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BACKGROUND: Calcium is the only reported dietary inhibitor of both heme- and nonheme-iron absorption. It has been proposed that the 2 forms of iron enter a common pool in the enterocyte and that calcium inhibits the serosal transfer of iron into blood. OBJECTIVES: We aimed to ascertain whether the inhibitory effect of calcium occurs during initial mucosal uptake or during serosal transfer and to compare the serosal transfer of heme and nonheme iron, which should not differ if the 2 forms have entered a common mucosal iron pool. DESIGN: Whole-gut lavage and whole-body counting were used to measure the initial uptake (8 h) and retention (2 wk) of heme and nonheme iron with and without a calcium supplement (450 mg). Two experiments tested basal meals with low iron bioavailability and 360 mg Ca (n = 15) or with high iron bioavailability and 60 mg Ca (n = 12). RESULTS: Added calcium reduced the initial uptake of heme iron by 20%, from 49% to approximately 40% from both meals (P = 0.02), and reduced the total iron absorbed from the low- and high-bioavailability meals by approximately 25% [from 0.033 to 0.025 mg (P = 0.06) and from 0.55 to 0.40 mg (P < 0.01), respectively]. Calcium did not affect the serosal transfer of either form of iron. CONCLUSIONS: Calcium supplementation reduced heme and total iron without significantly affecting nonheme-iron absorption, regardless of meal bioavailability. Calcium inhibited the initial mucosal uptake rather than the serosal transfer of heme iron. Differences in serosal transfer indicate that heme and nonheme iron did not enter a common absorptive pool within 8 h after a meal. Copyright © 2005 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

BACKGROUND: Results of cross-sectional studies suggest that in healthy people, iron absorption adapts to meet physiologic needs and stabilize iron stores, but this has not been adequately tested in longitudinal studies. OBJECTIVE: We tested whether heme- and nonheme-iron absorption decrease in response to increased iron intake and whether iron stores reach a steady state. DESIGN: In a randomized, placebo-controlled trial, heme- and nonheme-iron absorption by healthy men and women (n = 57) were measured before and after 12 wk of supplementation with 50 mg Fe/d as ferrous sulfate. Serum and fecal ferritin were measured during supplementation and for 6 mo thereafter. RESULTS: Initially, both heme- and nonheme-iron absorption were inversely associated with serum ferritin concentration. Volunteers who took iron supplements, even those with serum ferritin <21 microg/L (n = 5), adapted to absorb less nonheme iron (3.2% at week 12 compared with 5.0% at week 0, P: < 0.001) but not less heme iron from a beef-based meal. Serum ferritin concentration was slightly but significantly higher after iron supplementation than after placebo (difference = 13 ?g/L). This higher ferritin concentration persisted for >/=6 mo after supplementation, except in subjects with low iron stores, whose serum ferritin returned to baseline within 3 mo. Fecal ferritin excretion increased 2.5-fold (P: < 0.05) during supplementation. CONCLUSIONS: Healthy individuals, even those with low iron stores, had reduced nonheme-iron absorption from food in response to iron supplementation. Despite this partial adaptation, iron stores were greater after iron supplementation than after placebo and this difference was sustained, except in individuals with the lowest iron stores. Copyright © 2000 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

