight to our earlier proposal that malnutrition induced by subsistence rice diets that supply marginal-to-deficient levels of Fe, Zn, and Ca to human consumers could greatly enhance the risk of dietary Cd exposure (16). Also, as strongly pointed out earlier by Fox (38) and Fox et al. (6), there is a great need to conduct food Cd bioavailability studies with dietary Cd concentrations near those found naturally in foods, rather than at concentrations seldom reached in human diets, even from foods grown in environmentally contaminated areas.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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2 Mention of trade names or commercial products in this article is solely for providing specific information and does not imply recommendation or endorsement by the U.S. Department of Agriculture.
4 Abbreviations used: BW, body weight; MT, metallothionein; SFK, sunflower kernels; WT, wild-type.
Manuscript received 4 August 2004. Initial review completed 20 September 2004. Revision accepted 20 October 2004.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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