BACKGROUND: The characteristics of vegetarian diets suggest that these diets would have lower dietary iron bioavailability than nonvegetarian diets, but there is no evidence of iron deficiency in vegetarians. OBJECTIVE: We evaluated the responsiveness of serum and fecal ferritin to differences in iron absorption from controlled lactoovovegetarian and nonvegetarian diets. DESIGN: Twenty-one women aged 20-42 y with serum ferritin concentrations from 6 to 149 microg/L consumed lactoovovegetarian and nonvegetarian weighed diets for 8 wk each (crossover design). The diets differed substantially in meat and phytic acid contents. Nonheme-iron absorption was measured from the whole diets after 4 wk by using extrinsic 59Fe and whole-body counting. Ferritin in extracts of fecal composites and in serum was measured by enzyme-linked immunosorbent assay the last 2 wk of each diet. RESULTS: Nonheme-iron absorption was less from the lactoovovegetarian diet than from the nonvegetarian diet (1.1% compared with 3.8%; P < 0.01; n = 10). Diet did not affect hemoglobin, transferrin saturation, erythrocyte protoporphyrin, or serum ferritin. Substantially less fecal ferritin was excreted with the lactoovovegetarian diet than with the nonvegetarian diet (1.1 compared with 6.0 microg/d, respectively; P < 0.01; n = 21). CONCLUSIONS: This research indicates 1) 70% lower nonheme-iron absorption from a lactoovovegetarian diet than from a nonvegetarian diet; 2) an associated decrease in fecal ferritin excretion, suggesting partial physiologic adaptation to increase the efficiency of iron absorption; and 3) an insensitivity of blood iron indexes, including serum ferritin, to substantial differences in dietary iron absorption for 8 wk. Copyright (c) 1999 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

A supplementation trial starting with 224 postmenopausal women provided with adequate vitamin D and Ca was conducted to determine whether increased Cu and Zn intakes would reduce the risk for bone loss. Healthy women aged 51-80 years were recruited for a double-blind, placebo-controlled study. Women with similar femoral neck T scores and BMI were randomly assigned to two groups of 112 each that were supplemented daily for 2 years with 600 mg Ca plus maize starch placebo or 600 mg Ca plus 2 mg Cu and 12 mg Zn. Whole-body bone mineral contents, densities and T scores were determined biannually by dual-energy X-ray absorptiometry, and 5 d food diaries were obtained annually. Repeated-measures ANCOVA showed that bone mineral contents, densities and T scores decreased from baseline values to year 2. A priori contrasts between baseline and year 2 indicated that the greatest decreases occurred with Cu and Zn supplementation. Based on 5 d food diaries, the negative effect was caused by Zn and mainly occurred with Zn intakes ≥ 8·0 mg/d. With Zn intakes < 8·0 mg/d, Zn supplementation apparently prevented a significant decrease in whole-body bone densities and T scores. Food diaries also indicated that Mg intakes < 237 mg/d, Cu intakes < 0·9 mg/d and Zn intakes < 8·0 mg/d are associated with poorer bone health. The findings indicate that Zn supplementation may be beneficial to bone health in postmenopausal women with usual Zn intakes < 8·0 mg/d but not in women consuming adequate amounts of Zn.

Hearts from severely Cu-deficient rats show a variety of pathological defects, including hypertrophy and, in intact hearts, depression of contractile function. Paradoxically, isolated cardiomyocytes from these rats exhibit enhanced contractile properties. Because hypertrophy and enhanced contractility observed with other pathologies are associated with elevation of insulin-like growth factor-I (IGF)-I, this mechanism was examined for the case of dietary Cu deficiency. Male, weanling Sprague-Dawley rats were provided diets that were deficient (approximately 0.5 mg Cu/kg diet) or adequate (approximately 6 mg Cu/kg diet) in Cu for 5 wk. IGF-I was measured in serum and hearts by an ELISA method, cardiac IGF-I and IGF-II receptors and IGFBP-3 were measured by Western blotting analysis, and mRNAs for cardiac IGF-I and IGF-II were measured by RT-PCR. Contractility of isolated cardiomyocytes was assessed by a video-based edge-detection system. Cu deficiency depressed serum and heart IGF-I and heart IGFBP-3 protein levels and increased cardiac IGF-I receptor protein. Cardiac IGF-II protein and mRNA for cardiac IGF-I and IGF-II were unaffected by Cu deficiency. A Cu deficiency-induced increase in cardiomyocyte contractility, as indicated by increases in maximal velocities of shortening (-dL/dt) and relengthening (+dL/dt) and decrease in time to peak shortening (TPS), was confirmed. These changes were largely inhibited by use of H-1356, an IGF-I receptor blocker. We conclude that enhanced sensitivity to IGF-I, as indicated by an increase in IGF-I receptor protein, accounts for the increased contractility of Cu-deficient cardiomyocytes and may presage cardiac failure.

In a controlled feeding study, the effects of substituting 25 g soy protein for meat on calcium retention and bone biomarkers were determined. Postmenopausal women (n = 13) ate two diets that were similar, except that, in one diet, 25 g high-isoflavone soy protein (SOY) was substituted for an equivalent amount of meat protein (control diet), for 7 wk each in a randomized crossover design. After 3 wk of equilibration, calcium retention was measured by labeling the 2-d menu with (47)Ca, followed by whole-body counting for 28 d. Urinary calcium and renal acid excretion were measured at wk 3, 5, and 7. Biomarkers of bone and cardiovascular health were measured at the beginning and end of each diet. Calcium was similarly retained during the control and SOY diets (d 28, percent dose, mean +/- pooled sd: 14.1 and 14.0 +/- 1.6, respectively). Despite a 15-20% lower renal acid excretion during the SOY diet, urinary calcium loss was unaffected by diet. Diet also did not affect any of the indicators of bone or cardiovascular health. Substitution of 25 g high isoflavone soy protein for meat, in the presence of typical calcium intakes, did not improve or impair calcium retention or indicators of bone and cardiovascular health in postmenopausal women.

Women with functional ovaries have a lower cardiovascular risk than men and postmenopausal women. However, estrogen replacement therapy remains controversial. This study examined the effect of ovarian hormone deficiency and estrogen replacement on ventricular myocyte contractile function and PKB/Akt activation. Nulliparous female rats were subjected to bilateral ovariectomy (Ovx) or sham operation (sham). A subgroup of Ovx rats received estrogen (E(2)) replacement (40 microg. kg(-1). day(-1)) for 8 weeks. Mechanical and intracellular Ca(2+) properties were evaluated including peak shortening (PS), time to PS (TPS), time to 90% relengthening (TR(90)), maximal velocity of shortening/relengthening (+/-dL/dt), fura 2 fluorescence intensity (FFI), and decay rate. Levels of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a), phospholamban (PLB), and Akt were assessed by Western blot. Ovx promoted body weight gain associated with reduced serum E(2) and uterine weight, all of which were abolished by E(2). Ovx depressed PS and +/-dL/dt, prolonged TPS, TR(90), and decay rate, and enhanced resting FFI, all of which, with the exception of TPS, were restored by E(2). Ovx did not alter the levels of SERCA2a, PLB, and total Akt, but significantly reduced Akt activation [phosphorylated Akt (pAkt)], pAkt/Akt, and the SERCA2a-to-PLB ratio. These alterations in protein expression were restored by E(2). E(2) enhanced PS and +dL/dt in vitro, which was abolished by the E(2) receptor antagonist ICI-182780. Ovx reduced myocyte Ca(2+) responsiveness and lessened stimulating frequency-induced decline in PS, both ablated by E(2). These data suggest that mechanical and protein functions of ventricular myocytes are directly regulated by E(2).

Calcium balance is decreased by an increased intake of purified proteins, although the effects of common dietary sources of protein (like meat) on calcium economy remain controversial. We compared the effects of several weeks of controlled high and low meat diets on body calcium retention, using sensitive radiotracer and whole body scintillation counting methodology. Healthy postmenopausal women (n = 15) consumed diets with similar calcium content (approximately 600 mg), but either low or high in meat (12 vs. 20% of energy as protein) for 8 wk each, in a randomized crossover design. After 4 wk of equilibration of each diet, calcium retention was measured by extrinsically labeling the 2-d menu with (47)Ca, followed by whole body scintillation counting for 28 d. Urinary and blood indicators of bone metabolism were also determined for each diet. Calcium retention was not different during the high and low meat dietary periods (d 28, mean +/- pooled SD: 17.1 and 15.6%, +/-0.6%, respectively; P = 0.09). An initially higher renal acid excretion in subjects consuming the high meat compared with the low meat diet decreased significantly with time. The diets did not affect urinary calcium loss or indicators of bone metabolism. In conclusion, under controlled conditions, a high meat compared with a low meat diet for 8 wk did not affect calcium retention or biomarkers of bone metabolism in healthy postmenopausal women. Calcium retention is not reduced when subjects consume a high protein diet from common dietary sources such as meat.

Ethanol exposure during pregnancy elicits profound detrimental developmental and behavioral effects such as reduced levels of insulin-like growth factor-1 (IGF-1) in the fetus. However, few reports have addressed its impact on postpartum dams. This study was designed to examine the influence of gestational ethanol exposure on postpartum maternal organ oxidative damage and IGF-1 level. Pregnant female rats were pair-fed from Day 2 of gestation until labor with control or ethanol (6.36% (v/v)) liquid diets and were sacrificed 6 weeks after parturition (ethanol withdrawn after parturition). There was no difference in body weight during or after the gestational period between the control and ethanol groups. Litter size was significantly less for ethanol-fed dams. One-week postnatal pup survival was significantly lower in the ethanol-fed (57.1%) than the control (97.8%) group. Liver and kidney tissue IGF-1 levels and mRNA were elevated in the ethanol-fed mothers, accompanied by hepatic but not renal oxidative damage, indicated by profound lipid peroxidation (measured by malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE)) and protein carbonyl formation. The levels of glutathione (GSH), glutathione disulfide (GSSG) and GSH/GSSG ratios in liver and kidney were not different between the ethanol-fed and control dams. Collectively, these data suggest that gestational ethanol exposure may lead to postpartum oxidative organ damage and a possible compensatory increase in organ IGF-1 levels.

This study examined the effects of graded intakes of zinc (Zn) and copper (Cu) on serum insulin-like growth-factor-I (IGF-I) concentration and bone quality in growing rats. Using a 3 x 4 factorial design, weanling male Sprague-Dawley rats were randomly assigned to 12 groups (n = 7 per group) and were fed one of nine modified AIN-93G basal diets with varying amounts of Cu (0.3, 3 and 10 micro g/g) and Zn (5, 15 and 45 micro g/g) for 6 wk. A group of rats was pair-fed to each low Zn group. Although dietary Zn mainly influenced body weights (P < 0.0001), dietary Cu was the main determinant of most of the variables related to bone quality. Low Cu intake reduced serum IGF-I and femur breaking force and ultimate stress (by 27, 14 and 7%, respectively; P < 0.05) and increased bone IGF-I concentration (by 62%; P < 0.0001). Low Cu intake also increased femur nitrogen, hydroxyproline, hexosamine and calcium (Ca) concentrations of long bones (P < 0.05). Lumbar vertebrae dry weight and density were the lowest in the rats fed the low Cu diets (P < 0.001) and were higher in the rats fed high amounts of both Cu and Zn (P < 0.01). In summary, growing rats fed low and marginal Cu had lower serum IGF-I than those fed high dietary Cu. Bone strength was also reduced with low dietary Cu, despite compensatory changes in the bone matrix. In the presence of graded intakes of Cu, the effects of low dietary Zn were more pronounced on the spinal bones than the long bones.

Background: Quantitative data on the mucosal uptake and serosal transfer of nonheme-iron absorption in humans and the effects of calcium on these components are limited., Objective: Our objective was to measure the initial mucosal uptake and the subsequent serosal transfer of nonheme iron and to determine the effects of adding calcium to a meal on both heme- and nonheme-iron retention., Design: Whole-gut lavage and whole-body scintillation counting methods were applied to determine the 8-h uptake of nonheme iron and the 2-wk retention (absorption) of heme and nonheme iron in healthy adults (n = 17) after the consumption of meals of radiolabeled food., Results: The initial uptake and absorption of nonheme iron were 11% and 7%, respectively, and the absorption of heme iron was 15%. Two-thirds of the nonheme iron taken up by the mucosa within 8 h was retained by the body after 2 wk (serosal transfer index: 0.63). Serum ferritin correlated inversely with the initial uptake and absorption of nonheme iron, but not with the nonheme serosal transfer index or the absorption of heme iron. Adding calcium (127 mg in cheese) to the meal did not affect absorption., Conclusions: On the basis of its association with serum ferritin, the initial mucosal uptake was the primary control point for nonheme-iron absorption. An apparent reduction in heme-iron absorption associated with the lavage procedure suggested that uptake of heme iron may take longer and proceed further through the intestine than that of nonheme iron. The absorption of both forms of iron was unaffected by the addition of cheese to this meal with high iron bioavailability.

To further examine the interrelationships between manganese and iron absorption, the mucosal uptake, initial rate of loss, whole-body retention, and tissue distribution of an orally administered 54Mn radiotracer were compared between normal and beta2-microglobulin knockout [beta2m(-/-)] mice. These mutant mice are commonly used as a model for the study of human hemochromatosis, a hereditary iron-overload disease. Initial uptake of 54Mn by the intestinal mucosa, the liver, and the brain was not different between the two strains. The mutant mice had much higher concentrations of nonheme and total iron in the liver, but hepatic manganese, copper, magnesium, and zinc concentrations were similar between the two strains. In summary, the mucosal uptake and whole-body retention of manganese and tissue manganese concentrations were not altered in beta2m(-/-) mice; this suggests that normal homeostasis of manganese is not affected by the altered HFE protein-beta2m complex in these mice.

Background: Short-term measurements of iron absorption are substantially influenced by dietary bioavailability of iron, yet bioavailability negligibly affects serum ferritin in longer, controlled trials., Objective: Our objective was to test the hypothesis that in men fed diets with high or low iron bioavailability, iron absorption adapts to homeostatically maintain body iron stores., Design: Heme- and nonheme-iron absorption from whole diets were measured in 31 healthy men at 0 and 10 wk while the men consumed weighed, 2-d repeating diets with either high or low iron bioavailability for 12 wk. The diets with high and low iron bioavailability contained, respectively, 14.4 and 15.3 mg nonheme Fe/d and 1.8 and 0.1 mg heme Fe/d and had different contents of meat, ascorbic acid, whole grains, legumes, and tea., Results: Adaptation occurred with nonheme- but not with heme-iron absorption. Total iron absorption decreased from 0.96 to 0.69 mg/d (P < 0.05) and increased from 0.12 to 0.17 mg/d (P < 0.05) after 10 wk of the high- and low-bioavailability diets, respectively. This partial adaptation reduced the difference in iron bioavailability between the diets from 8- to 4-fold. Serum ferritin was insensitive to diet but fecal ferritin was substantially lower with the low- than the high-bioavailability diet. Erythrocyte incorporation of absorbed iron was inversely associated with serum ferritin., Conclusions: Iron-replete men partially adapted to dietary iron bioavailability and iron absorption from a high-bioavailability diet was reduced to approximately 0.7 mg Fe/d. Short-term measurements of absorption overestimate differences in iron bioavailability between diets.

This study was designed to examine the interactions among dietary iron (Fe), copper (Cu), and zinc (Zn) and their effects on Fe status and oxidative stress in female rats. In a three-factor central composite response surface design, rats were assigned to 15 groups and fed modified AIN-93G basal diets with varying amounts of Fe and Zn (7.0, 15.5, 45.8, 135.6, or 300 micrograms/g diet) and Cu (0.5, 1.1, 3.2, 9.2, or 20 micrograms/g diet) for 6 wk. Variations in hemoglobin, hematocrit, and serum ferritin were mainly related to dietary Fe. Liver nonheme Fe was directly affected by dietary Fe and was slightly attenuated by interactions between Cu and Zn, and Zn and Fe. Serum ceruloplasmin activity was primarily determined by an interaction between Cu and Zn with substantial moderation by the quadratic effect of dietary Cu. Liver and heart total superoxide dismutase (SOD) and Cu/Zn SOD activities were directly affected by dietary Cu. Dietary Fe was the only significant, yet weak, predictor of liver thiobarbituric acid reactive substances (TBARS) and vitamin E content and serum triacylglycerols. Variability in serum Cu was mostly determined by the interaction between Cu and Fe, with modification from the quadratic effect of dietary Cu. Serum Zn varied with dietary Zn with a small negative influence from the interaction between Cu and Fe. In summary, Fe status was minimally influenced by dietary Zn or Cu, and Fe intakes 10-fold greater than required did not induce overt oxidative stress in female rats. In addition, measures of antioxidant capacity were primarily influenced by dietary Cu and were optimal at moderate intakes of this micronutrient.

Bone formation occurs in an integrated, highly ordered manner, beginning in the embryonic period. Nutrients may affect bone formation by delaying cellular differentiation, altering responses to bone growth factors, affecting supply of needed nutrients, and/or affecting rates of synthesis of the matrix constituents. Several growth factors, both systemic and local, are being identified which affect bone formation. Matrix constituents include collagen and noncollagenous proteins, each of which are thought to have specific roles in bone formation, maintenance, or resorption. Among the nutrients which are known to affect bone formation at a cellular level are vitamins A, D, and K, ascorbic acid, zinc, magnesium, and calcium. Nutrients that are known to affect protein synthesis in general also affect bone formation. It is necessary for nutritionists to consider cellular as well as systemic effects of nutrients on bone formation.

The following study was designed to provide a comprehensive assessment of urinary riboflavin and flavin metabolites before and after ingestion of a riboflavin load in normal human volunteers. With respect to riboflavin, the total flavin excretion, the flavin-to-creatinine ratio, and the response of the flavin catabolites to the supplement indicate a well-nourished population. Differences in the effects of supplementation on the specific flavin catabolites across sex and age groups are included in detail for the first time. The feasibility of the use of flavin catabolites for determination of riboflavin status should be tested further in individuals with clinical signs of ariboflavinosis.

Although milk is one of the primary sources of riboflavin in the North American diet, the amounts of riboflavin and other flavin derivatives in milk have not been accurately quantified. In this study, a comprehensive assessment of milk was performed to identify and quantify greater than 95% of the flavins in this food. Riboflavin and flavin adenine dinucleotide (FAD) were the predominant flavins in all milk samples; 10-(2'-hydroxyethyl)flavin was next most common. The latter is potentially an antivitamin that may exert its effect at either the absorption or utilization level. Therefore, the presence of this analog should be considered when evaluating the riboflavin efficiency of milk. The large quantity of FAD indicates that precautions against underestimating FAD are warranted when determining total flavin content by fluorescence. This is particularly important because the fluorescence of FAD at pH 7.0 is only 10-20% of that for riboflavin. The presence of 7 alpha-hydroxyriboflavin (7-hydroxymethylriboflavin) in milk was ascertained by extensive testing. Traces of 8 alpha-hydroxyriboflavin (8-hydroxymethylriboflavin) were also detected. These metabolites may serve as indicators of cellular biochemical activity.

1. Two studies were performed to determine the effects of acid stress and ovariectomy on bone metabolism in young rats. In Expt 1, eighteen female weanling Sprague-Dawley-descended rats were ovariectomized, placed in one of three dietary groups and given a diet containing (g/kg): 6 calcium and 3, 6 or 12 phosphorus for 10 weeks. In Expt 2, thirty-two female weanling Sprague-Dawley-descended rats were ovariectomized, and thirty-two were left intact. Eight rats from each group were given a diet containing (g/kg): 6 Ca and 3 P, 12 P, 3 P + 1 S or 3 P + 20 ammonium chloride for 10 weeks. 2. Feeding diets containing 12 g P/kg resulted in decreased serum Ca and increased urinary P with no changes in femur composition. Feeding high-sulphate and ammonium chloride diets resulted in increased urinary Ca and, when combined with ovariectomy, lower femur Ca and P with no changes in femur hydroxyproline or hexosamines. 3. The findings reflect the more rapid turnover of the amorphous calcium phosphate salts found in greater amounts in bones of younger animals than for more stable apatitic crystals that predominate in bones of older animals.